Tesi sul tema "Cutaneous carcinoma"
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1
Lambert, Sally Ruth. "Molecular profiling of cutaneous squamous cell carcinoma". Thesis, Queen Mary, University of London, 2010. http://qmro.qmul.ac.uk/xmlui/handle/123456789/564.
Abstract (sommario):
Cutaneous squamous cell carcinoma (cSCC) is the second most common form of non-melanoma skin cancer and accounts for the majority of deaths from this disease. Its incidence is increasing rapidly, contributing significant morbidity to patients and a burden on healthcare resources. The molecular events underlying cSCC development remain largely uncharacterised, despite the well established role of ultraviolet radiation as a principal carcinogen. Genomewide analyses of the genetic changes underlying cSCC development have shown they are subject to large chromosomal aberrations, which often involve whole chromosome arms. Many of these events occur in a high proportion of tumours, yet the genes they target are unknown. In this study, genomewide expression microarray data has been obtained from a series of cSCC and integrated with single nucleotide polymorphism (SNP) microarray data, to provide a comprehensive analysis of the events associated with tumour development. In total, 222 genes were identified as differentially expressed in cSCC, of which, 21% were concordant with copy number changes. Previous genomewide SNP data of cSCC had identified microdeletions within the PTPRD gene in a subset of tumours (Purdie et al., 2009). This was investigated in further detail and revealed microdeletions in this gene were significantly associated with metastatic cSCC. Sequencing analysis showed 37% of cSCC had a mutation at this locus, which suggests PTPRD is aberrant in a significant proportion of tumours. Decreased expression levels of PTPRD were correspondingly found in moderately and poorly differentiated tumours. The role of PTPRD in skin biology is not known and further functional work is required to elucidate its role in skin cancer. Taken together, these data provide a valuable insight into the genetic background against which cSCC develop. Furthermore, the association of PTPRD disruption with aggressive tumours may potentially be of future benefit as a prognostic biomarker and therapeutic target.
2
Robinson, Kim. "Identification of novel molecular targets for cutaneous squamous cell carcinoma". Thesis, University of Dundee, 2014. https://discovery.dundee.ac.uk/en/studentTheses/78349252-d233-40ad-9724-7b186baf531b.
Abstract (sommario):
Cutaneous Squamous Cell Carcinoma (cSCC) is the most common human tumour with malignant potential which is responsible for over 1 in 4 skin cancer deaths in the UK. High risk groups exist such as, immunosuppressed patients and those with the genetic condition recessive dystrophic epidermolysis bullosa whom are burdened with increased cSCC incidence, metastasis and mortality. Current clinically available molecular targets for cSCC are limited. Moreover, the key molecular events in cSCC remain poorly defined, presumably including both loss/gain of DNA or through gene silencing by DNA modifications. Understanding the molecular events which lead to cSCC is paramount for developing successful, novel molecular targets for therapeutic purpose. Preceding this thesis, our group used two independent methods to identify potential molecular targets: microarray technology (Watt 2011) and Sanger sequencing (Wang 2011), of which some of the targets identified from these studies, formulate the basis of this thesis. Using microarray technology, a comparison between gene expression profiles of cultured cSCC and normal keratinocytes, identified a gene signature specific for cSCC. From this signature, five genes were identified as being over-expressed in cSCC compared to normal and whose gene expression was important for cell survival. Subsequently, three of these genes were further explored within this thesis: germ cell associated 2 (GSG2), bradykinin receptor B1 (BDKRB1) and protease serine 21 (PRSS21). To begin, genes were confirmed to be over-expressed at both mRNA and protein level. Following this conformation, several endpoints were monitored using standard assays of cell viability, proliferation and apoptosis, in cSCC keratinocytes using gene specific siRNA. Using this validation method, PRSS21 showed the most promise as a molecular target. Depletion of PRSS21 resulted in decreased cell viability through an increase in cytotoxicity and apoptosis. Therefore PRSS21 was further validated as a molecular target through stable overexpression in an immortalised normal human cell line with no endogenous PRSS21 expression. Subsequently, using 3D organotypic cultures, it was shown that the expression of PRSS21 clearly transformed these cells into an invasive phenotype, compared to the control. Finally, PRSS21 was shown to interact with the tumour suppressor maspin, potentially negatively regulating maspin dependant apoptosis. This data strongly suggests that both PRSS21 and maspin are potential targets in cSCC. The second method of identifying molecular targets was direct sequencing of tumour DNA, which identified loss of function notch mutations in ~75% of cSCC. It has been postulated that loss of notch function contributes to cSCC through a reduction in differentiation. Using three cSCC cell lines of known notch status (wild type/loss of function/notch null), cells were grown in organotypic culture, and the expression of markers associated with differentiation studied. With the aid of a gamma secretase inhibitor to inhibit notch signalling the contribution of notch to the expression of differentiation markers was studied in cSCC cells compared to normal human keratinocytes (NHK). There was a significant reduction in differentiation within the cSCC cell lines compared to NHK, regardless of notch status, and differentiation could be further reduced by the presence of GSI in the cSCC with wild type/loss of function notch expression. Furthermore, overexpression of a gamma secretase regulatable intracellular notch1 (ICN1) construct, showed an induction of involucrin in these cells, compared to cells overexpressing an empty vector control, confirming that notch1 contributes to differentiation. Overall this work highlights the importance of validating targets before embarking on expensive, time consuming experiments. In doing so, it reveals two potential molecular targets which could be important for the progression of cSCC, PRSS21 and maspin. Additionally it confirms the potential mechanism of notch loss of function in suppressing differentiation, suggesting that its re-activation would be is a valid approach to cSCC therapy.
