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1
OTON, GONZALEZ Lucia. "New biomarkers for human papillomavirus positive-head and neck squamous cell carcinomas". Doctoral thesis, Università degli studi di Ferrara, 2021. http://hdl.handle.net/11392/2478834.
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Il carcinoma a cellule squamose testa-collo (HNSCC) è una malattia eterogenea. La classificazione dei HNSCC si basa sulla posizione anatomica, lo stadio clinico, il fenotipo e la presenza del virus HPV, ed è importante per la scelta del trattamento appropriato. I tumori positivi all'HPV costituiscono un'entità diversa da quelli negativi all'HPV sia per il sito di insorgenza che la risposta al trattamento. Infatti, i tumori HPV-positivi di solito rispondono meglio ai trattamenti standard, e i pazienti presentano una sopravvivenza migliore. Tuttavia, un sottogruppo di questi pazienti presenta recidiva entro i primi due anni dalla diagnosi, e ridotta sopravvivenza. Perciò è necessaria la ricerca di nuovi marcatori che fungano da bersagli molecolari negli HNSCC, per poter aumentare la soppravivenza globale in tutti i gruppi. Diversi studi per comprendere le basi molecolari alla base della risposta differenziale nei pazienti HPV-positivi sono in corso, ma non è stata raggiunta una conclusione. Il problema principale è che non esistono linee guida standard per classificare i pazienti HPV-positivi. Molti studi indagano sul DNA dell'HPV, l'mRNA del virus e la sovraespressione di p16. Tuttavia, l'HPV potrebbe essere presente come infezione transitoria, l'espressione di p16 non è sempre osservata nei tumori HPV-positivi, e i livelli di mRNA dell'HPV potrebbere essere troppo bassi per essere rilevati. Pertanto, la rilevazione di marcatori classici non è sufficiente per stratificare i pazienti HNSCC-HPV positivi per la recidiva.
In questo mio studio, ho verificato che la combinazione di marcatori classici con marcatori sierologici è risultata un forte indicatore prognostico. In particolare, per il carcinoma a cellule squamose dell'orofaringe (OPSCC) la presenza della oncoproteina E7 nel siero al momento della diagnosi era correlata alla recidiva della malattia e alla sopravvivenza globale. La ricerca di E7 nel siero può essere utile come procedura non invasiva per la stratificazione dei pazienti HPV-positivi e il follow-up, aiutando a identificare i pazienti a rischio di recidiva e fornendo uno strumento per la selezione dei pazienti candidati alla riduzione dei trattamenti chemio/radioterapici.
Inoltre, poiché l'mRNA dell'HPV è necessario per promuovere la carcinogenesi e la long control region (LCR) del virus gioca un ruolo fondamentale nel controllo dell'espressione genica dell'HPV, abbiamo studiato come la variazione nucleotidica o la metilazione di questa regione influenzi l'espressione genica virale e la prognosi. Mentre la metilazione dell'LCR gioca un ruolo fondamentale nel controllo dell'mRNA virale, le variazioni della sequenza dell'HPV LCR resultano rilevanti per il legame con i fattori di trascrizione cellulari, influenzando l'espressione genica virale. Nello specifico, variazioni di sequenza all'interno del sito di legame del fattore di trascrizione YY1 erano correlate a una migliore sopravvivenza.
Infine, la mia tesi discute un insieme di geni disregolati nell'HNSCC in correlazione ai sottogruppi di malattia e alla prognosi dei pazienti. Abbiamo trovato significative differenze per l'espressione genica di EGFR, p16, c-Jun e RARB tra i sottogruppi HPV-positivi e negativi; questi marcatori possono aiutare a creare un profilo di espressione al fine di stratificare i pazienti HNSCC alla diagnosi e selezionare il trattamento adeguato. Inoltre, diminuzioni nei livelli di IRF6 sono stati correlati a recidiva in pazienti HPV negativi.
Nell’insieme i risultati presentati mostrano differenze molecolari tra tumori HPV-positivi e negativi, facendo luce su aspetti fondamentali della biologia dell'HPV e scarsamente studiati finora. Questi aspetti, sono ugualmente importanti per la sopravvivenza libera da progressione, e dovrebbero essere studiati in modo più approfondito in futuro come marcatori candidati per la stratificazione dei pazienti.Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease, and several attempts have been made to classify these tumors based on anatomic location, clinical stage and tumor phenotype. Once these characteristics are individualized, the appropriate treatment is chosen. For instance, HPV-positive HNSCCs have been defined as a different entity from HPV-negative based on its onset and treatment response. HPV-positive tumors usually respond better to standard treatment choices, while overall survival of these patients is improved. Still, a subset of these patients will present tumor recurrence within the first two years, presenting also reduced overall survival. There is a need to find new markers to serve as molecular targets in HNSCCs. Several studies are ongoing, in order to understand the molecular bases underneath this differential response in HPV-positive patients. Up to date, no common ground has been reached, the main issue being that there are no standard guidelines to classify HPV-positive patients. To improve stratification, many studies investigate HPV DNA, HPV mRNA and p16 overexpression. However, HPV might be present as a transient infection, and not active in the tumors, p16 expression is not always observed in HPV-positive tumors and HPV mRNA levels could be too low to be detected. In this study, similar to other studies, classical markers alone, were not sufficient to stratify HPV-positive HNSCC patients for disease recurrence. Nevertheless, the combination of classical markers with serological markers resulted a strong indicator of patient prognosis, particularly for oropharyngeal squamous cell carcinoma (OPSCC). HPV16 E7 oncoprotein presence in serum at the time of diagnosis correlated with disease recurrence and overall survival. Research for E7 oncoproteins in serum may be useful as a non-invasive procedure for patient stratification and follow-up, helping identify patients at risk for tumor recurrence, giving a tool for clinicians for candidate patients selection to de-escalate treatment. Furthermore, since HPV mRNA is necessary to promoter carcinogenesis and the long control region (LCR) of the virus plays a fundamental role in the control of HPV gene expression, we studied how variation or epigenetic control of this region could affect viral gene expression and patient prognosis. While methylation of the LCR plays a fundamental role in the control of HPV mRNA, the importance of regulation by other cellular transcription factors emerges, showing the importance HPV LCR sequence variations have for transcription factor binding and how they can greatly affect viral gene expression. Sequence variations within the YY1 transcription factor binding site, were correlated to improved patient survival, while patients carrying the reference sequence relapsed more frequently. Finally, my thesis discusses a set of genes dysregulated in HNSCC in correlation to the disease subgroups, and patient prognosis. Differences were significant for EGFR, p16, c-Jun and RARB gene expression between HPV-positive and negative subgroups; these markers may help create an expression profile in order to stratify HNSCC patients at diagnosis, and select the best treatment choice. Furthermore, diminished levels of IRF6 correlated to recurrence in HPV-negative patients. The findings presented in my thesis show molecular differences between HPV-positive and negative tumors and shed light on fundamental aspects of the HPV biology, that had been poorly studied in HNSCCs so far; first, the importance that HPV16 sequence has on the behavior of the virus and its pathogenic potential; and second, the presence of circulating viral oncoproteins in HPV-positive patients in serum. These aspects turned to be equally important related to patient’s progression free survival, and should be studied in more depth as candidate markers for patient stratification in the future.
2
Agwae, M. E. "The role of iRhom2 in the pathogenesis of head and neck squamous cell carcinomas (HNSCC)". Thesis, University of Liverpool, 2018. http://livrepository.liverpool.ac.uk/3022143/.
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It has been proposed that the Notch signalling pathway plays a key role in the pathogenesis of head and neck squamous cell carcinomas (HNSCC). It has also been shown that the sheddase, ADAM17, whose intracellular trafficking and subsequent maturation is dependent on iRhom2, is key in the activation of the Notch pathway at the cell membrane, leading to the release of an intracellular domain for downstream activities. This thesis investigates the levels and distribution of iRhom2 and ADAM17 in HNSCC, and functional changes resulting from up-regulation of iRhom2 in HNSCC cell lines. Immunoblotting, using protein samples extracted from fresh, snap-frozen tissues (68 HNSCC and 27 paired normal tissues), and probing for iRhom2 identified relatively high expression levels of this protein in 43/68 tumour samples compared to 5/27 normal samples (p < 0.05). Similar observations were obtained for ADAM17 expression, with high expression in 27/68 tumour samples compared to 4/27 normal samples (P < 0.05). A positive correlation was observed between levels of expressions of iRhom2 and ADAM17 in these tissues (though not statistically significant), but only iRhom2 expression correlated with patient survival (p < 0.05). Non-correlation of iRhom2 expression with other clinicopathological features was perhaps due to the relatively small number of samples investigated. Using a different cohort of HNSCC tissues, we also assessed levels of iRhom2 and ADAM17 and their intracellular distribution using tissue microarray (TMA) approach. Western blot results could not be corroborated with this methodology, given that most of the tissues stained negative for iRhom2, and 76/88 stained “highly positive” for ADAM17, with no observable specificity with ADAM17 staining pattern. Up-regulation of iRhom2 was achieved in the HNSCC cell lines, PE/CA-PJ15 and LIV37K; and in NOK (normal oral keratinocyte) cells and was, followed by shRNA knock-down of RHBDF2 (which codes for iRhom2). No observable differences were observed in the rate of cell replication when comparing wild-type, over-expressing and knock-down clones across each of the cell lines. However, a higher rate of cell migration was demonstrated in association with iRhom2 up-regulation, more in the HNSCC cell lines than the NOK. This higher rate of migration was shown to be reversed by the shRNA knock-down of RHBDF2, demonstrating that it is increased iRhom2 that is causative. Furthermore, a significant increase in the level of expression of mature ADAM17 was observed, following upregulation of iRhom2. iRhom2 and ADAM17 are both up-regulated in HNSCC, with up-regulation of iRhom2 associated with increased cell migration and decreased patient survival. Further experiments should aim to address whether it is the increased ADAM17 expression / activity and / or Notch activity that is the downstream effector of the observed effects. If will be important to expand the cohort of samples and cell lines used for this study to further validate the present findings, while also optimising some of the aspects that have not achieved significant results.
3
Bennett, Kristi Lynn. "Methylation in head and neck squamous cell carcinoma". Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1194544327.
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Wood, S. Matthew. "A Study of Head and Neck Squamous Cell Carcinoma Adhesion Mediated by Glycosphingolipids". Ohio University / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1314210756.
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Haylock, Anna-Karin. "Targeting molecules for diagnostics of Head and Neck squamous cell carcinoma". Doctoral thesis, Uppsala universitet, Öron-, näs- och halssjukdomar, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-315210.
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To personalize treatment for cancer, correct staging of the primary tumor, nodal disease and metastatic disease is of essence. By targeting tumor specific receptors with radiolabeled antibodies, specificity and accuracy of imaging may be improved. Radio-immunodiagnostics can potentially detect small volume disease, occult metastasis and recurrent cancer in treated tissue. This thesis focuses on evaluation of radio-immunoconjugates directed towards CD44v6, which is a surface receptor overexpressed in many head and neck squamous cell carcinomas. At the outset, the monoclonal chimeric antibody cMab U36 and its cleavage products Fab’ and F(ab’)2 were labeled with 125I and assessed in vitro and in vivo (paper I). The best distribution pattern and tumor to organ ratio was achieved with F(ab’)2. Due to the immunological responses humans can develop towards chimeric antibodies, they are not optimal for clinical use, and subsequently fully human antibody fragments were developed. AbD15179, which is a monovalent fragment, was labeled with 111In and 125I and evaluated in vitro and in mice bearing CD44v6-expressing tumors. Tumor to organ ratios were improved compared to cMab U36 derived fragments, and 111In-AbD15179 displayed a more favorable distribution compared to 125I-AbD15179 (Paper II). A bivalent Fab-dHXL, AbD19384 derived from AbD15179, was then constructed and labeled with 125I and evaluated in cell- and biodistribution studies. Furthermore, an imaging study in a small animal PET was performed with 124I-AbD19384 (Paper III). Uptake in kidneys was reduced and liver uptake increased compared to AbD15179 reflecting the larger molecule. The high CD44v6 expressing tumor was clearly visualized with maximum uptake at 48 hours post injection.In paper IV human single chain fragments towards CD44v6v were selected, and the top candidates A11 and H12 were further evaluated in vitro and in vivo. Single chain fragments are small molecules exhibiting fast clearance and high affinity to the target. The study proved this by demonstrating superior tumor to blood ratios of radiolabeled A11 and H12 compared to previously studied molecules.
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Lee, June Young. "The Role of Noxa/MCL-1 in Head and Neck Squamous Cell Carcinoma (HNSCC) Treatment". VCU Scholars Compass, 2015. http://scholarscompass.vcu.edu/etd/3748.
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Head and neck cancer is the sixth leading type of cancer with 90 percent of head and neck cancer arising from squamous cell lining on the epithelium of the oral and nasal cavity, pharynx, and salivary gland. Even with tremendous achievements on chemotherapeutic drugs and therapies, the long-term prognosis of patients with advanced head and neck squamous cell carcinoma (HNSCC) has shown little improvement over the last three decades. Cisplatin is one of widely used chemotherapeutic drugs for multiple
cancers, including head and neck cancer, but the prolonged use of this drug is limited by its toxicity and by the development of resistance. To overcome these major roadblocks to improved prognosis requires mechanism-based therapeutic strategies to maximize the antitumor effect of drugs while limiting their toxicities. Cisplatin exerts anticancer effects via multiple mechanisms, yet its most prominent mode of action involves the generation of DNA lesions followed by the activation of the DNA damage response and the induction of BCL-2 family-dependent mitochondrial apoptosis. DNA damage activates a tumor suppressor p53 to induce apoptosis. One of its functions is to induce the expression of several pro-apoptotic proteins such as Noxa, which binds to an anti-apoptotic BCL-2 family protein, MCL-1 (myeloid leukemia cell-1) to inactivate its pro-survival function and induce apoptosis. We examined Noxa expression and apoptosis induced by cisplatin in p53-wild-type HN30 and HN31, p53-truncated and inactive HN4 and HN12, and p53-deleted HN22 and HN8 HNSCC cell lines. We found that Noxa was induced in HN30 and HN31 cells and down-regulation of Noxa by shRNA (short-hairpin RNA) decreased apoptosis, indicating Noxa contribution to cisplatin-induced apoptosis. Interestingly, cisplatin treatment induced Noxa and apoptosis even in p53-deleted HN22 and HN8 cells, suggesting the existence of the p53-independent pathways for the induction of Noxa. Based on these observations, we hypothesized that modulation of Noxa/MCL-1 axis could mimic cisplatin-induced cell death. We found that Noxa overexpression induced cell death in all cell lines tested regardless of p53 status. This finding could be applicable as a potential therapeutic strategy to treat head and neck cancer.
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Adams, Allie K. "Targeting the DEK oncogene in head and neck squamous cell carcinoma: functional and transcriptional consequences". University of Cincinnati / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1427882536.
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Patel, Dhwani. "Regulation of EPS8 Dependent Pathways By Src in Head and Neck Squamous Cell Carcinoma". VCU Scholars Compass, 2015. http://scholarscompass.vcu.edu/etd/3810.
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Head and neck squamous cell carcinoma (HNSCC) is a type of cancer that begins in the epithelial cells that line the mucosal surfaces of the head and neck, including the oral cavity, pharynx, larynx, paranasal sinuses, nasal cavity, and salivary glands. Head and neck cancer is the sixth most common type of cancer with a 5-year survival rate of 60% for all cases. Over the past few years, a subset of cells with stem-like properties, called cancer stem cells, are believed to have tumor-initiation capabilities and are responsible for maintaining on-going tumor growth. Previous data from our lab suggested that cells grown in suspension, called spheroids, may have stem cell like properties.