3
Pirzado, Muhammad Suleman. "Investigating cell senescence in basal cell carcinoma". Thesis, Queen Mary, University of London, 2012. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8633.
Abstract (sommario):
The Aim of the project was to investigate cell senescence in basal cell carcinoma (BCC). Although the concept of oncogene-induced senescence (OIS) was originally confined to cultured cells, it is now well established that this mechanism has an important role in tumour biology. OIS represents a physiological response that restricts the progression of benign tumours into their malignant counterparts e.g. nevi to melanoma or adenoma to adenocarcinoma. Full malignancy is associated with the loss of important tumour suppressor genes including RETINOBLASTOMA and/or TP53. BCC of the skin is the most common skin tumour and is associated with mutational inactivation of the PTCH1 tumour suppressor gene (and less frequently oncogenic activation of SMOOTHENED). Although BCC does not appear to stem from precursor lesions - though mouse models of BCC display areas of basaloid hyperproliferation - and it is relatively stable at the genomic level, we sought to determine if these unique tumours display any characteristics of OIS. Human BCCs were positive for Senescence-associated β-galactosidase (SA-β-gal) activity (pH 6.0) and expressed known markers of senescence including DCR2, DEC1 (SHARP2) as well as the cell cycle inhibitors p15INK4b and p16INK4a. Interestingly, SA-β-gal activity was observed in stromal cells surrounding the tumour islands and this may account for why BCCs are difficult to culture in vitro as senescent cells are known to express increased levels of growth factors, cytokines and ECM proteins. To determine if OIS is associated with Hedgehog signalling in BCC, I employed a novel in vitro model of BCC created through PTCH1 suppression in human immortalised NEB1 keratinocytes. NEB1-shPTCH1 cells are viable and proliferative (albeit more slowly than control NEB1-shCON cells) and do not display SA-β-gal activity but they express higher levels of several senescent markers including DCR2 and p21WAF1. I also investigated senescence in a Mouse model of BCC in which one allele of Ptch1 is mutated and which on x-ray irradiation results in BCC formation. The expression of known markers of senescence including DCR2, DEC1 (SHARP2) as well as the cell cycle inhibitors p15INK4b, p16INK4a and p53 were all with the exception of p21WAF1 detected in these tumours. Together these data suggest that senescence is a characteristic of BCC and may explain why these tumours rarely metastasise.
4
Rose, Aidan Michael. "Transforming growth factor-beta signalling in human cutaneous squamous cell carcinoma". Thesis, University of Dundee, 2015. https://discovery.dundee.ac.uk/en/studentTheses/51b1a1c1-ac43-4f60-aa77-9002af3f2186.