We employed a model system where a primary HNSCC cell line, HN4, was used to set up spheroids. We found that expression of EPS8 and its downstream targets, FOXM1 and CXCL5, was increased in HN4 spheroids. In addition, we measured the expression of Nanog, as it is a transcription factor involved in the self-renewal of human embryonic stem cells. We also used a metastatic HNSCC cell line, HN12, to see how it compared to spheroids. We wanted to investigate the hypothesis that activation of Src potentiates EPS8 function to deregulate downstream signaling pathways. We used a small molecule tyrosine kinase inhibitor, Dasatinib, on HN4 spheroids and HN12 cells. We found that when Src is inhibited, EPS8 expression is decreased in HN4 spheroids and it also interferes with spheroid formation. The results of the current study were also able to show that the proliferation capability of HN12 cells is greatly diminished when treated with Dasatinib, due to G1 arrest in the cell cycle. When we measured for FOXM1, which is a cell cycle regulator, we found the levels were reduced in Dasatinib treated cells, preventing the cells from completing mitosis. With all of the data taken together, it suggests that Src does in fact play a role in regulating the downstream signaling pathways of EPS8, and its inhibition leads to the loss of cell proliferation. Additional studies need to be performed to discover whether Src inhibition will stop the proliferation of cancer stem cells, which are believed to be more resistant to cytotoxic therapies.
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Maxim, Nicolas T. Mr. "Tumor-Specific Cell Death Induction by Noxa Overexpression for Head and Neck Squamous Cell Carcinoma (HNSCC) Treatment". VCU Scholars Compass, 2016. http://scholarscompass.vcu.edu/etd/4230.
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The primary focus of this research is the mechanisms of cell death in head and neck squamous cell carcinoma (HNSCC) treatment. These cancers typically originate in squamous cells that line the moist mucosal surfaces of head and neck. HNSCC is commonly treated with a platinum based agent, cisplatin. While the drug does offer strong antitumor effects, its prolonged use often results in tumor-acquired resistance, which limits treatment effectiveness. We have shown that cisplatin treatment induces the expression of a pro-apoptotic BCL-2 family member Noxa, which then initiates caspase- dependent apoptosis through its binding and sequestration of pro-survival protein MCL-1 for its inactivation. Without Noxa induction, cell death is significantly reduced when treating HNSCCs with cisplatin. The objectives of this study are (1) to determine the molecular mechanisms by which Noxa induces cell death in HNSCC cells; (2) to determine the molecular mechanisms of cisplatin-resistance in isogenic HNSCC cell lines.
We observed an increase of apoptosis by ectopic expression of Noxa in all HNSCC cell lines tested, but not in immortalized human normal oral keratinocytes (NOK), suggesting that Noxa overexpression is sufficient to induce tumor-specific cell death. Noxa-induced cell death was mediated by BAX and BAK activation. BAK activation was mediated through Noxa binding to MCL-1, but not BCL-XL. Cisplatin- resistant cells induced less Noxa and apoptosis, supporting that Noxa induction is prerequisite for apoptosis induced by cisplatin. Taken together, Noxa induces tumor- specific cell death in HNSCC cells primarily through BAX and BAK activation, which suggests the therapeutic potential of this protein.
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Chiriseri, Edina. "Human papilloma virus and oral cancers : sexual behaviour as a risk factor". Thesis, De Montfort University, 2017. http://hdl.handle.net/2086/16084.
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AIM & OBJECTIVES: Human papilloma virus (HPV) has been related to cervical infection, however, its part in Head and Neck Squamous Cell Carcinoma (HNSCC) is still debatable and is easy to refute. Suspicion of HPV causation is heightened when carcinomas arise in patients that are young and have never smoked. The present UK based study undertaken at Northampton NHS Trust endeavoured to determine the extent to which HPV is an entity in HNSCC in the UK. Furthermore, the study investigated whether sexual behaviour (as measured by sexual health clinic (SHC) attendance) is linked the acquisition of HPV associated HNSCC in young age groups. HNSCC incidences and sexual trends in the UK were collected from publicly available databases to identify if there were any changes at a national level in sexual behaviours and their influence on HNSCC in young age groups. MATERIALS & METHODS: PCR was used to evaluate the presence of HPV in biopsy samples from of 99 patients diagnosed with HNSCC at Northampton Hospital from 2006 to 2014. Patient demographics on age, sex, smoking, alcohol use and SHC attendance were also collected. All HPV PCR positive biopsies were further genotyped using an ABI 3130xl genetic analyser. Databases in the UK; including GLOBOCAN, NATSAL and PHE were searched for data on HNSCC prevalence, sexual behaviour trends and vaccine uptake. Multinomial regression explored the relationship between HPV positivity and sex, age, smoking, drinking, race and SHC attendance. RESULTS: PCR showed that 25.2% (25/99) of biopsies tested were positive for HPV and were all obtained from white participants. Most specimens (23, 92%) were high-risk (HR) HPV 16 positive with a mean age of 56 for HPV positivity and 72% of the cases 50-60 years old. Smokers were 11% in total (11/99) with most 88.9% participants (88/99) being non-smokers. HPV positivity was strongly linked with non-smoking history (p < 0.001); no alcohol abuse (p < 0.001); male gender (p < 0.001); young age less than 60 years (p < 0.001) and SHC attendance (p < 0.001). A Kruskal-Wallis post hoc test affirmed the impact of age on HPV positivity (p= < 0.05). GLOBOCAN and Cancer Research demonstrated a rising UK HNSCC pattern of over 200% for both sexes from 1975 to 2011. The three NATSAL surveys undertaken in 1990-1991, 1999-2001 and 2010-2012 demonstrated an overall increase in opposite and same sex partners. The UK average of individuals engaging in oral sex was in the younger age groups of between 16 and 54 with at least 70% of males and 63% females of that age engaging in oral sex. Finally, NASTAL 1, 2 and 3 surveys reported 20 vs 15; 25 vs 55; 55 vs 65 of males and females respectively with more than 10 sexual partners to have attended the SHC. The UK immunization take-up was over 90% countrywide. CONCLUSION: Few research studies have been conducted to date on HPV as a cause of HNSCC in the UK. The present research showed 25.2% of HNSCC to be caused by HPV, with the high risk (HR) genotype 16 (the leading cause of cervical cancer) accounting for 92% (23/25) of the cases. These outcomes affirmed the high prevalence of HR-HPV in HNSCC, with a rate of 25.2% similar to those reported previously. Routine HPV testing in those aged below 60 is therefore warranted. Smoking and drinking showed negative correlation; the young age of below 60 and attendance of the SHC for both sexes showed a positive correlation with HPV positive HNSCC. NATSAL data showed increased sexually risky behaviour coupled with attending the SHC in younger ages for both sexes. Increased sexually risky behaviour as shown in NASTAL surveys may be the reason why young age and SHC attendance is positively correlated with HPV HNSCC. The study highlights a conceivable relationship between HPV positive HNSCC in those under 60 years with no smoking history who attended the SHC. Smoking and drinking are known risks for HNSCC in those past 65 years of age; the negative association with HPV HNSCC in the young in the present research revealed smoking and drinking to have reduced association with HPV HNSCC. The reported HR-HPV positive HNSCC in young age groups inform future vaccination strategies and consequently decrease the quantity of HPV HNSCC's.
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Bradburn, Jennifer Elizabeth. "Reactive species promotion of head and neck squamous cell carcinoma". Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1166555968.
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Espinosa-Cotton, Madelyn. "Interleukin-1 signaling contributes to the anti-tumor efficacy of Cetuximab in head and neck squamous cell carcinoma". Diss., University of Iowa, 2018. https://ir.uiowa.edu/etd/6570.
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Despite the incorporation of the epidermal growth factor receptor (EGFR) inhibitor cetuximab into the clinical management of recurrent and metastatic (R/M) head and neck squamous cell carcinoma (HNSCC), only a small subset of patients responds to cetuximab, despite EGFR overexpression in virtually all of their tumors. At this time, there is a lack of validated predictive biomarkers to predict which patients will respond to cetuximab. Our previous work suggests that cetuximab activates the interleukin-1 (IL-1) pathway via tumor release of IL-1 alpha (IL-1α), although the implications of activating this pathway are unclear. The IL-1 pathway plays a central role in immune response and displays both pro-tumor and anti-tumor activities. IL-1 may promote tumor growth by upregulating the secretion of pro-inflammatory mediators involved in angiogenesis and metastasis. On the other hand, IL-1 signaling may promote antitumor immunity via enhancement of natural killer (NK)-cell mediated antibody-dependent cell-mediated cytotoxicity (ADCC) and T cell activity, which are important mechanisms of action of cetuximab.
The goal of this work is to determine how modulation of the IL-1 pathway affects HNSCC tumor response to cetuximab and if IL-1 may serve as a predictive biomarker for patient response to cetuximab. Blockade of IL-1 signaling did not enhance the anti-tumor efficacy of cetuximab, while IL-1α overexpression and treatment with recombinant IL-1α and IL-1α nanoparticles increased HNSCC tumor response to cetuximab in immunodeficient and immunocompetent HNSCC mouse models. Mechanistically, these results appear to be due to activation of an anti-tumor NK and T cell-mediated immune response. Additionally, we found that both nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) and inducible nitric oxide synthase (iNOS) activity may be involved in the efficacy of IL-1-induced ADCC against cetuximab-coated HNSCC cells. Altogether, these results suggest that IL-1 signaling is necessary for HNSCC tumor response to cetuximab. Furthermore, we have shown that pre-treatment serum and tumor IL-1 ligands can predict progression-free survival of HNSCC patients treated with standard-of-care cetuximab and chemotherapy, cetuximab combined with other targeted therapies, and cetuximab monotherapy. Overall, we propose that IL-1α warrants further study as a novel therapeutic to enhance response to cetuximab and as a predictive biomarker for HNSCC response to cetuximab.
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Field, Brittany. "MUTANT P53 REGULATION OF CXC-CHEMOKINE EXPRESSION IN HEAD AND NECK SQUAMOUS CELL CARCINOMA". VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/442.
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Head and neck squamous cell carcinoma (HNSCC) is the 6th most common type of cancer in the western hemisphere with a five-year survival rate of only 50% for patients with a localized tumor, which decreases significantly to as low as 5% for those patients with tumors that have metastasized to distant sites of the body. It has been found that both mutant p53 and epidermal growth factor receptor (EGFR) signaling pathways function to increase the expression of CXCL5, which has been identified as a key mediator in the process of tumor metastasis. Previous data from our lab suggested that the p53 homolog, p63, may function as a negative regulator of CXCL5 and that mutant p53 may inhibit this molecule to elevate CXCL5 expression levels. In the current study we utilized an model system in which the H179L p53 mutant was expressed in HN4 cells to investigate the hypothesis that mutant p53 enhances expression of CXCL5 by both interfering with p63 function and cooperating with EGFR/EPS8 signaling, leading to increased cell proliferation and motility. The results of the current study indicate a role for mutant p53 in head and neck squamous cell carcinoma proliferation, migration and tumorigenicity, possibly through enhancement of CXCL5 expression. We were able to show that mutant p53 expression caused an increase in the expression of this chemokine in addition to increasing proliferation and migration of the cells compared to the vector control. Additionally, we showed that p63 protein is a negative regulator of CXCL5 that is downregulated in the cells expressing mutant p53, which suggests that through direct interaction, mutant p53 may function to inhibit p63 function as well as target it for degradation. These results support the hypothesis that GOF mutant p53 enhances expression of CXCL5 by interfering with p63 function in cancer cells. The results of the current study results also showed that upon treatment with EGF, HN4 cells expressing mutant p53 express elevated levels of CXCL5; and that the mutant p53-expressing HN4 cells cooperate with EGFR/EPS8 signaling to further deregulate chemokine expression. These data taken together suggest there are complex interactions taking place between mutant p53, p63, EGFR signaling, and CXCL5 to regulate the biological processes that promote tumor progression that could lead to metastasis. Additional studies are needed to further elucidate the molecules involved in the mutant p53 mechanism that promotes tumorigenesis.
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CITRON, FRANCESCA. "An integrated approach identifies mediators of local recurrence in head and neck squamous cell carcinoma". Doctoral thesis, Università degli Studi di Trieste, 2018. http://hdl.handle.net/11368/2924765.
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Head and Neck Squamous Cell Carcinoma (HNSCC) represents the sixth most common cancer worldwide, with about 550,000 new cases/year.
Despite the development of precise and accurate surgery followed by radio- and/or chemo-therapy, in the last decade patients’ overall survival was only slightly improved. In particular, only 40-50% of patients with advanced HNSCC will survive for 5 years. The main worse prognostic event is considered the onset of loco-regional and distant recurrences, that is also accepted as surrogate markers of patients’ overall survival. HNSCC is a heterogeneous disease and, although many studies have been conducted to clarify the molecular mechanisms behind the development of local or distant metastasis, no clear molecular mediators of recurrence formation have been identified and no valid biomarkers exist to identify and treat patients at high-risk of recurrence.
We aimed to fill this gap taking advantage of an unbiased approach in which we evaluated microRNA (miRNA) expression profile in a cohort of HNSCC primary tumours from recurrent and non-recurrent patients.
We identified and validated a four-miRNA signature, composed by miR-1, miR-9, miR-133a and miR-150 that could be used as biomarker of recurrence. All these miRNAs are not only well-known molecular modulators of cell plasticity in different tumours, but intriguingly in our HNSCC model they are also able to classify HNSCC patients at high- or low-risk of recurrence formation.
We demonstrated that these miRNAs collectively impinge on the epithelial-mesenchymal transition process. In silico and wet lab approaches showed that miR-9, expressed at high levels in recurrent HNSCC, targets the epithelial genes SASH1 and KRT13, while miR-1, miR-133a and miR-150, expressed at low levels in recurrent HNSCC, collectively target SP1 and TGF pathways.
In vivo, a six-genes signature comprising the above targets, consistently predicts low progression free- and overall-survival in different panels of HNSCC samples. This is of particular clinical relevance, since the detection of this gene signature in tumours specimens could identify patients with poor prognosis who may benefit for a more accurate targeted therapy.
In a preclinical model of HNSCC recurrence, the combined pharmacological inhibition of SP1 and TGF pathways, when timely administered, induced HNSCC cell death and prevented recurrence formation.
By integrating different experimental approaches, we identified critical mediators of recurrence formation in advanced HNSCC. Since both SP1 and TGF pathways could be pharmacologically targeted, their combined inhibition may merit to be considered for future clinical development.
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Bortnik, Vuk. "CRISPR-Cas9 Targeting of E7 Oncogene in HPV-positive Head and Neck Squamous Cell Carcinomas". Thesis, Griffith University, 2019. http://hdl.handle.net/10072/390025.
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Background and Aims: Head and neck squamous cell carcinomas (HNSCCs) include cancers of the oral cavity, larynx, hypopharynx, and oropharynx. It is estimated that ~25% of HNSCCs are Human papillomavirus (HPV) positive. With the incidence on constant increase, HPV-positive HNSCCs have already overtaken the number of cervical cancer cases, another type of HPV-driven cancer. Current treatments include excision of tumour, chemotherapy and radiotherapy, while the 5-year survival rates are 45% with significant quality of life reduction and morbidity associated with first-line treatment regimens. Several prophylactic HPV vaccines exist and provide protection against infection from major high-risk HPV types, though without the ability to treat already established infections. These factors strongly indicate a pressing need for a new line of treatments to relieve the burgeoning pressure of HPV-positive HNSCCs.