Abstract (sommario):
There is an urgent need to define the key pathological driving events in human cutaneous squamous cell carcinoma (cSCC) in order to identify novel therapeutic targets. Already the second most common form of human non-melanoma skin cancer, the incidence of cSCC has continued to rise at epidemic proportions over the past two decades. Rarely, cSCC can be highly aggressive, causing significant soft-tissue defects in sun-exposed areas of skin and progressing to metastatic disease, which is usually associated with poor survival. The transforming growth factor-β (TGF-β) signalling pathway is known to play key regulatory roles in skin homeostasis and wound repair. Murine studies indicate that loss of TGF-β signalling is sufficient to drive cSCC, but conclusive evidence for a similar role in human cSCC remains elusive. Combining immunohistochemical and genetic studies of the TGF-β signalling pathway on human cSCC tissue, with a thorough examination of TGF-β responses in human primary cSCC cell lines in-vitro, this thesis aims to investigate the complex role of TGF-β signalling in human cSCC. An extensive tissue micro-array analysis demonstrated the consistent reduction of endogenous TGF-β signalling activity in human primary cSCC. This intriguingly correlated with higher risk thick tumours pathologically, indicating that TGF-β is likely to act primarily as a tumour suppressor in human cSCC and its reduction or loss may impart a significant growth advantage for cSCC tumour cells. This tumour suppressor effect was reflected in-vitro, whereby the majority of primary cSCC cell lines remained sensitive to TGF-β mediated growth arrest. Resistance to TGF-β tumour suppression was also identified, and mechanistically its main protagonist in cSCC cell lines appeared to be mutational loss of TGF-β receptors. Consolidating in-vitro findings, both whole exome sequencing and 454 pyrosequencing of human cSCC tissue revealed frequent functionally damaging mutations of both TGF-β type 1 and type 2 receptors, indicating that mutational loss of the TGF-β pathway may be a key driving event in human cSCC tumourigenesis. Perhaps most interestingly, mutational loss of TGF-β type 2 receptors in cSCC cell lines appeared to result in a novel pro-oncogenic dependence on TGF-β type 1 receptor kinase activity, highlighting not only the important paradoxical role of TGF-β mediated tumour promotion in cSCC, but also the potential for signalling crosstalk between alternative TGF-β superfamily members, namely Activin signalling, to drive tumourigenesis in the absence of active TGF-β signalling. Although further mechanistic studies are required to support this hypothesis, the mutational status of TGF-β type 2 receptors may not only provide a powerful prognostic tool for patients with cSCC, but also represent an important biomarker for the targeted use of TGF-β inhibitors in potentially aggressive disease where pro-tumourigenic responses could be driving disease progression.
5
Dworkin, Amy Marie. "ENVIRONMENTAL AND GENETIC CONTRIBUTIONS OF SUSCEPTIBILITY TO CUTANEOUS SQUAMOUS CELL CARCINOMA". The Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1266000583.
6
Ismail, Ferina. "Ultraviolet Radiation-induced Apoptosis in the Pathogenesis of Cutaneous Squamous Cell Carcinoma". Thesis, Queen Mary, University of London, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.522322.
7
Azimi, Ali. "PROTEOMIC ANALYSIS OF ACTINIC KERATOSIS, BOWEN’S DISEASE AND CUTANEOUS SQUAMOUS CELL CARCINOMA". Thesis, The University of Sydney, 2018. http://hdl.handle.net/2123/20449.
Abstract (sommario):
Cutaneous squamous cell carcinoma (cSCC), premalignant actinic keratosis (AK) and Bowen’s disease (BD) are highly prevalent, heterogeneous keratinocytic skin lesions (KSLs). Discrepancies between clinical presentations and histologic analyses of KSLs frequently lead to misdiagnoses or delayed diagnoses. Biomarkers that can accurately stratify KSLs by their malignant potential are urgently needed to support a paradigm shift in skin cancer care to personalised, precision medicine. In this thesis, a liquid chromatography tandem mass spectrometry (MS) platform was employed to conduct comprehensive proteomic profiling of formalin-fixed and paraffin embedded samples of normal skin and KSLs. Using complementary MS approaches, namely information dependent acquisition (IDA) and sequential windowed acquisition of all theoretical fragment ion mass spectra (SWATH-MS), 3574 proteins were quantified overall allowing the identification of novel protein signatures for KSL subtypes. Proteomic findings were further investigated in silico using transcriptome databases, and several interesting targets were confirmed by immunohistochemistry. Distinct proteome profiles corresponding to subcategories of cSCC and precursor lesions were found, demonstrating the potential of MS-based approaches to deliver reliable diagnostics and disease staging. The bioinformatic analysis provided new insights into molecular pathways disrupted in different KSLs. The successful application of a non-invasive tape-stripping method for proteome sampling of KSLs was also demonstrated. This work represents the most comprehensive proteome study of KSLs to date. The identification of deferentially altered proteins and molecular pathways between subtypes of KSLs will inform the development of diagnostic, therapeutic and disease staging strategies. Further exploration and implementation of the approaches described herein could have a major impact on patient outcomes and reduce the cost burden of KSLs.
8
Emich, Helena. "Clinical implications of cancer stem cell properties in oral squamous cell carcinoma". Thesis, Queen Mary, University of London, 2014. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8479.
Abstract (sommario):
CD44 has been described as a marker of cancer stem cells in oral squamous cell carcinoma (OSCC). The main objective of this study was to characterise expression of CD44 in both fresh samples of human OSCC and in cell lines generated from them, and to examine its correlation with selected clinicopathological parameters of the tumours of origin. The epithelial fraction in 20 fresh OSCC samples was identified by the standard method using the negative selection technique with antibodies against non-tumour cells. A novel method of identifying the epithelial fraction, termed positive selection, was also developed and used for analysis of 14 additional OSCC samples. This new method, using epithelial-specific antibodies, led to a considerable improvement in the efficiency and the accuracy of the procedure. The frequency of CD44+ cells in the epithelial fraction of the tumour specimens was assessed by FACS and varied widely (3-97%). High frequency of CD44+ cells in tumour samples was found to be associated with high tumour grade, discohesive invasion front and presence of lymph node metastases (p<0.01, as calculated with Spearman’s ranked test and Fisher’s exact test). It was also observed, that the percentage of CD44+ cells changes when cells isolated from tumour samples are propagated in culture. Nearly all cells in cell lines generated from OSCC samples showed CD44 expression when analysed by FACS. However, a markedly higher level of CD44 expression (as assessed by median fluorescence intensity for cell surface CD44) was found for early passage cell lines generated from metastatic OSCC and lymph node metastases as compared to cell lines generated from nonmetastatic OSCC. These findings show that a high frequency of CD44+ cells in fresh OSCC tissue and a high level of CD44 expression in cultured OSCC cells correlate 11 with more aggressive tumour behaviour. These results might provide important information of prognostic and therapeutic value.
9
Martins, Vera Lisa Coelho. "Increased invasive behaviour of cutaneous squamous cell carcinoma with knock-down of Type VII collagen". Thesis, Queen Mary, University of London, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.497913.
Abstract (sommario):
Type Vll collagen (ColVII) is the main component of anchoring fibrils, structures within the lamina densa of the basement membrane responsible for dermal-epidermal adherence in skin. Mutations in the human ColVll gene, C0L7A1, cause the severe inherited blistering disorder recessive dystrophic epidermolysis bullosa (RDEB) affecting skin and mucosae associated with a greatly increased risk of skin cancer. The aim of this study was to investigate the effect of loss of ColVII on cutaneous SCC behaviour using RNAi.
10
Mooney, Craig Paul. "Cutaneous Squamous Cell Carcinoma of the Head and Neck Identifying Metastasis and High-Risk Characteristics". Thesis, The University of Sydney, 2021. https://hdl.handle.net/2123/24946.
Abstract (sommario):
Introduction: Head and Neck cutaneous Squamous Cell Carcinoma (HNcSCC) is one of the most common cancers in the world and is particularly prevalent in Australia. Regional metastasis remains one of the most important determinants of survival but predicting which lesions metastasise remains a challenge. Current staging systems have been shown to poorly stratify patient survival.
Methodology: Three studies were initiated: (1) A prospective trial of patients with high risk primary HNcSCC underwent sentinel node biopsy (SNB) to identify subclinical metastasis. Patients were followed to determine the accuracy of SNB, overall rate of metastasis and clinicopathological predictors of metastasis. Retrospective reviews of patients with metastatic HNcSCC treated at a quaternary referral head and neck oncology service was undertaken to characterise the prognostic impact of (2) Soft tissue metastases (STM) and (3) Location (parotid v neck) of regional metastasis.
Results: (1)105 high risk lesions underwent SNB with a total subclinical nodal metastasis rate of 14.3%. SNB identified 67% of patients with regional metastasis. The risk of metastasis is increased in the presence of perineural invasion and increasing depth of invasion and number of high-risk features. (2) A review of 200 patients with STM identified a poor five-year overall survival (OS) of 36% and that increasing number of deposits was a significant predictor of reduced survival on multivariable analysis. (3) A review of 535 patients with regional metastasis determined that multiple regional metastases and metastases to neck nodes were associated with reduced survival.
Conclusion: Regionally metastatic HNcSCC is associated with a significant mortality rate in Australia. Methods to identify regional metastases early, before the development of multiple nodal metastases or STM, may improve survival rates. SNB is one such potential method; however, work is needed to better identify predictors of nodal metastases.
11
Rahman, Muhammad Mahmudur. "Characterisation of a novel in vitro model of basal cell carcinoma (BCC) through stable PTCH1 suppression in immortalised human keratinocytes". Thesis, Queen Mary, University of London, 2013. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8658.