The discovery of clustered regularly interspaced short palindromic repeat (CRISPR)-associated nuclease sequences (Cas) and its ability to induce site-specific modifications is set to revolutionise the field of human gene therapy. CRISPR/Cas9 system has the advantage over other genome-editing systems due to its low off-target effects and permanent editing capabilities. In case of HPV-positive tumours, this system lends itself in targeting major HPV oncogenes, particularly E6 and E7. Members of our lab recently demonstrated the absolute requirement of E7 for the survival of cervical cancer tumours using CRISPR/Cas9 technology. Therefore, we wanted to see whether this “oncogene addiction” occurs in HPV positive HNSCCs. This project explores the therapeutic potential of CRISPR/Cas9 editing technology for HPV-positive HNSCCs by targeting the HPV E7 oncogene in vitro.
Methodology: HPV16-positive HNSCC cell lines were initially assessed for E7 expression levels via digital PCR and immunoblotting. To CRISPR-edit 16E7, cells were then transfected with plasmids bearing Cas9 gene and gRNAs targeting 16E7 by lipid-based transfection using a range of transfection methods, including chemical transfection and electroporation. To extenuate the problem associated with delivery of large plasmid DNAs, we then designed synthetic gRNA molecules and transfected HNSCC cells constitutively expressing Cas9 protein. Cell viability was then assessed by the MTT and RT-GLO assays at various times post-transfection.
Results: We confirm that several HNSCC cell lines express the E7 protein and digital PCR revealed the absolute gene expression of E7 in these cells. We successfully deleted E7 using CRISPR, which was confirmed by immunoblotting. However, loss of E7 alone did not kill the cells, either using plasmid DNA or synthetic gRNA mediated CRISPR editing methods. To our surprise, loss of cell viability was only seen in cells that have had both E6 and E7 oncogenes CRISPR-edited.
Conclusions: Here, we showed that unlike cervical HPV carcinomas, head and neck HPV-positive carcinomas require the loss of both E6 and E7 oncogenes to die. Future work aims to place focus on targeting both E6 and E7 oncogenes on a wider range of HNSCC cell lines both in vitro and in vivo.Thesis (Masters)
Master of Medical Research (MMedRes)
School of Medical Science
Griffith Health
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Kim, Sung Woo. "Combining Noxa-Inducing Drugs with ABT-263 to Efficiently Increase Cell Death in Head and Neck Squamous Cell Carcinoma (HNSCC)". VCU Scholars Compass, 2017. http://scholarscompass.vcu.edu/etd/4847.
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Head and neck cancer is the sixth leading cancer worldwide. Head and neck squamous cell carcinoma (HNSCC) accounts for more than 90% of incident cases. Despite intense, multimodality treatment regimens for HNSCC including surgery, chemotherapy, and radiation, little progress has been made over the past 30 years in improving overall survival rates. Tumor cell death induced by both conventional and targeted chemotherapy is often mediated by the BCL-2 family-dependent mitochondrial apoptotic pathway. However, initiators of this apoptotic pathway, such as p53, are more than 50% of the time mutated or deleted in HNSCC rendering the disease refractory to treatment. To counter such resistance, direct therapeutic targeting of the BCL-2 family is conceptually appealing. For this purpose, we use three clinically-available drugs: cisplatin, fenretinide, and ABT-263 (navitoclax). Both cisplatin and fenretinide are known to induce a BH3-only pro-apoptotic protein, Noxa, which binds to and inactivates multi-domain anti-apoptotic protein MCL-1 and release from its interaction with multi-domain pro-apoptotic protein BAK, followed by the phosphorylation via CDK2 for the proteasome-mediated degradation. Activated BAK can now go through conformational change for the oligomerization at the outer membrane of the mitochondria to release cytochrome c into the cytosol and induce caspase-dependent apoptotic cell death. ABT-263 directly binds to multi-domain anti-apoptotic proteins, such as BCL-2 and BCL-XL, to inhibit their activity and leads to the activation of multi-domain pro-apoptotic protein BAX to induce apoptosis.
We hypothesize that combining the Noxa-inducing drugs (cisplatin or fenretinide) along with ABT-263 can efficiently induce BAX and BAK activation and significantly increase cell death in HNSCC cells by simultaneously inhibiting the activity of MCL-1, BCL-2, and BCL-XL. Combination-induced treatments in four cell lines (HN8, HN30, HN31, and UMSCC1) tested led to significant increase in apoptotic cell death. Cisplatin and ABT-263 combined treatment is inducing the expression of Noxa and leading to increase in apoptosis in HN30, HN31, UMSCC1, but not HN8. Similarly, fenretinide and ABT-263 combined treatment is inducing the expression of Noxa in all four cell lines tested and is largely relying on expression of Noxa.
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Simonet, Stéphanie. "Radiosensitizing effect of AGuIX® in Head and Neck Squamous Cell Carcinoma (HNSCC) : from cellular uptake to subcellular damage". Thesis, Lyon, 2018. http://www.theses.fr/2018LYSE1042/document.
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Les cancers des Voies Aérodigestives Supérieures sont classés parmi les dix cancers les plus agressifs du fait de leur radioresistance intrinsèque et leur forte probabilité de récurrence. L’objectif de ce travail a été d’étudier le potentiel radiosensibilisant de nanoparticules à base de gadolinium, AGuIX®, sur un modèle cellulaire de cancer des VADS. Après avoir déterminé et validé les conditions optimales de radiosensibilisation de notre modèle par les AGuIX®, leur localisation après internalisation ainsi que les conséquences biologiques générées à l’échelle subcellulaire ont été successivement étudiées. Enfin, une approche préliminaire protéomique a été initiée afin d’identifier des cibles moléculaires potentielles impliquées dans cette radiosensibilisation. Le traitement des cellules SQ20B avec 0.8mM Gd pendant 24h se sont révélées être optimales avec un DEF (dose enhancement factor) de 1.3. Les AGuIX® sont localisées presque exclusivement dans les lysosomes après internalisation. La radiosensibilisation est liée à une surproduction de radicaux libres oxygénés, minimisée toutefois par des défenses antioxydantes endogènes élevées. Le traitement combiné (AGuIX®+ irradiation) déclenche spécifiquement la mort cellulaire autophagique et s’accompagne d’une augmentation significative du nombre de cassures double brins résiduelles complexes. L’étude protéomique préliminaire a permis d’identifier une cible moléculaire potentiellement impliquée dans cette radiosensibilisation (la ribonucléotide réductase), cible qui fera l’objet d’une suite à ce travail. De plus, la prochaine étape sera de comprendre les mécanismes qui relient les AGuIX® internalisées dans les lysosomes avec l’augmentation de la mort cellulaire autophagique après irradiationHead and Neck Squamous Cell Carcinoma is ranked among the top ten deadliest cancers due to its high radioresistance and recurrence. One radiosensitizing strategy is the use of high-Z metal nanoparticles. In this study, ultrasmall gadolinium-based nanoparticles, AGuIX®, were used for their potential as a radiosensitizing agent. The objectives of this work were to determine the radiosensitizing conditions of AGuIX® in an HNSCC cell model, their localization after uptake, and the biological consequences generated at the subcellular level after the combined treatment. A preliminary proteomic approach was initiated in order to identify potential molecular targets involved in radiosensitization. The treatment of SQ20B cells with 0.8mM Gd for 24h resulted in a dose enhancement factor (DEF) of 1.3. AGuIX® were predominantly localized in lysosomes. The overproduction of radical oxygen species following AGuIX® + radiation was intimately involved in the radiosensitization, although largely subdued by the high level of endogenous antioxidant defenses. Autophagy was specifically triggered after the combined treatment, while other irradiation-induced cell deaths remained unchanged. The number of complex, residual double strand breaks (DSBs) was specifically increased with AGuIX® combined to radiation. Lastly, our preliminary proteomic analysis allowed the isolation of potential molecular targets with great promise. Collectively, it seems that the radiosensitizing effect observed in this work may result from a combination of events.Future work is required to understand the mechanisms linking lysosomes-entrapped AGuIX® with the upregulation of autophagic cell death after radiation
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Mukhtar, Lenah. "Targeting the Mevalonate Pathway Enhances the Efficacy of Epidermal Growth Factor Receptor – Tyrosine Kinase Inhibitors in Head and Neck Squamous Cell Carcinoma". Thesis, Université d'Ottawa / University of Ottawa, 2020. http://hdl.handle.net/10393/40391.
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Epidermal growth factor receptor (EGFR) is highly expressed in head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) and is a key regulator of tumor cell growth and survival. Erlotinib, also known as tarceva, (a first-generation) and afatinib, also known as giotrif, (a second-generation) are tyrosine kinase inhibitors (TKIs) of EGFR. These TKIs are recognized therapeutic agents in these tumor types, as they inhibit EGFR signaling but show limited activity as single agents. Novel strategies will likely require EGFR-TKIs combination with an agent(s) that will enhance their therapeutic efficacy. Recently, we have demonstrated that combining statins, inhibitors of the mevalonate pathway, with erlotinib enhanced EGFR inhibition and induced synergistic cytotoxicity through the activation of cellular integrated stress response pathway (ISR) regulated by the induction of activating transcription factor 3 (ATF3). In our Phase I clinical trial, combining rosuvastatin with erlotinib, while demonstrating clinical activity, this treatment also showed statin-induced myopathies likely the result of diminished ubiquinone levels, which limited their utilization. Therefore, alternative strategies are warranted. Targeting geranylgeranyl diphosphate (GGPP) synthesis or its incorporation, a downstream mevalonate metabolite, represents such an approach with the potential to circumvent statin-associated toxicities but retain the efficacy in combination with EGFR inhibitors. In this project, we evaluated the effect of the combination of geranylgeranyl transferase-I inhibitor (GGTI-298) with the EGFR inhibitor, tarceva, (aim 1) and a GGPP synthase inhibitor, digeranyl bisphosphonate (DGBP), with the EGFR inhibitor, afatinib, (aim 2). For aim 1, we demonstrated that GGTI-298 treatment induced ATF3 expression in SCC9 and SCC25 cells and in a cohort of ex-vivo tumor tissues. Furthermore, GGTI-298 and tarceva induced synergistic cytotoxicity in SCC cells that was dependent on ATF3 expression, as ATF3 deficient murine embryonic fibroblasts (ATF3-/- MEFs) displayed attenuated cytotoxicity in response to GGTI-298 alone and in combination with tarceva. Similarly, SCC9 sub-lines that were selected as resistant to GGTI-298 through prolonged exposure to this agent also failed to demonstrate synergy with treatment of GGTI-298 in combination with tarceva. For aim 2, we demonstrated that the specific GGPP synthase inhibitor, DGBP, induced cytotoxicity in SCC cells. We further demonstrated this specificity as specific shRNA targeting of GGPP synthase as well as the inhibitor DGBP significantly enhanced the cytotoxic activity of the EGFR-TKI afatinib in SCC cells. DGBP as well as afatinib treatments induced ATF3 expression in SCC cells in vitro and in a cohort of ex-vivo tumor tissues. Co-administration of the downstream metabolite GGPP inhibits the induction of ATF3 and the cytotoxic and apoptotic effects associated with DGBP treatment. Furthermore, the synergistic cytotoxicity induced by the combination of DGBP and afatinib in SCC cells was also dependent on the expression of ATF3 through the induction of cellular stress response pathways. Taken together, these results suggest the potential clinical utility of combining downstream mevalonate inhibitors (GGTI-298 or DGBP) with EGFR inhibitors in HNSCC patients as a novel and more refined combination therapeutic approach.
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Hautea, Rhea P. "Vitamin D- induced down regulation of RAD51 in head and neck squamous cell carcinoma (HNSCC), In Vitro and In Vivo". Scholarly Commons, 2011. https://scholarlycommons.pacific.edu/uop_etds/786.
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The active form of Vitamin D (VD3) has been shown to induce pro-apoptotic and anti-proliferative effects in several mammalian cancer cell types. The molecular mechanisms of tumor suppression, however, are not clearly understood. Previous research has shown that head and neck squamous cell carcinoma (HNSCC) responds to VD3. This thesis used both in vivo and in vitro models to examine the effect of VD3 in HNSCC. Former work in the Albala laboratory showed that hamsters that received systemic VD3 and topical treatment of 7,12-dimethylbenz(a)anthracene (DMBA) to the buccal pouch showed no or delayed carcinogenesis over the 14-week study compared to DMBA-only treated hamsters. This research further investigated the effect of VD3 in this hamster model. Using immunohistochemical (IHC) and western blot analysis, we demonstrate that systemic application of VD3to hamsters downregulates Rad51 expression in the buccal pouch and hinders the onset of tumor formation. Rad51 is a protein that plays a critical role in cell proliferation and homologous recombinational DNA repair. In the in vitro model, we show that Rad51 expression decreased in response to 100nM VD3 in HNSCC cell lines. The dose and time-dependence of VD3 on these cells was also examined. Western blot analysis and comet assay investigations confirmed that the SCC25 cell line is most sensitive to 100nM VD3 than to other doses tested, and that VD3 impairs the DNA-damage response. SiRNA and co-immunoprecipitation studies examined the potential of Chk 1 and p38 MAPK as upstream regulators of Rad51. Rad51 protein expression was found to be associated with early carcinogenesis from HNSCC cancer patients using IHC studies of human carcinomas from the oral cavity. This study focused on further identifying the role of Rad51 in response to VD3 in HNSCC.
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Lin, Mau-Ting. "Identification of frequent gains of DNA copy number and characterization of potential novel oncogenes in head and neck squamous cell carcinoma". Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1196177703.
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Shaikh, Mushfiq Hassan. "The Role of Human Papillomaviruses in the Aetiopathogenesis of Head and Neck Cancer in South Asia, and Approaches to Treatment". Thesis, Griffith University, 2017. http://hdl.handle.net/10072/366967.
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Malignancies of the upper aero-digestive tract are a major public health problem, especially in South Asia. The major risk factors in South Asia remain smoked/smokeless tobacco, areca nut, alcohol abuse and poor diet, with limited evidence for human papillomavirus (HPV). Although HPV-associated head and neck
squamous cell carcinoma (HNSCC) is well documented in the western world, studies on South Asian populations are few and inconsistent. However, the incidence of HPV-associated head and neck cancer (HNC) has increased in recent years. Certain high-risk types of HPV infection are regarded as well-established risk factors for cervical cancer and a subset of HNSCC; however, their true role and importance in the progression of HNSCC remain unclear. Although HPV-associated HNC patients
generally have a better prognosis than those with HPV-negative disease, current chemo- and radio-therapies are largely non-specific and have considerable toxicities. RNA interference (RNAi), which has shown great promise as a highly specific therapy for other diseases, has potential for treating HPV-associated HNC, especially if disease progression is dependent on the continual expression of HPV oncogenes.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Dentistry and Oral Health
Griffith Health
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Caggiano, Emily Grace. "Characterization of cold atmospheric plasma treatment as a novel transfection technique to knock down nucleolin in head and neck squamous cell carcinoma". Ohio University Honors Tutorial College / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ouhonors155622670397153.
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Sun, Zhifeng [Verfasser]. "MicroRNA-34a regulates epithelial–mesenchymal transition (EMT) in cancer stem (like) cells (CSCs) of head and neck squamous cell carcinoma (HNSCC) and is a possible molecular target / Zhifeng Sun". Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2015. http://d-nb.info/1079840990/34.
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GHIANI, LAVINIA. "THE HISTONE POST-TRANSLATIONAL MODIFICATION LANDSCAPE IN HPV+ AND HPV- HEAD AND NECK SQUAMOUS CELL CARCINOMA: CHARACTERIZING THE ONCOGENIC ROLE OF THE H3K36ME2 METHYLTRANSFERASE NSD2". Doctoral thesis, Università degli Studi di Milano, 2021. http://hdl.handle.net/2434/820678.