Abstract (sommario):
Basal cell carcinoma (BCC) of the skin is predominantly associated with mutational inactivation of the PTCH1 tumour suppressor gene resulting in constitutive activation of the Hedgehog (HH) developmental pathway. Tumour formation is linked to induction of the GLI (GLI1 and GLI2) transcription factors via a pathway that is thought to require the transmembrane protein SMOOTHENED (SMO) and accordingly, SMO is attracting much interest as a drug target in cancer therapy. However, although there has been a high degree of success in treating some BCCs with anti-SMO compounds, many tumours are only partially or unresponsive which indicates that SMO-independent mechanisms may contribute to tumour formation and/or viability. To further understand how loss of (or reduced) PTCH1 function contributes to BCC, RNAi (retroviral shRNA) was employed to suppress PTCH1 in NEB1 and N/Tert immortalised human keratinocyte cells. Compared to control (shCON) cells, PTCH1 knockdown (shPTCH1) cells displayed more compact colony formation as well as increased GLI1 (but not GLI2) expression however, whereas the increase of GLI1 was suppressed upon transfection with SMO siRNA in shPTCH1 cells, it was insensitive to the presence of the SMO antagonists Cyclopamine-KAAD and SANT1 in shCON cells. The reason for this is unclear but SMO levels were increased and more nuclear in shPTCH1 cells indicating that SMO may have nuclear signalling capability that is unresponsive to certain SMO antagonists. Indeed, cDNA microarray profiling revealed that 80% of the genes that were differentially expressed in NEB1-shPTCH1 cells (>2-fold, p<0.01) remained differentially expressed in the presence of Cyclopamine-KAAD; this includes the chemokines CXCL10 and CXCL11 which were recently shown to be over-expressed in BCC thus helping validate the efficacy of NEB1-shPTCH1 cells as an in vitro tumour model. In addition, functional gene grouping has predicted novel biological processes downstream of PTCH1 that may be important in BCC biology including NF-κB signalling. In summary, the data presented in this thesis suggests that the mechanism(s) through which the loss of PTCH1 leads to BCC formation may be more complex than has been inferred from previous studies.
12
Gressel, Katherine Lynne. "Alterations in Endogenous Retinoids with Acute UVB Exposure and in the Progression of Cutaneous Squamous Cell Carcinoma". The Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1429785553.
13
Pyczek, Joanna [Verfasser], Heidi [Akademischer Betreuer] Hahn, Michael [Gutachter] Schön e Holger [Gutachter] Bastians. "Hedgehog signaling in cutaneous squamous cell carcinoma / Joanna Pyczek ; Gutachter: Michael Schön, Holger Bastians ; Betreuer: Heidi Hahn". Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2018. http://d-nb.info/1151398918/34.
14
Ramachandran, Sudarshan. "Identification of genetic and host factors associated with clinical phenotypes in patients with cutaneous basal cell carcinoma". Thesis, Keele University, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.402689.
15
Fleming, Jessica L. "Utilizing Cancer Resistant and Susceptible Mice to Identify the Genetic Contributions to Cutaneous Squamous Cell Carcinoma Susceptibility". The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1354289625.
16
Al-Myouf, Abdullah Abdulaziz. "Cadherins, catenins and associated proteins in normal epidermis, basal cell carcinoma and other cutaneous tumours : an immunohistochemical study". Thesis, University of Glasgow, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.341723.
17
Gomaa, Wafaey Mohammad. "Role of cutaneous fatty acids binding protein in head and neck squamous cell carcinoma : a molecular pathology study". Thesis, University of Liverpool, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.430887.
18
Kha, Stephanie Tieu. "An Investigation of Cellular Proliferation and Nuclear Morphology in the Multi-Step Progression of Cutaneous Squamous Cell Carcinoma". Thesis, The University of Arizona, 2015. http://hdl.handle.net/10150/579258.
Abstract (sommario):
With 3.5 million cases diagnosed in more than 2 million people in the United States annually, skin cancer leads as a frequent and devastating disease carrying a large public health burden. Understanding the multi-step disease progression is crucial for developing interventional strategies that can reduce the incidence as well as the risk of recurrence for non-melanoma skin cancers. In this study of 40 tissue samples, cellular proliferation is quantified and analyzed in four categories that represent the stages of progression for SCC carcinogenesis: Normal, Sun-exposed, Actinic Keratosis, and Squamous Cell Carcinoma. The results in this study show an exponential increase in levels of Proliferative Cell Nuclear Antigen (PCNA) expression with each progressed category, as well as a positive association with nuclear morphology feature values related to sun-damaged nuclei that were published in a previous study. These findings support the utility of investigative techniques from the field of immunohistochemistry in studying the UV-induced skin carcinogenesis model for the multi-step disease progression of cutaneous squamous cell carcinoma. Furthermore, this study elucidates the complexities involved in clinical histological diagnoses for non-melanoma skin cancers.
19
Bertheim, Ulf. "Impaired reparative processes in particular related to hyaluronan in various cutaneous disorders : a structural analysis". Doctoral thesis, Umeå : Univ, 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-276.