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Background: HNSCC is a heterogeneous group of tumors caused mainly by environmental factors and human papillomavirus (HPV) infections. HPV- and HPV+ HNSCC are considered distinct entities, however, they are still treated with the same therapeutic strategies. HPV-induced tumorigenesis is mainly mediated by the E6/E7 oncoviral proteins, that, among all, alter the epigenetics of the host cells. Nevertheless, epigenetic profiles of HNSCC subtypes have not been clearly profiled.
Results and Conclusion: hPTMs super-SILAC analysis of HNSCC cell lines and patients’ tissue samples revealed significant differences in the enrichment levels of some hPTM in HPV+ samples compared to HPV- ones and in tumoral tissues compared to normal ones.
We focused on one of these identified hPTM and demonstrated that its levels are regulated by E6 and E7. We identified a histone modifier responsible for this hPTM whose levels are upregulated by E6/E7 and are higher in HPV+ compared to HPV- HNSCC cell lines and patients’ tissue samples, as is for the related hPTM. Silencing this enzyme through shRNA in HNSCC cell lines reduced proliferation and migration rates in both subtypes. It also downregulates the expression levels of some EMT mesenchymal makers and of a crucial oncogene involved in HNSCC. RNA-seq analysis revealed that other programs are instead specifically regulated according to the subtype: immune-response related genes are mainly activated in HPV- cell lines, while genes involved in cell differentiation in the HPV+ ones. Our research paves the way to novel lines of research and identifies a promising novel epigenetic target for HNSCC treatments.
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Zhang, Liefen [Verfasser], Yahya [Akademischer Betreuer] Acil e Medina Oula Antti Rafael [Gutachter] Peñate. "Effect of Cilengitide and Vismodegib on Primary Cell Cultures and Cell Lines of Head and Neck Squamous Cell Carcinoma (HNSCC) after Targeting Integrin and Hedgehog Pathways / Liefen Zhang ; Gutachter: Oula Antti Rafael Peñate Medina ; Betreuer: Yahya Acil". Kiel : Universitätsbibliothek Kiel, 2020. http://d-nb.info/121164930X/34.
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Li, Qike, A. Grant Schissler, Vincent Gardeux, Ikbel Achour, Colleen Kenost, Joanne Berghout, Haiquan Li, Hao Helen Zhang e Yves A. Lussier. "N-of-1-pathways MixEnrich: advancing precision medicine via single-subject analysis in discovering dynamic changes of transcriptomes". BIOMED CENTRAL LTD, 2017. http://hdl.handle.net/10150/625841.
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Background: Transcriptome analytic tools are commonly used across patient cohorts to develop drugs and predict clinical outcomes. However, as precision medicine pursues more accurate and individualized treatment decisions, these methods are not designed to address single-patient transcriptome analyses. We previously developed and validated the N-of-1-pathways framework using two methods, Wilcoxon and Mahalanobis Distance (MD), for personal transcriptome analysis derived from a pair of samples of a single patient. Although, both methods uncover concordantly dysregulated pathways, they are not designed to detect dysregulated pathways with up- and down-regulated genes (bidirectional dysregulation) that are ubiquitous in biological systems. Results: We developed N-of-1-pathways MixEnrich, a mixture model followed by a gene set enrichment test, to uncover bidirectional and concordantly dysregulated pathways one patient at a time. We assess its accuracy in a comprehensive simulation study and in a RNA-Seq data analysis of head and neck squamous cell carcinomas (HNSCCs). In presence of bidirectionally dysregulated genes in the pathway or in presence of high background noise, MixEnrich substantially outperforms previous single-subject transcriptome analysis methods, both in the simulation study and the HNSCCs data analysis (ROC Curves; higher true positive rates; lower false positive rates). Bidirectional and concordant dysregulated pathways uncovered by MixEnrich in each patient largely overlapped with the quasi-gold standard compared to other single-subject and cohort-based transcriptome analyses. Conclusion: The greater performance of MixEnrich presents an advantage over previous methods to meet the promise of providing accurate personal transcriptome analysis to support precision medicine at point of care.
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Sandström, Karl. "Radioimmunodiagnosis of Head and Neck Squamous Cell Carcinomas : Preclinical Studies". Doctoral thesis, Uppsala universitet, Öron-, näs- och halssjukdomar, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-156523.
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Despite improvements in treatment, the prognosis for patients with advanced head and neck squamous cell carcinomas (HNSCC) has only improved to a minor degree. To raise the success rate and minimize morbidity further developments in diagnostics are highly desired. Radioimmunodiagnosis could offer a more specific and sensitive diagnostic method. Herein, we have evaluated different radioimmunoconjugates directed against CD44v6 and epidermal growth factor receptor (EGFR) for imaging of HNSCC. The studies were performed in a murine HNSCC xenograft model. Initially, the 111In-labeled anti CD44v6 chimeric monoclonal antibody U36 (cMAb U36) was evaluated. The novel radioimmunoconjugate showed high and accumulating tumor uptake. Since small molecules might be advantageous for imaging, due mainly to their shorter circulation half-life in the bloodstream, we then investigated antibody fragments F(ab’)2 and Fab’ derived from cMAb U36. The highest tumor-to-blood ratio was achieved with the dimeric antibody fragment F(ab’)2, compared with both the intact anti-body and monomeric Fab’. Furthermore, the possibility of improving EGFR-targeted imaging was explored by pre-blocking EGFR. The liver uptake of injected labeled human epidermal growth factor (hEGF) was significantly reduced when an excess of unlabeled hEGF was injected 30 minutes in advance. However, as hEGF stimulates cell proliferation it may be inadvisable to treat cancer patients with large amounts. Alternatively, pre-blocking with an anti-EGFR Affibody molecule (ZEGFR:955)2 demonstrated similar decrease in liver uptake as unlabeled hEGF. Finally, (ZEGFR:955)2 was compared with other Affibody molecules with higher affinity to EGFR, ZEGFR:1907 and (ZEGFR:1907)2, as pre-blocking agents. In addition, a novel hEGF radioimmunoconjugate, [67Ga]Ga-NOTA-Bn-NCS-hEGF was used for EGFR targeting. The dimeric (ZEGFR:1907)2 showed greatest reduction in non-tumor uptake, and highest tumor-to-organ ratio in EGFR expressing organs, when injected in advance of the radioimmunoconjugate. To summarize, the results presented here demonstrate how different radioimmunoconjugates as well as pre-blocking EGFR can improve the radioimmunodiagnosis of head and neck squamous cell carcinomas.
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Ekberg, Tomas. "Diagnosis and Radioimmunotherapy of Head and Neck Squamous Cell Carcinomas". Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Universitetsbiblioteket [distributör], 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8395.
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Burgy, Mickaël. "Intérêt pronostic et thérapeutique de l'axe miR-30a/e-3p -Cav1 dans les carcinomes épidermoïdes de la tête et du cou". Electronic Thesis or Diss., Strasbourg, 2025. http://www.theses.fr/2025STRAJ002.
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Le pronostic péjoratif des carcinomes épidermoïdes de la tête et du cou (CETEC) tient en partie aux mécanismes encore non élucidés de résistances aux thérapies actuelles. De plus l’absence de biomarqueurs complique le développement de stratégies thérapeutiques reposant actuellement sur le stade de la maladie excluant les caractéristiques biologiques tumorales. Dans ce projet de recherche translationnelle, nous avons identifié la cavéoline-1 (Cav1) et les miR-30a/e-3p comme des biomarqueurs pronostiques de la survie et de la récidive tumorale. Nous avons validé l’implication de l’axe CAV1/EREG/YAP dans la résistance au Cetuximab et à la radiothérapie. Nous avons également identifié miR-30a/e-3p à la fois comme des régulateurs de la voie du TGF-β via la répression de TGFBR1 et BMPR2 à l‘origine d’une diminution de l’agressivité tumorale, et également comme des immunomodulateurs favorisant l’activité phagocytaire des macrophages envers les cellules tumorales. Enfin nous avons pu développer un modèle de tumoroïdes issus de pièces opératoires de patients atteints de CETEC ayant permis de valider certains de nos résultats et destiné à un projet de recherche de drug-testingThe poor prognosis of head and neck squamous cell carcinomas (HNSCC) patients is partly attributed to resistance mechanisms against current therapies, which remain poorly understood. Furthermore, the absence of biomarkers complicates the development of therapeutic strategies currently based on disease staging, excluding the tumor's biological characteristics. In this translational research project, we identified caveolin-1 (Cav1) and miR-30a/e-3p as prognostic biomarkers for survival and recurrence. We validated the involvement of the CAV1/EREG/YAP axis in the resistance to Cetuximab and radiotherapy. We also identified miR-30a/e-3p both as regulators of the TGF-β pathway through the repression of TGFBR1 and BMPR2 leading to reduced tumor cell aggressiveness and as immunomodulators promoting the phagocytic activities of macrophages towards tumor cells. Finally, we developed a tumoroid model derived from resected tissue of HNSCC patients which confirmed several of our results and will be used in a drug-testing research project
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Baboci, Lorena. "Human papillomavirus - associated head and neck squamous cell carcinomas in North-East Italy". Doctoral thesis, Università degli studi di Padova, 2014. http://hdl.handle.net/11577/3423688.
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Background: Specific oncogenic types of human papillomaviruses (HPV), most frequently HPV16, are causally associated with a subset of head and neck squamous cell carcinomas (HNSCC). HPV DNA associated tumors appear to be heterogeneous in prevalence over time and geographically, in the oncogenic activity (direct and indirect viral markers) and clinical behavior. However, it remains unclear which biomarkers can reliably determine which HNSCC are truly driven by HPV transformation.
Aims: In the present thesis, the first aim was to determine the prevalence of the truly HPV-associated HNSCC tumors in North-East Italy. The second aim, was to investigate the association of HPV DNA positivity with other viral (viral load, oncoE6 protein, HPV antibodies) and cellular (p16INK4a, pRb) markers. The third aim, was to evaluate the prognostic significance of HPV-association tumors for clinical outcome (i.e. survival).
Materials and Methods: Overall, 247 fresh frozen and 53 (21%) formalin-fixed paraffin-embedded (FFPE) tumor tissue biopsies and 102 (41%) sera were collected from 247 newly detected HNSCC patients from North-East Italy. Clinical parameters for each patient were obtained from the clinical database.
HPV DNA was determined by polymerase chain reaction (PCR) with consensus MY09/MY11 primers and Restriction Fragment Length Polymorphism (RFLP) analysis and/or BSGP5+/6+-PCR/Multiplex Papillomavirus Genotyping (MPG) capable of detecting all known 51 mucosal HPV types.
The HPV DNA+ tumor tissues were further analyzed for i) viral load by HPV16 qPCR and quantitative BSGP5+/6+-PCR/MS; ii) detection of HPV E6*I transcripts by RT-PCR; iii) expression levels of cellular protein p16INK4a and pRb by IHC; and iv) presence of HPVE6 protein for types 16 and 18 by the commercial OncoE6TM Oral Test; Antibodies to HPV early and late proteins of the eight most frequent high-risk HPV types were determine din all available sera by bead-based multiplex serology.
Results: Overall, HPV DNA+ was 8.5% (21/247), type 16 was detected in 95% (20 cases) and type 58 in 5% (1 case). No multiple infections were detected. The HPV RNA+ was 6% (14/244). Oropharynx was the site with the highest HPV prevalence by DNA (27%) and RNA (20%). In the other anatomic sites, HPV prevalence was < 8%.
Among the HPVDNA+ RNA+ tumors, i) 93% of the HPV16+ tissues (13/14) showed high viral load; ii) 60% (6/10) showed both up-regulation of p16INK4a and down-regulation of pRb; iii) and in 100% (8/8) HPV16 E6 oncoprotein was detected. All sera of 7 HPV-driven tumors showed strong positive antibody reactions with HPVE6 and E7 proteins, 6 for type 16 and 1 for type 58, type-concordant with the related tumor. Another single serum HPV16 DNA+ in the tumor, showed positivity for all early HPV16 proteins suggestive of an HPV-driven tumor. Kaplan-Meier analyses for the oropharynx showed a trend for better survival in the HPV-associated group than in the HPV negative ones.
Conclusions: A low HPV prevalence was found in HNSCC of the population living in the North-East of Italy. Oropharynx was the preferential site for HPV infection while the HPV prevalence in the other anatomic sites appeared negligeable. We observed that the HPVDNA+ RNA+ samples showed a good correlation with the other markers like high viral load, presence of the E6 oncoprotein, and HPVE6 and E7 seromarkers. In contrast to recent reports we did not find a good correlation between HPVDNA+ RNA+ and the up-regulation of p16INK4a and down-regulation of pRb. Survival analyses showed a better prognosis in the HPV-driven patients with tumors occurring in the oropharynx.Il papillomavirus umano (HPV), più frequentemente il tipo 16, sono causalmente associati agli tumori squamosi di testa collo (HNSCC). Questi tumori sono caratterizzati da un'elevata eterogeneità geografica e una migliore risposta alla terapia. L'obiettivo di questo studio è di valutare la prevalenza e l'attività biologica di HPV in HNSCC nel nord dell'Italia. La genotipizzazione per se non è sufficiente a definire il ruolo del virus nella patogenesi HNSCC. E' necessario analizzare e verificare la presenza di altri marker diretti come i trascritti virali, la carica virale, oncoE6 proteine e anticorpi HPV e dei marker indiretti come l'espressione delle proteine cellulari p16INK4a e pRb. I risultati ottenuti sono stati alla fine correlati con la sopravivenza. Nel presente studio sono stati arruolati 247 pazienti del Nord-Est dell'Italia. Sono stati raccolti biopsie tumorale congelate per tutti i pazienti, e per un sottogruppo dei blocchetti di paraffina e del plasma. La presenza del DNA virale è stato determinato con i) reazione a catena della polimerasi con primer consenso MY09/MY11 e tipizzazione con digestione enzimatica e/o ii) BSGP5+/6+ -PCR/Multiplex Papillomavirus Genotype (MPG). I casi HPV DNA positivi sono stati ulteriormente analizzati per: i) carica virale (quantitative PCR); ii) presenza dei trascritti virali (E6*I method); iii) l'espressione delle proteine cellulari p16INK4a e pRb (immunohistochimica, IHC); iv) espressione dell'oncoproteina E6 (OncoE6TM kit, AVC); v) anticorpi anti HPV (Multiplex HPV serology). La prevalenza basata sulla positività del DNA virale era del 9% (21/247). HPV16 è stato trovato nel 95% (20/21) dei casi, 1 HPV58 è stato identificato come infezione singola. La prevalenza basato sul HPV DNA+RNA+ era del 6% (14/244). L'orofaringe era il sito con la più elevata prevalenza di HPV (HPV DNA+ = 27%, HPV DNA+ RNA+ = 20%). 86% (12/14) dei campioni aveva un'alta carica virale per il tipo analizzato; ii) over espressione p16INK4a nel 90% (9/10), down-regulation pRb nel 55% (6/11); iii) la presenza dell'oncoproteina E6 era presente nel 100% (8/8) dei casi testati. La presenza di anticorpi anti HPV è stata valutata in 102 plasmi; 8 su 102 erano positivi per anticorpi HPV, con elevata correlazione con lo status HPV dei relativi tessuto tumorale. Le analisi di Kaplan-Meier per l'orofaringe hanno mostrato un trend di migliore sopravvivenza nei pazienti con tumori HPV positivi per DNA e RNA rispetto ai pazienti HPV negativi. Bassa prevalenza di HPV nei tumori testa collo nel nord dell'Italia confrontato ad altri paesi. L'orofaringe rimane il sito prediletto dell'infezione per l'HPV (27 %). HPV16 era il principale tipo trovato (95%). Migliore sopravvivenza dei pazienti con tumori HPV positivi.