20
Iannacone, Michelle R. "Case-Control Study of Sunlight Exposure and Cutaneous Human Papillomavirus Seroreactivity in Basal Cell and Squamous Cell Carcinomas of the Skin". Scholar Commons, 2011. http://scholarcommons.usf.edu/etd/3164.
Abstract (sommario):
Non-melanoma skin cancer (NMSC), comprised of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), is the most common cancer in Caucasians. Ultraviolet radiation (UVR) exposure is the most important environmental risk factor for both BCC and SCC development. However, the precise relationship between UVR and the risk of NMSC is complex, and the relationship may differ by skin cancer type. It has been hypothesized that intermittent patterns and childhood sunlight exposure are important for BCC while continuous (chronic) and lifelong (i.e. childhood and adulthood) sunlight exposure is important for SCC. Epidemiologic studies have demonstrated that cutaneous human papillomavirus (HPV) infection may also be a risk factor for developing NMSC. However, the pathway by which cutaneous HPV is associated with NMSC remains unclear. It is hypothesized that UVR exposure may interact synergistically with cutaneous HPV in NMSC development.
The goal of the research study was to evaluate the relationship between levels of sunlight exposure and BCC and SCC and to investigate differences in sunlight-associated BCC and SCC risk by genus-specific cutaneous HPV serostatus. To address these goals, we conducted a clinic based case-control study of histologically confirmed BCC and SCC cases recruited from a university dermatology clinic and controls with no history of cancer and screened negative for current skin cancer. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for the associations between measures of sunlight exposure and BCC and SCC. Multiplicative interactions were tested by placing an interaction term for the product of genus-specific HPV seroreactivity and sunlight related factors in the logistic regression models.
Measures of both intermittent and continuous patterns of sunlight exposure were associated with both types of skin cancer (i.e. BCC and SCC). Specifically, history of blistering sunburn (a marker of intermittent sunlight exposure) and occupational sunlight exposure (i.e. having a job in the sun for at least 3 months for >10 years) were both associated with BCC and SCC. The major differences in patterns of sunlight exposure between BCC and SCC were observed for sunlight exposure in one's thirties. Additionally, sunlight exposure in one's twenties was associated with SCC, regardless of pattern of exposure; similar associations were not observed for BCC. Measures of timing of sunlight exposure consistently demonstrated that childhood/adolescent sunlight exposure was more important for SCC than BCC. These included number of moles on the forearms and entire body (measure of increased childhood sunlight exposure), and younger age at first and tanning bed use. Younger age at first blistering sunburn was statistically significantly associated with both BCC and SCC.
NMSC cases were more likely to be seropositive for cutaneous HPV antibodies compared to controls. Compared to tanning, having a propensity to sun burn (p=0.006), or poor tanning ability (p=0.003) were significantly associated with a higher seroprevalence to genus beta HPV types within SCC cases. Statistically significant interactions were observed between poor tanning ability and genus-specific seropositivity with NMSC. Specifically, the associations between poor tanning ability and BCC (p interaction=0.02) and SCC (p interaction=0.01) were significantly stronger among individuals that were seropositive for antibodies to genus alpha HPV types. Similarly, the association between poor tanning ability and SCC was stronger among those seropositive for genus beta HPV types (p interaction=0.001). No additional significant interactions were observed for BCC or SCC between cutaneous sensitivity, history of blistering sunburn, or cumulative sunlight exposure and genus-specific seroreactivity.
In conclusion, associations with patterns of sunlight exposure appeared to be similar between BCC and SCC cases. With the exception of age at first blistering sunburn, factors measuring timing of sunlight exposure demonstrated stronger and statistically significant relationships with SCC. Additionally, of the sunlight related factors measured, only the associations between poor tanning ability and BCC and SCC were significantly modified by HPV seropositivity to types in genera alpha or beta.
21
Gudenschwager, Basso Erwin Kristobal Felipe. "Characterization of the expression of angiogenic factors in the feline placenta during development and in feline cutaneous squamous cell carcinoma". Diss., Virginia Tech, 2018. http://hdl.handle.net/10919/97990.
Abstract (sommario):
Throughout gestation, the blood vessel network of the placenta is formed sequentially by processes known as vasculogenesis and angiogenesis, which together meet the needs of the growing fetus. Normal placental angiogenesis is critical to support adequate fetal growth and assure the health of the offspring. Proper angiogenesis requires precise regulation of expression of agents that modulate this process; otherwise, pathologies of pregnancy such as preeclampsia may occur. The placenta is composed of different layers of tissue, including the lamellar (LZ), junctional, and glandular zones, each with a vascular morphology attuned to its function. We hypothesized that higher expression of pro-angiogenic factors is associated with increased morphological metrics in the LZ, the major vascularized zone. Thus, we aimed to characterize the major changes in morphology and vascular development in the placenta throughout pregnancy in cats, alongside a compressive analysis of the expression of major angiogenic factors and their receptors in the placenta, with an emphasis on the identification and interaction of different isoforms of the VEGF family.