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Shankar, Athiva. "Epidemiological and molecular insights into Human Papillomavirus-related head and neck squamous cell carcinomas". Thesis, University of Dundee, 2016. https://discovery.dundee.ac.uk/en/studentTheses/dfd76e62-d92e-4e51-90b3-dacd1f6e34b0.
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Over the last decade, Scotland has witnessed a rising incidence in squamous cell carcinomas of the head and neck (HNSCC), a phenomenon thought to be linked to infection with high-risk Human Papillomavirus (HPV). HPV-associated HNSCC are a distinct disease presenting unique epidemiological, biological and clinical challenges. However, establishing HPV-related disease is impaired by non-standardised testing protocols and lack of a consensus on the efficacy of existing biomarkers such as p16. This is further complicated by the absence of additional biological markers and a dearth in our understanding of the molecular mechanisms underlying HPV-driven tumourigenesis. While HPV positivity is more commonly detected in the oropharynx, its prevalence and clinical impact in other head and neck subsites remains largely unexplored. The research presented in this thesis was undertaken to determine the prevalence of high-risk HPV in a heterogeneous cohort of 293 HNSCC patients from Tayside and to evaluate the validity of EBP50, a scaffolding protein involved in cell polarity which is targeted by high-risk HPV, as a potential marker for HPV-driven HNSCC. The p16 status of the patients in the cohort was already known and tissue specimens were genotyped for HPV using PCR. HPV infection, defined as p16 positivity and a positive HPV DNA status, was identified in 14% of the cohort. The majority (83%) of the HPV-positive tumours involved the oropharynx while the oral cavity, pharynx and the nasal cavity (17%) were involved to a much smaller extent. High-risk HPV type 16 was the most prevalent HPV type. Patients with HPV-positive tumours had significantly improved overall survival (OS) (2 year OS, 77% vs 57%) and recurrence free survival rates (RFS) (2 year RFS, 92% vs 77%) compared to patients with HPV-negative tumours. A positive tumour HPV status was found to be an independent prognostic indicator (HR 0.216; 95% CI 0.06 – 0.771) and so, given the high morbidity and debilitating physical and psychological problems associated with prevailing aggressive treatment regimens, it is imperative that this knowledge is harnessed to develop and improve treatment strategies. EBP50 expression was evaluated, by immunohistochemical analysis, first in normal oral mucosa and followed up in a smaller subset of 156 HNSCC patients from the main cohort. In the normal tissue EBP50 expression was predominantly membranous. In the tumour samples four distinct EBP50 expression patterns were observed and, of these, weak/ negligible cytoplasmic EBP50 expression showed a strong correlation, only marginally lower than p16 overexpression, with HPV DNA status and was observed largely in patients with tumours of the oropharynx and no history of smoking. Absence of EBP50 expression in the plasma membranes of tumour cells was a recurring pattern in a majority of the tumour samples. The scale of this study, comprising a Tayside cohort of unprecedented size, will undoubtedly contribute to the existing knowledge of HPV incidence in head and neck cancer in Scotland. Furthermore, this study presents compelling preliminary evidence for further researching weak/negligible cytoplasmic EBP50 expression as being a potential indicator of HPV-positivity in HNSCC.
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Kuo, Michael Jeo-Ming. "Aberrations of chromosome arms 5q and 8p in squamous cell carcinomas of the head and neck". Thesis, University of Birmingham, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.340558.
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Luangdilok, Sutima. "An Investigation of Signalling Pathways linked to Lymphatic Metastasis in Squamous Cell Carcinomas of the Head and Neck". Thesis, Institute of Cancer Research (University Of London), 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.487311.
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Squamous cell carcinomas of the head and neck (SCCHN) spread predominantly by local invasion and lymphatic dissemination. The aim of this project was to learn more about the molecular mechanisms of lymphatic metastasis in this disease. EGFR is a major driver of progression, invasion and metastasis in SCCHN. Ip. addition, signalling via chemokine receptors such as CXCR4 and CCR7 and the lymphangiogenic cytokine receptor VEGFR-3 has been implicated in lymphatic metastasis. My first aim was to measure expression levels in SCCHN cell lines, determine their interactions with EGFR and the signalling pathways involved in their regulation. Most SCCHN cell lines expressed VEGF-A, -C, -D, CCR7 and CXCR4. VEGF-A expression was PI3K- and MAPK-dependent, whereas VEGF-C expression was regulated by MAPK only. Possible EGFR transactivation by CXCLl2 (CXCR4 ligand) or CCL21 (CCR7Iigand) was identified. Metastatic processes also depend on intrinsic properties of tumour cells. PI3K and PLCyl are important regulators of cell motility downstream of EGFR. In addition, Syk, a nonreceptor tyrosine kinase, has been implicated in PI3K and PLCyl signalling pathways in B-cells and chemomigration in nasopharyngeal carcinoma. Recently, an interaction between Syk and EGFR has been reported. My second aim was to explore the role of Syk in SCCHN. Syk overexpression enhanced chemomigration in vitro, whereas inhibition by piceatannol or siRNA inhibited cell migration, haptotaxis and matrix interactions; these effects were associated with changes in activation ofPLCyl or AKT. In clinical samples, high Syk expression was associated with higher risk of recurrence, was significantly correlated with worse survival and may be of prognostic value in SCCHN. Coordinated EGFR signalling regulates many key processes in lymphangiogenesis/angiogenesis and invasion that contribute to lymphatic metastasis in SCCHN. Key molecules and their integrated signaling pathways could be useful for prognosis and have the potential to provide novel therapeutic targets in SCCHN.
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Zahr, Stephanie. "GGTI-298 in Combination with EGFR Inhibitors: Evaluating a Novel Therapy in Head and Neck Squamous Cell Carcinomas". Thèse, Université d'Ottawa / University of Ottawa, 2013. http://hdl.handle.net/10393/25488.
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Overall survival of the metastatic forms of epithelial derived cancers, especially head and neck squamous cell carcinomas (HNSCC), has not significantly improved even with the application of aggressive combined modality approaches incorporating radiation and chemotherapy. Cumulative evidence implicates the epidermal growth factor receptor (EGFR) as an important therapeutic target in HNSCC. We have previously demonstrated that the combination of lovastatin, a potent inhibitor of the mevalonate pathway, with EGFR tyrosine kinase inhibitors induced robust synergistic cytotoxicity. However, the use of high dose statins in our clinical trial was associated with significant toxicities including higher than anticipated rate of muscle pathologies. Our goal was to uncover novel downstream targets of the mevalonate pathway that may enhance the efficacy or limit toxicities of this novel combination therapeutic approach. In this study we have demonstrated that GGTI-298, an inhibitor of protein geranylgeranylation, through its ability to disrupt the actin cytoskeleton, inhibits EGFR dimerization and cellular trafficking. This novel mechanism targeting the EGFR has clinical implications as GGTI-298 in combination with tarceva, a clinically relevant EGFR inhibitor, showed enhanced cytotoxicity and inhibitory effects on EGFR activation and its downstream signaling.
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Zheng, Xiangpeng. "Specificity and feasibility of HN-5 peptide for diagnosis and targeted therapy of head and neck squamous cell carcinomas : a dissertation /". San Antonio : UTHSC, 2007. http://proquest.umi.com/pqdweb?did=1400957411&sid=1&Fmt=2&clientId=70986&RQT=309&VName=PQD.
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Leick, Lisa [Verfasser]. "Analysis of molecular components, causing Fanconi anemia-like phenotype in HPV-16 infected head and neck squamous cell carcinomas / Lisa Leick". Ulm : Universität Ulm, 2017. http://d-nb.info/1147484694/34.
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Mourtada, Jana. "Mécanismes d’activation de la réponse immunitaire par DNp63 dans les cancers des voies aérodigestives supérieures HPV-positifs". Electronic Thesis or Diss., Strasbourg, 2023. http://www.theses.fr/2023STRAJ127.
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Les tumeurs HPV+ de l’oropharynx sont hétérogènes d’un point de vue pronostic et moléculaire. Le pronostic des tumeurs se distinguent respectivement par la présence ou l’absence d’une signature moléculaire dépendante du facteur de transcription ΔNp63. Nous avions démontré que ΔNp63 inhibe les capacités migratoires et invasives des lignées cellulaires de cancer ORL HPV+, et augmente leur sensibilité aux chimiothérapies à base de sel de platine, suggérant son rôle dans la progression tumorale. Une analyse fonctionnelle de ΔNp63 nous a permis de montrer que son expression stimule la phagocytose de cellules cancéreuses par des macrophages in vitro. De manière cohérente, l’analyse du transcriptome de notre même modèle cellulaire met en évidence que ΔNp63 régule l’expression de facteurs diffusibles comme des chimiokines et des interleukines, parmi lesquels la protéine DKK3. Nos résultats montrent que la sécrétion de DKK3 par les cellules cancéreuses active la voie NF-kB dans les macrophages, et mimique les effets de ΔNp63 dans la régulation de la phagocytose. L’induction de la voie NF-kB par DKK3 dans les macrophages est réalisée par l’intermédiaire de son récepteur CKAP4. Enfin, nos analyses suggèrent que ∆Np63 régule l’expression de facteurs impliqués dans l’inflammasome, ainsi que celles d’autres cytokines comme TNFRSF11B, CCL26, CCL11, TIMP1 et TIMP2. L’ensemble de nos résultats montrent que ΔNp63 joue un rôle original dans le pronostic des patients HPV+ à travers la régulation de molécules sécrétées, impliquées dans le recrutement et l’activation de cellules immunitairesHPV+ oropharyngeal tumors display both prognostic and molecular heterogeneity. Patients prognosis can be distinguished by the presence or absence of a molecular signature that depends on the ΔNp63 transcription factor. We demonstrated that ΔNp63 inhibits the migratory and invasive capabilities of HPV+ HNSCC cell lines and increases their sensitivity to platinum-based chemotherapy, implying its role in tumor progression. A functional analysis of ΔNp63 revealed its ability to stimulate the phagocytosis of cancer cells by macrophages in vitro. Consistently, a transcriptomic analysis of the same cellular model highlighted that ΔNp63 regulates the expression of secreted factors, including chemokines and interleukins, among which is the DKK3protein. Our findings indicate that DKK3 secretion by cancer cells activates the NF-κB pathway in macrophages, mimicking ΔNp63's effects on phagocytosis regulation. Induction of the NF-κB pathway by DKK3 in macrophages is mediated by its receptor CKAP4. Finally, our analyses suggest that ∆Np63 regulates the expression of factors involved in the inflammasome, as well as those of other cytokines such as TNFRSF11B, CCL26, CCL11, TIMP1 and TIMP2. Altogether, our results show that ΔNp63 plays a unique role in the prognosis of HPV+ patients by regulating secreted molecules involved in the recruitment and immune cell activation
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Ylipalosaari, M. (Merja). "Matrix metalloproteinases (MMPs) in oral carcinomas". Doctoral thesis, University of Oulu, 2005. http://urn.fi/urn:isbn:9514277309.
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Abstract
Matrix metalloproteinases, MMPs, are a family of enzymes capable of modulating connective tissue components. The expression of several MMPs is increased in oral squamous cell carcinomas (OSCCs). They are assumed to have an important role in the development and progression of OSCCs. However, the exact role and mechanism of the regulation of MMPs in malignant transformation are still largely unknown.
In this study, tumour-associated trypsin-2 (TAT-2) was detected in OSCC tissue sections, and its role in MMP-2 and -9 regulation in carcinoma cells was evaluated. The TAT-2 gene was transfected into two different OSCC cell lines and one immortalized oral epithelial cell line. In TAT-2-transfected cells, MMP-9 activation increased OSCC cell invasion in chicken chorionallantoic membrane assay. Increased intravasation was prevented by tumour-associated trypsin inhibitor or specific gelatinase-inhibiting CTT-peptide. TAT-2 also converted MMP-1, -8, -13 and -3 into smaller molecular weight forms in vitro. However, TAT-2-transfected OSCC cells showed no conversion. TAT-2 was demonstrated to degrade powerfully type I collagen into small fragments in vitro. The cell surface receptor αvβ6 integrin is strongly up-regulated in OSCCs. By using β6-transfected OSCC cells, it was demonstrated that αvβ6 integrin down-regulates MMP-13 expression. However, this integrin did not regulate other collagenases or TIMP-1. β6-transfected cells invaded more efficiently through the basement membrane matrix, but their migration through type I collagen remained unchanged. MMP-8 expression was detected for the first time in head and neck squamous cell carcinoma (HNSCC) cell lines and corresponding cultured dermal and tumour fibroblasts. The localization of MMP-8 in HNSCC was determined by immunohistochemical stainings and in situ hybridization. MMP-8 production levels in carcinoma cells were faint and sporadic in HNSCCs sections. Ninety-two primary mobile tongue SCCs were subjected to MMP-8 immunohistochemical staining, and the staining results were compared to survival rates. MMP-8 was associated with improved disease-free survival in females but not in males.
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Smith, Eric A. B. S. "DEK is a Homologous Recombination DNA Repair Protein and Prognostic Marker for a Subset of Oropharyngeal Carcinomas". University of Cincinnati / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin150480040523791.
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Poi, Ming. "Low-barrier hydrogen bonding in bovine pancreatic Phospholipase A₂ and somatic INK4A-ARF locus mutations : a significant mechanism of gene inactivation in head and neck squamous cell carcinomas /". The Ohio State University, 2002. http://rave.ohiolink.edu/etdc/view?acc_num=osu1486402544589967.
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Souza, Caique Fernandes de. "Validação do envolvimento dos genes KRT6A, KRT19, MSLN e KLK8 por RT-PCR quantitativa em tempo real em carcinomas epidermóides de cabeça e pescoço". Universidade de São Paulo, 2010. http://www.teses.usp.br/teses/disponiveis/41/41131/tde-02022011-143444/.