Microscopic analysis of tissue specimens from different stages of pregnancy revealed increased thickness of the LZ, especially during early to mid-gestation, at which time the tissue is composed of abundant materno-fetal interdigitations that appears rich in capillaries. VEGF proteins were detected in placental tissue in both fetal and maternal cells of the placenta, suggesting stimulatory interactions between different cell types to promote growth and angiogenesis. Gene expression analysis of placenta revealed upregulation of the pro-angiogenic factor VEGF-A in mid-pregnancy, followed by a steady decline toward term, consistent with morphologic changes in the LZ. In contrast, another pro-angiogenic factor, PlGF, showed a marked increase toward term; Flt-1, which acts as a receptor or reservoir for PLGF and VEGF A, was also upregulated at late pregnancy. Increased ratios of PLGF:VEGF-A may contribute to LZ proliferation in the last trimester. These findings are consistent with the creation of a proangiogenic placental state during gestation. Overall, we expect that this research will help elucidate mechanisms of placental vascularization, which can be applied to the design of improved strategies to treat vascular complications of pregnancy.
Lastly, we applied the tools developed for placental studies to investigate pathologic angiogenesis in cutaneous squamous cell carcinoma (CSCC), a common skin cancer with major economic and medical impacts in humans and veterinary species. The creation of a new blood supply is essential for growth and metastasis of many tumor types. The goal of this study was to measure expression of variants of proteins that stimulate angiogenesis or transmit an angiogenic stimulus in feline CSCC. The results were mixed, with differences detected in expression of some regulatory agents and, for others, unexpectedly lower expression in CSSC compared to controls. Interestingly, the expression of VEGF-A relative to the protein that transmits its signal (KDR) was elevated in CSCC, suggestive of an altered signaling relationship. This finding supports our hypothesis and is consistent with human SCC studies. Our results encourage further studies on angiogenic factor variants in feline CSCC.PHD
22
Hernández, Ruiz Eugenia. "Mecanismos epigenéticos con valor pronóstico en el carcinoma escamoso cutáneo". Doctoral thesis, Universitat Autònoma de Barcelona, 2019. http://hdl.handle.net/10803/669702.
Abstract (sommario):
El carcinoma escamoso cutáneo es el segundo cáncer cutáneo más frecuente. A pesar de que la
mayoría de los pacientes se diagnostican en etapas precoces y la cirugía es curativa,
aproximadamente un 5% de los pacientes desarrollan metástasis, generalmente a territorios
linfáticos vecinos, lo que empeora el pronóstico con una supervivencia menor al 20% a los 10
años.
Existen diferentes sistemas de clasificación que permiten estratificar a los pacientes en función
del riesgo metastásico. Uno de las más utilizados es la clasificación de la American Joint
Committee on Cancer, la AJCC8, y ha demostrado ser superior a otros sistemas de clasificación
a la hora de identificar los pacientes de alto riesgo. No obstante, es necesario identificar nuevos
factores pronósticos.
Recientemente se ha estudiado el papel en cáncer de la familia de represores epigenéticos
Polycomb que actúan como represores de la transcripción y silencian los genes sobre los que
actúan. Se han descrito dos grupos en mamíferos: el complejo 2 o de iniciación, cuya subunidad
catalítica más importante es EZH2 y el complejo 1 o de mantenimiento, cuya subunidad más
importante es RING1B. Su expresión se ha demostrado en diferentes tumores sólidos y está
aumentada en tumores metastásicos.
Con el fin de estudiar el papel de las proteínas Polycomb en carcinoma escamoso cutáneo
realizamos un estudio retrospectivo multicéntrico en el que se incluyeron un total de 107
carcinomas escamosos, 56 CEC primarios que dieron lugar a metástasis (metastásicos) y 51
CEC primarios no metastásicos (grupo control) que no habían desarrollado metástasis en un
período de seguimiento de 5 años.
En nuestro primer estudio demostramos, mediante técnicas de inmunohistoquímica que EZH2 y
RING1B están sobreexpresados en carcinomas escamosos cutáneos metastásicos. Mediante
estudios funcionales en líneas celulares de carcinoma escamoso hemos observado que EZH2 y
RING1B regulan la vía NF-kb; de forma inversa, es decir en las células en las que se depleciona
Polycomb la vía NF-kb está activada.