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Os carcinomas de cabeça e pescoço (CECPs) compreendem um grupo de tumores que atingem vários sítios do trato aerodigestivo superior, incluindo cavidade oral, orofaringe, hipofaringe e laringe. Esses carcinomas são clinicamente heterogeneous e resultam de modificações cumulativas em genes que regulam proliferação, migração celular e apoptose. São estimados aproximadamente 500.000 novos casos de CECP anualmente no mundo. No Brasil, cerca de 14.000 novos casos são esperados em 2010, somente para cavidade oral. As taxas de morbidade e mortalidade e as limitações das estratégias terapêuticas enfatizam a necessidade de um melhor entendimento dos padrões moleculares envolvidos na iniciação e na progressão desses tumores, e de abordagens preventivas e terapêuticas efetivas. Infelizmente, apesar da intensa pesquisa nessa área, poucos marcadores moleculares são conhecidos que exibam sensibilidade e especificidade para diagnóstico e prognóstico de CECP. Em um estudo prévio, nós avaliamos dados de três bibliotecas SAGE de carcinoma de laringe com a finalidade de identificar eventos associados ao desenvolvimento e à agressividade de CECP. Utilizando abordagens estatísticas e de Bioinformática, nós identificamos 60 genes com expressão elevada ou reduzida em tumores metastáticos versus não-metastáticos e em ambos os grupos versus tecidos normais. O objetivo do presente estudo foi avaliar a expressão de quatro genes desta lista, os das queratinas 6A (KRT6A) e 19 (KRT19), da mesotelina (MSLN) e da calicreína 8 (KLK8), em um conjunto de 63 carcinomas primários de cabeça e pescoço e suas margens cirúrgicas e em quarto linhagens celulares (Hep-2, FaDu, SCC9 e UM-SSC-38) por RT-PCR em tempo real. Como amostra de referência para as linhagens, foram utilizados queratinócitos orais humanos normais, cultivados sobre uma camada de sustentação de fibroblastos irradiados. Todos os genes exibiram níveis de transcritos reduzidos ou ausentes nas linhagens celulares, exceto MSLN, que mostrou um padrão irregular de expressão. Em tumores primários, os genes KRT19 e MSLN apresentaram expressão diminuída em laringe, o mesmo sendo observado para o gene KLK8 em tumores de língua metastático. Além disso, foi detectada expressão elevada de MSLN e KLK8 em tumores não metastáticos de soalho de boca e expressão reduzida de KRT19 em tumores de soalho de boca e língua metastáticos. Os resultados levantam questões sobre o papel desses genes em processos biológicos associados com a tumorigênese de cabeça e pescoço e sobre sua participação no fenótipo neoplásico.Head and neck squamous cell carcinomas (HNSCCs) encompass a group of tumors that affect a variety of sites in the upper aero-digestive tract, including oral cavity, oropharynx, hypopharynx and larynx. These carcinomas are clinically heterogeneous and result from cumulative changes in genes that regulate cell proliferation, migration and death. It is estimated that approximately 500,000 new cases of HNSCC are diagnosed worldwide each year. In Brazil, about 14,000 new cases are expected in the year 2010, only in oral cavity. The morbidity and mortality rates and the limitations of therapeutic strategies emphasize the need for a better understanding of the molecular pathways involved in the initiation and progression of these tumors and for effective preventive and therapeutic approaches. Unfortunately, despite intense research, few molecular markers are known to exhibit sensitivity and specificity for the diagnosis or prognosis of HNSCC. In a previous study, we evaluated data from three SAGE libraries of larynx carcinoma in order to identify events associated with the development and aggressiveness of HNSCCs. Using statistical and bioinformatic tools, we identified sixty top-up and 60 top-downregulated genes in metastatic versus non-metastatic tumors and in both these tumors versus normal tissues. The objective of the present study was to evaluate the expression of four genes from this list, keratin 6A (KRT6A), keratin 19 (KRT19), mesothelin (MSLN) and kallikrein 8 (KLK8), in a set of 63 primary carcinomas of head and neck and their surgical margins and in four cell lines (Hep-2, FaDu, SCC9 and UM-SSC-38) by real time RT-PCR. As a reference sample for cell lines, we used normal human oral keratinocytes grown on irradiated fibroblast feeder layer. All genes exhibited no or decreased levels of transcripts in the cell lines, except MSLN, which displayed an irregular pattern of expression. In primary tumors, KRT19 and MSLN genes were downregulated in larynx, and KLK8 in metastatic tongue tumors. In addition, MSLN and KLK8 were upregulated in non-metastatic floor of the mouth tumors and KRT19 was down regulated in metastatic floor of the mouth and tongue tumors. The results open questions about the role of these genes on biological processes related to head and neck tumorigenesis and on neoplastic phenotype.
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Santos, Denise Takehana dos. "Mapeamento topográfico metabólico de carcinomas espinocelulares de cabeça e pescoço utilizando a fusão de imagens 18 F-FDG PET - TC". Universidade de São Paulo, 2005. http://www.teses.usp.br/teses/disponiveis/23/23139/tde-09082005-124541/.
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O objetivo desta pesquisa foi estabelecer uma metodologia para avaliar carcinomas espinocelulares (CEC) de cabeça e pescoço, identificando e distinguindo áreas de maior atividade metabólica dentro da neoplasia, associando dados simultaneamente adquiridos, obtidos por diferentes modalidades de aquisição de imagens, combinando informações metabólicas e anatômicas num único exame. A população estudada consistiu de 17 pacientes com carcinoma espinocelular (CEC) de cabeça e pescoço pertencentes aos arquivos do Departamento de Imagem do Hospital do Câncer, São Paulo. As imagens de TC (tomografia computadorizada) e do 18 F-FDG-PET (tomografia por emissão de pósitrons) foram simultaneamente adquiridas utilizando um aparelho não dedicado. Os dados originais foram transferidos para uma estação de trabalho independente com programa de computação gráfica para o processamento dos grupos individuais e fusão em um único grupo, contendo os dados fisiológicos e metabólicos. Os achados foram definidos como positivos na presença de focos com aumento da concentração do radiofármaco em áreas não relacionadas à distribuição normal do mesmo. Em 77% dos casos (n=13), a hipercaptação foi detectada ao centro da lesão e em 23% (n=4) dos casos houve comportamento diferente, com hipercaptação excêntrica. A fusão de imagens simultaneamente adquiridas num único exame ( 18 F- FDG PET e TC) possibilitou o mapeamento topográfico metabólico das lesões estudadas e foi possível localizar áreas de maior atividade metabólica dentro do próprio 13 tumor, verificando recidivas ou metástases, possibilitando aumentar as opções quanto ao planejamento radioterápico ou cirúrgico a serem seguidos.The aim of this study is to propose a methodological approach to evaluate head and neck squamous cell carcinoma (SCCA) in order to identify and to distinguish areas of higher metabolic activity inside the lesion combining the functional metabolic and morphological data simultaneously acquired in a non dedicated PET-CT device. The study population consisted of 17 patients, with SCCA of the head and neck carcinoma. These patients were submitted to a non-dedicated 18 F- FDG- PET imaging using a system with low dose CT and Positron emission coincidence acquisition capabilities. The image acquisition was then transferred to an ENTEGRA 2 NT workstation to generate groups of individual images (metabolic and anatomical data) and image fusion (CT + PET). In those patients with anomalous concentrations of 18 F-FDG, the lesion was depicted on three planes (axial, coronal and sagittal) in CT, PET, and the image fusion at the computer screen. The findings were defined as positive in the presence of well-defined focal area of increased uptake in regions unrelated to the normal biodistribution of the tracer on visual inspection. Two examiners interpreted the images in different sessions, in order to get an agreement. Subsequently, the sites of higher metabolic activity inside the tumor were identified and classified in centric or eccentric, according to their relative location. Observing the images, we found 77.00% of the patients with the site of higher activity at the center of lesion. In 23.00% of the patients a different 15 behavior, with the tracer increased eccentrically to the lesion. This technique gave a realistic view of the functional metabolism, locating the anatomical tumor area and helping in future treatment planning.
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Borba, Marcus Antônio de Mello. "Análise da expressão imunoistoquímica da proteína p63 e de seu valor prognóstico em carcinomas epidermóides da laringe". Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/5/5132/tde-12092008-142022/.
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INTRODUÇÃO: Alterações genéticas múltiplas são comuns durante a carcinogênese e, nesse panorama, o gene supressor tumoral TP53 é um dos mais associados à transformação maligna. Recentemente, dois genes similares ao TP53, foram identificados, o TP73 e o TP63. O TP63 situa-se no cromossomo 3q e tem papel comprovado no desenvolvimento epidérmico, sendo detectado em vários tecidos humanos. Inúmeros trabalhos relacionaram a expressão da proteína p63 com carcinomas do trato aerodigestivo superior. OBJETIVOS: O presente estudo objetivou avaliar a expressão Imunoistoquímica da proteína p63 e seu valor prognóstico nos carcinomas epidermóides da laringe. CASUÍSTICA E MÉTODOS: Foram estudados retrospectivamente 127 pacientes submetidos a laringectomia total no Instituto Nacional de Câncer, Rio de Janeiro, entre 1998 e 2000. Houve 111 doentes masculinos e 16 femininos, 69 brancos e 58 não-brancos, com idade entre 36 a 93 anos, média de 59 e mediana de 58 anos. Dezenove tumores eram glóticos, 16 supraglóticos e 92 acometiam mais de um local, correspondendo a 15%, 13% e 72% respectivamente. Quanto ao estadiamento clínico, dois casos eram do estádio I (1,6%), 21 do II (16,5%), 82 do III (64,6%) e 22 do IV (17,3%). Noventa e seis pacientes (75,6%) receberam radioterapia complementar. A técnica imunoistoquímica, com anticorpos monoclonais do clone 4A4, foi utilizada para estudar a expressão da p63. O percentual de células imunocoradas positivamente foi estimado conforme os seguintes escores: 0: ausência de imunocoloração; 1: imunocoloração em < 30% das células neoplásicas; 2: imunocoloração em > 30% e < 70% das células neoplásicas; e 3: imunocoloração em > 70% das células neoplásicas. Foram observados 62 casos do escore 3 (+++), 60 do escore 2 (++), 4 do 1 (+) e 1 caso sem expressão (0), correspondendo respectivamente a 48,8%, 47,2%, 3,1% e 0,8% da amostra. Através de análises uni e multivariadas, a imunoexpressão da proteína p63 e os outros fatores de provável impacto prognóstico foram avaliados quanto ao grau de associação aos eventos recidiva e óbito. RESULTADOS: A análise multivariada identificou a imunoexpressão da proteína p63 e o envolvimento da hipofaringe como preditivas para ocorrência de recidiva e óbito pelo carcinoma. A sobrevida global foi de 73,9% em 24 meses e de 59,5% em 60 meses. A sobrevida livre de recorrência foi de 77,2% e 75,1%, e a sobrevida relacionada ao óbito pelo carcinoma foi de 79% e 67% em 24 e 60 meses respectivamente. CONCLUSÕES: Apenas a recidiva associou-se estatisticamente à expressão da proteína p63. A p63 se mostrou altamente expressa nos carcinomas epidermóides de laringe e, apesar dos poucos casos com expressão reduzida, a hipoexpressão da p63 foi preditiva de um pior prognóstico nesses doentes.INTRODUCTION: Multiple genetic changes are common during carcinogenesis and, in this scene, the gene TP53 is one of the most associated with malignant transformation. Recently, two related genes to the TP53, were identified, the TP73 and TP63. The TP63 stands on the chromosome 3q and has a proven role in the epidermal development, being detected in several human tissues. Many work linked the expression of p63 protein with carcinomas of the upper aero-digestive tract. OBJECTIVE: The objective of this study was to evaluate the immunohistochemical expression of p63 protein and its prognostic value in squamous cell carcinomas of the larynx. CASUISTRY AND METHODS: The p63 expression has been examined in 127 patients who were submitted to total laryngectomy, with or without adjuvant radiotherapy, in the Brazilian National Cancer Institute, between 1998 and 2000. There were 111 male patients and 16 female, 69 white and 58 non-white, aged between 36 to 93 years, average 59 and median of 58 years. Nineteen tumors were glottic, 16 supraglottic and 92 affected more than one place, corresponding to 15%, 13% and 72% respectively. As to the clinical staging, two cases were stage I (1.6%), 21 of the II (16.5%), 82 of the III (64.6%) and 22 of the IV (17.3%). Ninety-six patients (75.6%) received complementary radiotherapy. The immunohistochemical technique with the use of monoclonal antibodies of clone 4A4, has been used to study the expression of p63. The percentage of positive cells was estimated as the following scores: 0: no immunostaining; 1: immunostaining in <30% of neoplastics cells; 2: immunostaining in >30% and <70% of neoplastics cells; And 3: immunostaining in >70% of neoplastics cells. Sixty two cases were observed in score three, 60 in score two 4 in score one (+) and 1 case without expression (0), corresponding respectively to 48.8%, 47.2%, 3.1% and 0.8% of the sample. Through uni and multivariate analysis, the immunoexpression of p63 protein and the other factors likely to impact prognosis were evaluated on the degree of association to recurrence and death. RESULTS: The multivariate analysis identified the immunoexpression of protein p63 and the involvement of the hypopharynx as statistically significant for the risk of recurrence and death by cancer. The overall survival was 73.9% in 24 months and 59.5% at 60 months. CONCLUSIONS: The disease-free survival was 77.2% and 75.1%, and the disease-specific survival was 79% and 67% at 24 and 60 months respectively. The p63 protein was highly expressed in squamous cell laryngeal carcinomas. In spite of few cases with reduced expression, p63 protein underexpression was statistically associated to the recurrence and may have a negative impact upon prognosis.
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Campofiorito, Cristina Maria Meireles. "Correlação dos ligantes de quimiocinas e de seus respectivos receptores em relação à invasão de linfonodos nos carcinomas epidermóides em cabeça e pescoço". Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/5/5155/tde-27042007-135738/.
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Tanto a invasão local como o comprometimento de linfonodos cervicais tem grande impacto na sobrevida de pacientes portadores de carcinomas epidermóides de cabeça e pescoço. Em nosso trabalho nós primeiramente determinamos a expressão dos receptores de quimiocinas de CXCR1 a CXCR5, além de CCR7 e CX3CR1 pelo método do ensaio de proteção à ribonuclease (RPA) em 98 fragmentos de tumores primários, 91 fragmentos de mucosas adjacentes e 26 linfonodos comprometidos e correlacionamos estes dados com parâmetros anátomo-patológicos e sobrevida. CXCL12 ligante do receptor CXCR4 e CCL19 e CCL21 ambos ligantes de CCR7 foram determinados em 38 fragmentos de tumores, 33 mucosas adjacentes e 25 linfonodos comprometidos pela técnica de real-time PCR. Os tumores primários apresentam expressão aumentada do mRNA de CXCR1 (P=0.013), CXCR3 (P=0.008) e CXCR4 (P=0.025). Não observamos correlações entre status linfonodal ou tamanho de tumor. Os linfonodos comprometidos expressam mais mRNA dos receptores de quimiocinas CXCR4, CXCR5, CCR7 e CX3CR1 (todos com P<0.0001) em comparação aos tumores comprometidos. Observamos um aumento de sobrevida (P=0.048) e uma tendência a aumento de sobrevida livre de doença (P=0.074) nos pacientes negativos para a expressão de CX3CR1 (n=17) em comparação aos pacientes positivos (n=21) somente no subgrupo de pacientes portadores de carcinomas da cavidade oral. O mesmo foi observado com os pacientes CCR7 negativos também no subgrupo de pacientes portadores de carcinomas da cavidade oral, tanto em sobrevida global (P=0.024) como para sobrevida livre de doença (P=0.049). Em relação aos ligantes de quimiocinas observamos um aumento do mRNA de CCL21 em linfonodos comprometidos em relação aos tumores primários (P=0.059). Concluímos que a interação quimiotática entre CCR7 e de seu ligante CCL21, poderia ser um mecanismo de atração de células tumorais para os linfonodos em tumores de cavidade oral, além disso a negatividade da expressão do mRNA de CCR7 e CX3CR1 são candidatos marcadores de uma melhor sobrevida em carcinomas epidermóides de cavidade oral.Local invasion and lymph nodal spread impact in the outcome of Head and Neck squamous cell carcinoma (HNSCC) patients (pts). We determined CXCR1-5, CCR7 and CX3CR1 mRNA expression by means of RNAse protection assay in 98 HNSCC primary tumors and 91 adjacent mucosa and 26 metastatic lymph nodes, correlating this data with outcome. CXCL12 and CCL19/CCL21, ligands for CXCR4 and CCR7, were determined in 38 tumor fragments, 33 adjacent mucosas and 25 de metastatic lymph nodes, by means of Quantitative Real-Time PCR. Tumors presented higher CXCR1 (P=0.013), CXCR3 (P=0.008) and CXCR4 mRNA (P=0.025) expression as compared to mucosa. No correlations are observed neither lymph nodal status nor tumor size impacted on chemokine receptor expression. Metastatic lymph nodes expressed more CXCR4, CXCR5, CCR7 and CX3CR1 (P<0.0001) as compared to matched tumors. We found a longer overall survival (OS) (P=0.048) and a trend toward longer disease free survival (DFS) (P=0.074) in CX3CR1 negative (n=17) as compared to positive pts (n=21) only in oral subgroup. The same occurred for CCR7 negative oral SCC, in terms of OS (P=0.024) and DFS (P=0.049). We conclude that, of the chemokine receptors here studied, CCR7 and CX3CR1 mRNA expression seems to better reflect outcome in oral subsite only. In addition, CCL21, a CCR7 ligand mRNAs is more expressed in metastatic lymph nodes than tumors (P=0.059). Further studies are warranted to confirm these results.
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Valero, Mayor Cristina. "Capacidad pronóstica de los parámetros hematológicos en sangre periférica pre-tratamiento en los carcinomas escamosos de cabeza y cuello". Doctoral thesis, Universitat Autònoma de Barcelona, 2018. http://hdl.handle.net/10803/662610.
Texto completo da fonteResumo:
Introducción. Múltiples estudios vinculan la carcinogénesis y la inflamación en ambas direcciones. Por un lado, la inflamación crónica promueve el desarrollo de tumores, y por otro lado, la mayoría de los tumores muestran un infiltrado de células relacionadas con la respuesta inflamatoria que estimula la progresión tumoral. Además, el fracaso del sistema inmune en controlar y erradicar las células tumorales podría ser en parte responsable de la progresión tumoral. El grado de inflamación sistémica se correlaciona con el resultado oncológico en algunos modelos tumorales. Estudios realizados en diferentes tumores sólidos han asociado una disminución en el control de la enfermedad y la supervivencia con el aumento de los recuentos circulantes de neutrófilos y monocitos, la disminución de linfocitos, y una elevación del ratio entre neutrófilos y linfocitos (NLR). Objetivos. El objetivo del presente estudio es valorar la capacidad pronóstica de los recuentos de neutrófilos, monocitos, linfocitos y del NLR en sangre periférica pre-tratamiento en una gran serie de pacientes con carcinomas escamosos de cabeza y cuello (CECC) tratados consecutivamente en una sola institución. Además, se analizó por separado la cohorte de pacientes con tumores orofaríngeos según el estatus del Virus del Papiloma Humano (HPV). Material y Métodos. Los datos clínicos utilizados en este estudio se obtuvieron de forma retrospectiva de una base de datos que recoge prospectivamente datos epidemiológicos, de tratamiento y de seguimiento de los pacientes con CECC tratados en nuestra institución desde 1985. Se incluyeron 824 pacientes con un resultado anatomopatológico de carcinoma escamoso de cavidad oral, orofaringe, laringe o hipofaringe diagnosticado en nuestro centro entre enero de 2000 y diciembre de 2012 con un seguimiento mínimo de 2 años. Sólo incluimos los pacientes para los que obtuvimos los parámetros hematológicos dentro de las 4 semanas previas al inicio del tratamiento. Se analizó la supervivencia específica y la supervivencia libre de recidiva local, regional y a distancia de acuerdo con el recuento de neutrófilos, monocitos, linfocitos y el NLR. Resultados. Observamos una disminución ordenada en la supervivencia específica según aumentaba la categoría cuartil de neutrófilos, monocitos y NLR. En el caso de los linfocitos, sólo los pacientes en el cuartil inferior presentaron una supervivencia específica menor. Tras realizar un análisis de partición recursiva (RPA) considerando la supervivencia específica como variable dependiente, se obtuvieron cuatro nodos terminales en función de las cifras de neutrófilos y monocitos. La supervivencia específica a los 5 años para los pacientes del primer nodo (Neutrófilos <4.80x109/L – Monocitos <0.52x109/L) fue del 83.9%, para los pacientes del segundo nodo (Neutrófilos <4.80x109/L – Monocitos >0.52x109/L) fue del 73.1%, para los pacientes del tercer nodo (Neutrófilos entre 4.80-7.99x109/L) fue del 61.4%, y para los pacientes del cuarto nodo (Neutrófilos >7.99x109/L) fue del 47.4%. Al analizar los pacientes con tumores de orofaringe según el estatus HPV, los pacientes con tumores HPV positivos contaron con niveles de neutrófilos y monocitos y con un NLR significativamente inferiores a los correspondientes a los pacientes con tumores HPV negativos. No se encontraron diferencias en cuanto al recuento de linfocitos. Conclusiones. Un recuento elevado de neutrófilos y de monocitos y un NLR elevado, analizados pre-tratamiento en sangre periférica, se relacionaron con un peor pronóstico en pacientes con CECC de forma independiente, tanto al analizar la supervivencia específica como al analizar la supervivencia libre de recidiva local, regional y a distancia. Los linfocitos no mostraron capacidad pronóstica. Consideramos que la capacidad pronóstica del NLR, dependió básicamente del recuento de neutrófilos. La clasificación de los pacientes según el recuento de neutrófilos y de monocitos podría ser considerada un biomarcador útil de supervivencia en pacientes con CECC.Background. Multiple studies link carcinogenesis and inflammation in both ways. On one hand, chronic inflammation promotes tumor development, and on the other hand, most tumors show an infiltrate of cells related to the inflammatory response that stimulate tumor progression. Moreover, the failure of the immune system to control and eradicate tumor cells could be partly responsible for the tumor progression. The degree of systemic inflammation correlates with the oncologic outcome in some tumor models. Studies carried out in different solid tumors have associated a decrease in disease control and survival with the increase of the circulating counts of neutrophils and monocytes, the decrease of lymphocytes, and an elevated ratio between neutrophils and lymphocytes (NLR). Objectives. The objective of the present study is to assess the prognostic capacity of the pre-treatment count of neutrophils, monocytes, lymphocytes and NLR in peripheral blood in a large series of patients with squamous cell carcinomas of the head and neck (HNSCC) treated consecutively in a single institution. In addition, the cohort of patients with oropharyngeal tumors was analyzed separately according to the status of the Human Papillomavirus (HPV). Materials and Methods. The clinical data used in this study were obtained retrospectively from a database that prospectively collects epidemiological, treatment and follow-up data of patients with HNSCC treated in our institution from 1985. We included 824 patients with an anatomopathological result of squamous cell carcinoma of the oral cavity, oropharynx, larynx or hypopharynx diagnosed in our center between January 2000 and December 2012 with a minimum follow-up of 2 years. We only included patients for whom we obtained the hematological parameters within 4 weeks prior to the start of treatment. The disease-specific survival and the local, regional and distant disease-free survival were analyzed according to the count of neutrophils, monocytes, lymphocytes and NLR. Results. We observed an ordered decrease in disease-specific survival as the quartile category of neutrophils, monocytes, and NLR increased. In the case of lymphocytes, only patients in the lowest quartile showed a poorer disease-specific survival. Considering the disease-specific survival as the dependent variable, a recursive partitioning analysis (RPA) classified the patients according to the neutrophil and monocyte counts. The 5-year disease-specific survival for the first node (Neutrophils <4.80x109/L - Monocytes <0.52x109/L) was 83.9%, for the second node (Neutrophils <4.80x109/L – Monocytes >0.52x109/L) it was 73.1%, for the third node (Neutrophils between 4.80-7.99x109/L) it was 61.4%, and for the fourth node (Neutrophils >7.99x109/L) it was 47.4%. When analyzing patients with oropharyngeal tumors according to HPV status, patients with HPV positive tumors had significantly lower neutrophil and monocyte counts and NLR than patients with HPV negative tumors. No differences in lymphocyte counts were found. Conclusions. A high pre-treatment count of neutrophils and monocytes and an elevated NLR, analyzed in peripheral blood, were independently associated with a worse prognosis in patients with HNSCC when analyzing the disease-specific survival and the local, regional and distant disease-free survival. The lymphocytes did not show prognostic capacity. We considered that the prognostic capacity of the NLR, basically depended on the neutrophil count. A classification of the patients according to neutrophil and monocyte counts could be considered a useful biomarker of survival in patients with HNSCC.
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Giudice, Fernanda Salgueiredo. "O envolvimento da remodelação da cromatina no controle do comportamento agressivo dos carcinomas epidermoides de cabeça e pescoço". Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/23/23141/tde-13042013-103307/.
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Modificações nas histonas são conhecidas por regular a estrutura conformacional da cromatina e a expressão gênica em células adultas e células-tronco pluripotentes. Tem sido postulado que a acetilação e deacetilação das histonas podem influenciar a expressão de genes envolvidos na iniciação, progressão e metástase tumoral, além de contribuir para o desenvolvimento de resistência à quimioterapia. Assim, buscou-se avaliar a influência das modificações nas histonas sobre a biologia do carcinoma epidermoide de cabeça e pescoço (CECP) e sua respectiva subpopulação de células semelhantes às células-tronco (CSC). Inicialmente, foi checado os níveis de acetilação da histona H3 (membro das histonas nucleares associado à compactação da cromatina) em um painel representativo de linhagens celulares de CECP. Posteriormente, para estudar a influência do estroma tumoral no padrão de acetilação da histona H3, o microambiente do tumor foi mimetizado através da utilização de meio condicionado derivado do cultivo de fibroblastos e cultura primária de células endoteliais humanas. Além disso, validamos esses resultados in vitro por meio de amostras humanas de CECP. Finalmente, a acetilação e deacetilação da cromatina foi induzida, respectivamente, pela administração dos inibidores das enzimas histona deacetilase tricostatina A (TSA) e histona acetiltransferase curcumina, em linhagens celulares de CECP. Foi feita a análise da formação de esferas (ensaio funcional de células-tronco), juntamente com a verificação dos níveis de ALDH, marcador de células-tronco (citometria de fluxo - FACS), além da determinação do índice de proliferação tumoral (Ki-67) e realização dos ensaios de invasão e migração celular. Linhagens celulares de CECP apresentaram níveis baixos de acetilação da histona H3 e demonstraram capacidade de retenção de uma subpopulação de CSC. Apenas o meio condicionado de células endoteliais humanas foi capaz de alterar a conformação da cromatina, uma vez que induziu o aumento da acetilação da histona H3. Interessantemente, foi também notado um concomitante aumento da agressividade de linhagens celulares de CECP (aumento dos níveis de BMI-1 e vimentina). Esses resultados foram confirmados em amostras humanas de CECP que mostraram, apenas no fronte de invasão, células com cromatina acetilada. Curiosamente, essas mesmas células também expressaram vimentina. Os tratamentos com TSA e curcumina resultaram na diminuição significativa da subpopulação de CSC, interrompendo a formação de esferas e reduzindo os níveis de ALDH. Além disso, o tratamento com curcumina mostrou resultados muito interessantes, uma vez que gerou uma redução evidente da invasão celular e impactou por completo o potencial de migração tumoral, sendo nesse sentido mais eficiente que a cisplatina, droga antineoplásica bem estabelecida. Por outro lado, o tratamento com TSA induziu a transição epitélio-mesenquimal nas linhagens celulares de CECP, detectada pelo aumento da expressão de vimentina e indução de um fenótipo fusiforme, juntamente com o aumento da invasão tumoral e os níveis de BMI-1. Portanto, a organização da cromatina está envolvida na modulação da presença de CSC e os altos níveis de acetilação das histonas intensificam o comportamento agressivo de células de CECP.Histone modifications are known to regulate chromatin conformation structure and gene expression in adult cells and pluripotent stem cells. It has been postulated that histone acetylation and deacetylation could influence the expression of genes involved in cancer initiation, progression, metastasis, and development of resistance to chemotherapies. Here, we sought to evaluate the influence of histone modifications over the biology of head and neck squamous cell carcinoma (HNSCC) and its stem cell-like subpopulation (CSC). Initially, we checked the status of histone H3 acetylation (a member of the core histones associated to chromatin compaction) in a representative set of HNSCC cell lines. Subsequently, to analyze the influence of tumor stroma over the histone H3 acetylation, we mimicked the tumor microenvironment by using conditioned medium from fibroblasts and primary human endothelial cells. Further we validated these in vitro findings through human samples of HNSCC. Finally, we induced chromatin acetylation and deacetylation by the administration of the histone deacetylase inhibitor trichostatin A (TSA) and histone acetyltransferase inhibitor curcumin, respectively, in HNSCC cell lines. The analysis of spheres formation (stem cell functional assay), along with the levels of stem cells marker ALDH (showed by flow cytometry - FACS), tumor proliferation index (Ki-67), invasion and migration cellular potencial were verified. HNSCC cell lines showed lower levels of histone H3 acetylation and ability to retain a subpopulation of CSC. Only conditioned media from human endothelial cells was able to alter the conformation of chromatin, since it induced the increase of histone H3 acetylation. Interestingly, it was also noted a concomitant augment of HNSCC cell lines aggressiveness (enhanced BMI-1 and vimentin levels). These findings were confirmed in human samples of HNSCC that showed, only at the invasive front, cells with acetylated chromatin. Curiously, these same cells also expressed vimentin. TSA and curcumin treatments resulted in significant decrease of the CSC subpopulation by disrupting the spheres and reducing the levels of ALDH. Also, curcumin treatment showed exciting results since it caused an evident reduction of cellular invasion and it impacted the tumoral migration potential, being more efficient than cisplantin, a well-established antineoplastic drug. However, TSA induced epithelial to mesenchymal transition in HNSCC cell lines detected by the upregulation of vimentin and the induction of a fusiform phenotype along with augmented tumor invasion and the levels of BMI-1. Chromatin organization is involved in the modulation of CSC where high levels of histone acetylation intensify the aggressive behavior of HNSCC cells.
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Lailler, Claire. "Biomarqueurs du microenvironnement tumoral pour la stratification thérapeutique des cancers tête et cou". Thesis, Amiens, 2021. https://tel.archives-ouvertes.fr/tel-03881131.
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Les Cancers Epidermoïdes de la Tête et du Cou (CETC) représentent les septièmes tumeurs les plus fréquentes au niveau mondial en 2020. Si les perspectives thérapeutiques ont évolué favorablement ces dix dernières années, la recherche de biomarqueurs utiles pour la stratification thérapeutique reste un enjeu de taille pour ces tumeurs. En outre, l'induction d'une immunité adaptative antitumorale apparait comme un mécanisme de plus en plus important pour l'efficacité des thérapeutiques approuvées dans les CETC. Dans cette perspective, l'étude des interactions entre cellules tumorales et cellules immunitaires du microenvironnement tumoral (MT) est incontournable. Plusieurs thérapies anticancéreuses ont été rapportées pour induire la mort des cellules tumorales par ferroptose, une nécrose régulée dépendante du fer survenant lors d'un stress oxydant non résolu par la cellule. Nous nous sommes intéressés dans la première partie de nos travaux à la possibilité d'exploiter la ferroptose dans les CETC positifs au Papillomavirus Humain (CETC HPV+ve), les CETC HPV+ve montrant habituellement un état de stress oxydant supérieur aux CETC négatifs pour l'HPV (CETC HPV-ve). Nous avons mis en évidence une expression faible de SLC7A11, transporteur essentiel de la cellule pour la synthèse du glutathion inhibiteur du stress oxydant, dans les CETC HPV+ve par rapport aux CETC HPV-ve in silico. In vitro, nous avons mis en évidence une vulnérabilité supérieure à la ferroptose induite par l'érastine dans les lignées de CETC exprimant les protéines transformantes E6/E7 de l’HPV par rapport à leurs lignées parentales. Dans la deuxième partie de nos travaux, nous avons étudié la régulation de l'expression du ligand PD-L1 (Programmed Death-Ligand 1) par différentes thérapies approuvées dans les CETC. L'expression de PD-L1 par les cellules tumorales et inflammatoires du MT est en effet responsable en partie de l'inactivation fréquente des cellules T cytotoxiques du MT, et représente donc un obstacle pour l'induction de l'immunité adaptative antitumorale. Nous avons mis en évidence une régulation spécifique de PD-L1 par le 5-fluorouracile (5-FU) dépendante de la réponse aux dommages de l'ADN ainsi que de la voie JAK / STATHead and Neck Squamous Cell Carcinomas (HNSCC) were the seventh most frequent tumors worldwide in 2020. Although therapeutic perspectives have evolved favorably over the last ten years, the search for useful biomarkers for therapeutic stratification remains a major challenge for these tumors. In addition, the induction of antitumor adaptive immunity seems to be an increasingly important mechanism for the efficacy of approved therapies in HNSCC. In this perspective, the study of the interactions between tumor cells and immune cells of the tumor microenvironment (TM) is essential. Several anticancer therapies have been reported for the induction of tumor cell death by ferroptosis, an iron-dependent regulated necrosis that occurs during unresolved oxidative stress in the cell. In the first part of our work we focused on the possibility of exploiting ferroptosis in Human Papillomavirus positive HNSCC (HPV+ve HNSCC), which usually show higher oxidative stress than HPV negative HNSCC (HPV-ve HNSCC). Using in silico analyses, we observed low expression of SLC7A11, an essential transporter in the cell for the synthesis of glutathione, an inhibitor of oxidative stress, in HPV+ve HNSCC compared to HPV-ve HNSCC. In vitro, HNSCC cell lines expressing HPV E6/E7 transforming proteins showed higher sensitivity to erastin-induced ferroptosis compared to their parental cell lines. In the second part of our work, we studied the regulation of PD-L1 (Programmed Death-Ligand 1) expression by different approved therapies in HNSCC. The expression of PD-L1 by tumor and inflammatory cells of the TM is indeed partly responsible for the frequent inactivation of cytotoxic T cells of the TM, and thus represents an obstacle for the induction of antitumor adaptive immunity. We observed a specific regulation of PD-L1 by 5-fluorouracil (5-FU) that was dependent on the DNA damage response and the JAK / STAT pathway
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Lima, Fanny Dantas de. "Fase 1 do estudo da aplicação da vacina de DNA HSP 65 (Heat Shock Protein) do Mycobacterium leprae no tratamento de formas avançadas de carcinomas epidermóide de cabeça e pescoço". Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/5/5146/tde-04062007-095208/.
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O objetivo deste estudo foi descrever e mapear a toxicidade local e sistêmica da aplicação da vacina de DNA HSP 65 do Mycobacterium leprae em pacientes com formas avançadas de carcinoma epidermóide de cabeça e pescoço e definir qual a dose máxima tolerada. Trata-se de um estudo prospectivo, randomizado, aberto, sem grupo controle, de fase 1, com utilização de uma nova vacina para o tratamento de dezoito pacientes com carcinoma epidermóide avançado de cabeça e pescoço, sem opção terapêutica curativa, índice de Karnofsky maior que 70%, sem outra doença sistêmica grave. Propôs-se 3 grupos de 6 indivíduos, cada grupo recebendo diferente dose da vacina, respectivamente 150ug; 600ug e 1200ug por dose. A administração desta foi feita em 3 injeções com intervalo de 21 dias. Durante 90 dias os pacientes eram rigorosamente avaliados clinico e laboratorialmente quanto à ocorrência de eventos adversos (EA). A pesquisa de EA foi baseada no Common Terminology Criteria for Adverse Events (CTCAE) elaborado pelo National Cancer Institute (NCI). No primeiro grupo (150ug) um paciente morreu por sangramento abundante de úlcera tumoral antes do fim do protocolo. Todos os pacientes referiram aumento da dor; três tiveram maior edema e dois piora da astenia; três tiveram infecções de pele e/ou tecido subcutâneo da cabeça e pescoço e um infecção do trato respiratório superior. No 2º grupo (600ug) três pacientes faleceram antes dos 90 dias de protocolo por causas não relacionadas ao tratamento, descritas a seguir: complicações de gastrostomia, rápida progressão tumoral e hemorragia fatal e carcinomatose pulmonar. Neste grupo um paciente não teve EA; cinco tiveram piora da dor; quatro aumento do edema; dois maior astenia; três celulite de face e dois apresentaram sinusite aguda. Como neste grupo observou-se toxicidade classificada como relacionada ao tratamento graus 3 e 4 em mais de um terço dos pacientes decidiu-se escalonar para baixo a dose no 3º grupo para 400ug. No último grupo três pacientes morreram por progressão tumoral rápida, sem completar o protocolo, então incluiu-se três novos indivíduos. Todos tiveram maior dor; três aumento do edema; três piora da astenia; um caso de erisipela; três com infecção pulmonar e um com sinusite aguda; um paciente apresentou linfonodomegalia peri-tumoral após receber a vacina. Concluiu-se que a administração desta vacina neste grupo de pacientes é segura na dose de 400ug e tem como principal toxicidade aumento dos sinais inflamatórios na lesão tumoral e maior ocorrência de infecções locais e respiratórias.This study goal was to describe and graduate the local and systemic toxicity of intratumoral injections of HSP (Heat Shock Protein) 65 DNA vaccine in advanced-stage head and neck squamous cell carcinoma (SCCHN) patients and to define the highest well tolerated dose for them. This is a prospective, non-randomized, uncontrolled, phase 1 study, using a new vaccine to treat eighteen patients with advanced-stage SCCHN patients without any option for curative treatment, Karnofsky performance status greater than 70% and no organ failure. The patients were divided into 3 groups of 6 patients each one, receiving different vaccine doses, 150ug; 600ug e 1200ug per dose, respectively. They received three injections with a 21 days interval. The patients were rigorously evaluated into their clinical and laboratory aspects looking for adverse events (AE) during 90 days. Toxic effects were monitored according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). In the first group (150ug) one patient died due to an ulcerate lesion extensive bleeding before the protocol end. All the patients referred pain increase; tree had greater edema; two had strong fatigue; tree presented with cutaneous infections of head and neck and one with an acute sinusitis. In the second group (600ug) three patients died before the 90th day protocol, all considered unrelated to treatment, following described: gastrostomy complications, a fatal bleeding after rapid progression of the tumor and pulmonary carcinomatosis. In this group one patient didn\'t have adverse events; five had pain worsening; four had increase of edema; two had greater fatigue; tree had facial cellulitis and two had acute sinusitis. Due to grade 3 and 4 adverse events occurred in more than one third of patients of this group we decided to lower the dose of the third group to 400ug. In the last group three patients also died before protocol completion, all due to cancer progression, so we had to include three more patients in this group. All of them presented greater pain; tree had increasing of edema; tree had fatigue worsening; tree had pulmonary infections; one had acute sinusitis and lymphoadenomegalia besides the tumor lesion. We concluded that intratumoral injections of M.leprae HSP 65 DNA in advanced-stage SCCHN patients is safe at the dose of 400ug/injection and cause tumor flare adverse events and an increase rate of local and respiratory infections.
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Diez, Tejerina Santiago. "La expresión del eje CXCL 12/CXCR4 como predictor de la respuesta a nivel regional en pacientes con carcinomas escamosos de cabeza y cuello". Doctoral thesis, Universitat Autònoma de Barcelona, 2016. http://hdl.handle.net/10803/378021.
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Finalidad:
El eje CXCL12/CXCR4 es un sistema de quimioquinas (ligando) y su receptor, que funcionan normalmente y son necesarios para la homeostasis de diversos sistemas de nuestro cuerpo. Se sospecha que algunos carcinomas de cabeza y cuello utilizan este eje para diseminarse hacia ganglios regionales del tumor primario. Existen pocos trabajos que sustancien esta vía como posible marcador que prediga la aparición de recidivas ganglionares. Estudiamos la capacidad pronóstica del eje CXCL12/CXCR4 sobre la posible recidiva ganglionar en pacientes tratados de CECC.
Diseño experimental y resultados:
Se analizaron muestras tumorales y sanas de 111 pacientes afectos de CECC (cavidad oral, orofaringe, laringe e hipofaringe) tratados con intención radical con seguimiento mínimo de 3 años. Se valoró la aparición de recidiva ganglionar, la supervivencia libre de recidiva regional, local y a distancia, y la supervivencia ajustada en función de la expresión del eje CXCL12/CXCR4 y la expresión de otras vías inflamatorias relacionadas con la respuesta al tratamiento y la capacidad de diseminación conocidas (COX, NFκB, IL-1, CD-45, MPO, MPC-1,MMP- 2 y 9, Hsp-90 y SOD).
Pudimos comprobar que la expresión de CXCL12 fue menor y las de CXCR4 mayor en el tumor que en la mucosa sana. Los pacientes fueron distribuidos, a través de un método de análisis de partición recursiva, en grupos según la expresión de CXCL12 y CXCR4. Los pacientes con expresión baja de CXCR4 y, alta de CXCR4 y alta de CXCL12, tuvieron un riesgo bajo de recidiva tumoral a nivel ganglionar, 2.6% y 4.5% respectivamente. El grupo de pacientes formado por una alta expresión de CXCR4 y baja de CXCL12 contaron con un riesgo alto de recidiva regional, un 34.0%. El análisis multivariante calculó un riesgo 10.7 veces mayor de aparición de recidiva regional en éstos pacientes respecto a los del grupo anterior. Todo ello independientemente de la categoría de extensión inicial del tumor a nivel regional, del tipo de tratamiento realizado sobre las áreas ganglionares o del control local de la enfermedad. Adicionalmente se demostró una correlación significativa entre la expresión transcripcional de CXCL12 y de CXCR4 con PGIS (PGI2), SOD-2 y COX-2, PGIS, VEFG y MMP-2 respectivamente.
Conclusiones:
La expresión de CXCL12 fue inferior y las de CXCR4 superior de forma significativa en las muestras de tumor que la correspondiente a las muestras de mucosa sana. Los niveles de expresión de CXCL12/CXCR4 no difirieron en función de la localización del tumor ni del estatus del HPV.
La expresión baja de CXCL12 y elevada de CXCR4 en pacientes con CECC demuestra un claro aumento en el riesgo a padecer una recidiva ganglionar durante la evolución del tratamiento de estos pacientes, disminuyendo la supervivencia de forma significativa con respecto a los pacientes con expresión CXCL12 y CXCR4 alta o con expresión CXCR4 baja.
Existe una correlación entre CXCL12/CXCR4 y la expresión de diversos genes relacionados con la respuesta al tratamiento y la capacidad de diseminación de los CECC como PGIS, COX-2 , VEFG y MMP-2.Purpose: The CXCL12 / CXCR4 axis is a chemokine system (ligand) and its receptor, which function normally and are necessary for the homeostasis of various body systems. It is suspected that some head and neck carcinomas using this axis to spread to regional lymph from the primary tumor. Few studies have substantiated this pathway as a possible marker to predict the occurrence of lymph node recurrences. We studied the prognostic axis CXCL12 / CXCR4 on possible nodal recurrence in patients treated for HNSCC. Experimental design and results: Healthy and tumor samples from 111 patients with HNSCC (oral cavity, oropharynx, larynx and hypopharynx) and treated with radical intent with minimum follow-up of 3 years were analyzed. The appearance of lymph node recurrence, regional recurrence free survival, local or remote and survival adjusted depending on the expression of CXCL12/CXCR4 axis expression and other inflammatory pathways associated with response to treatment and was rated capacity known spread (COX, NFkB, IL-1, CD-45, MPO, MPC-1, MMP-2 and 9, Hsp-90 and SOD). We found that the expression of CXCL12 was lower and CXCR4 higher in the tumor than in healthy mucosa. Patients were distributed through an analysis method of recursive partitioning, in groups according to the expression of CXCL12 and CXCR4. Patients with low expression of CXCR4 and high CXCR4 and CXCL12 high, had a low risk of tumor recurrence at nodal level, 2.6% and 4.5% respectively. The patient group consisting of high expression of CXCR4 CXCL12 and counted down with a high risk of local relapse, 34.0%. Multivariate analysis calculated a 10.7 times greater risk of regional recurrence in these patients compared to the previous group. All this regardless of the category of initial tumor extension at regional level, the type of treatment performed on nodal areas or local control of the disease. Additionally, a significant correlation between the transcriptional expression of CXCL12 and CXCR4 with PGIS (PGI2), SOD-2 and COX-2, PGIS, VEGF and MMP-2 respectively is shown. Conclusions: CXCL12 expression was significantly lower and upper CXCR4 in tumor samples corresponding to samples of healthy mucosa. Expression levels of CXCL12/CXCR4 not differ depending on the location of the tumor nor HPV status. The low expression of CXCL12 and CXCR4 elevated in patients with HNSCC shows a clear increase in the risk of suffering a relapse during evolution nodal treatment of these patients, decreasing significantly with survival compared to patients with high expression of CXCL12 and high CXCR4 or CXCR4 expression low. There is a correlation between CXCL12/CXCR4 and the expression of various genes related to response to treatment and the ability to spread the HNSCC as PGIS, COX-2, VEGF and MMP-2.
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Thibaudeau, Chloé. "Thérapie photodynamique pour le traitement des carcinomes épidermoïdes de la tête et du cou : étude des mécanismes moléculaires de photosensibilisants à base de ruthénium". Electronic Thesis or Diss., Strasbourg, 2024. http://www.theses.fr/2024STRAJ035.
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Les carcinomes épidermoïdes de la tête et du cou (CETEC) sont des cancers fréquents et de mauvais pronostic avec une survie globale à 5 ans inférieure à 50%. La thérapie photodynamique (PDT) est une alternative thérapeutique consistant en l’injection systémique d’un photosensibilisant (PS) dont la toxicité est localement activée par illumination de la tumeur. A travers l’étude de deux PS à base de ruthénium (Ru1 et Ru2), nous avons mis en évidence l’efficacité anti-tumorale in vitro de ces deux PS dans des lignées de CETEC, avec des IC50 < 1µM après activation à la lumière. Nos résultats montrent que Ru1 et Ru2 sont deux capables d’induire in vitro des marqueurs de l’autophagie, de la ferroptose et de la mort cellulaire immunogène. Cependant, alors que Ru1 semble induire une apoptose tolérogène, caspase-7 dépendante et corrélée avec l’induction d’un stress du réticulum endoplasmique, Ru2 ne semble pas ou peu induire ces mécanismes mais induit une immunogénicité in vivo. L’ensemble de nos résultats mettent en avant la complexité des mécanismes impliqués dans la phototoxicité de ces PS et la nécessité d’analyses plus approfondies avant leur transfert en cliniqueHead and neck squamous cell carcinomas (HNSCC) are frequent cancers with a poor prognosis, and a 5-year overall survival below 50%. Photodynamic therapy (PDT) is a therapeutic alternative involving the systemic injection of a photosensitizer (PS) whose toxicity is locally activated by tumor illumination. Through the study of two ruthenium-based PS (Ru1 and Ru2), we have demonstrated the in vitro anti-tumor efficacy of these two PS in HNSCC cell lines, with IC50 < 1µM after light activation. Our results show that Ru1 and Ru2 are both capable of inducing markers of autophagy, ferroptosis and immunogenic cell death in vitro. However, whereas Ru1 appears to induce a tolerogenic, caspase-7-dependent apoptosis correlated with the induction of endoplasmic reticulum stress, Ru2 appears to induce little or none of these mechanisms but induces immunogenicity in vivo. Taken together, our results highlight the complexity of the mechanisms involved in the phototoxicity of these PS and the need for further analysis before their transfer to the clinic