La vía NF-kb está asociada a inflamación. Pudimos observar que la quimiotaxis de neutrófilos
era mayor hacia los sobrenadantes procedentes de cultivos celulares en los que se ha
deplecionado Polycomb. Además, valoramos el infiltrado inflamatorio en los microarrays de
tejidos tumorales y observamos que los carcinomas escamosos no metastásicos presentaban un
porcentaje mayor de neutrófilos y eosinófilos en el estroma. Por lo tanto, las proteínas Polycomb
pueden estar silenciando genes implicados en la respuesta inmune del queratinocito, de tal
manera que la expresión de polycomb reprimiría la respuesta inmune antitumoral y favorecería
el escape de las células tumorales y el desarrollo de metástasis a distancia.
El microambiente tumoral formado por el estroma, la celularidad inflamatoria acompañante, los
fibroblastos asociados al tumor y las células endoteliales de los vasos sanguíneos no son simples
observadores sino que interactúan con las células tumorales. Además de las células
inflamatorias, los fibroblastos asociados al tumor pueden facilitar o impedir la diseminación de
las células tumorales por su capacidad de producir diferentes tipos de fibrosis con valor
pronóstico. La desmoplasia se ha asociado tradicionalmente a mal pronóstico y en algunos
tumores sólidos, como el adenocarcinoma de páncreas, el estroma desmoplásico, supone una
barrera para el infiltrado de las células tumorales y la difusión de fármacos quimioterápicos. En
algunos tumores sólidos como en carcinoma colorrectal se han descrito diferentes patrones de
reacción fibrótica con valor pronóstico. En nuestro segundo estudio investigamos los diferentes
patrones de reacción fibrótica en nuestra serie de carcinomas escamosos cutáneos. El patrón
inmaduro, caracterizado por cambios mixoides sin inflamación, se asociaba con gemación
tumoral, desmoplasia, invasión perineural, profundidad tumoral y el desarrollo de metástasis.Cutaneous squamous cell carcinoma is the second most common skin cancer. Despite the majority of patients are diagnosed at an early stage and surgical excision is curative, about 5% of patients develop metastasis, usually to regional lymph nodes, and prognosis worsens with a 10- year overall survival of less than 20%. There are different classification systems that allow stratifying patients in function of the metastatic risk. The new American Joint Committee on Cancer classification, AJCC8, is superior in identifying high risk patients but there is much more to investigate in this field. Recently, the expression of the family of transcriptional repressors Polycomb, that silence and inactivate the genes that they regulate, have been detected in different solid tumors and it is increased in metastatic tumors. Two complexes have been identified in mammals, PCR2 or initiation complex, being EZH2 its main catalytic subunit and PRC1 or maintenance complex formed by different proteins such as RING1B and BMI1. We performed a multicentric descriptive study and 107 cutaneous squamous cell carcinomas were included; 56 metastatic carcinomas and 51 non-metastatic carcinomas that hadn´t developed metastases in a 5-year period time. In our first study we have demonstrated, using immunohistochemical stains, that EZH2 and RING1B expression is increased in metastatic cutaneous squamous cell carcinomas. In vitro functional studies using cell lines revealed that EZH2 and RING1B regulate NF-kb, since NF-kb, pathway is upregulated in Polycomb deplected cells. NF-kb, pathway is associated with inflammation. We could observe that chemotaxis of neutrophils is higher towards supernatants from cell cultures in which Polycomb proteins have been deplected. In our group of non-metastatic cutaneous squamous cell carcinomas we detected lower levels of Polycomb proteins expression using immunohistochemical stains, lower percentage of cells expressing Polycomb and lower intensity of Polycomb expression. When evaluating the inflammatory infiltrate, and despite using tissue microarrays we could also observe that non metastatic carcinomas showed higher amount of neutrophils and eosinophils in their stroma. Polycomb proteins may act silencing genes implicated in the immune response of keratinocytes and may favour the escape of tumoral cells from the immune system and the development of distant metastasis. Tumor microenvironment is not just an observer and plays an important role interacting with tumoral cells. Besides inflammatory cells, stromal fibroblasts can facilitate or inhibit tumoral cell dissemination, since they can produce different types of fibrosis with a prognostic value. Desmoplasia has always been linked to worse prognosis and some solid tumors such as pancreatic adenocarcinoma are characterized by a desmoplastic stroma which is a barrier to immune cell infiltratrion and also to chemotherapy. Ueno et al described three different types of fibrotic reaction in colorrectal carcinoma with prognostic value. In our second study we investigated the different fibrotic reaction patterns in whole hematoxilin-eosin stained sections in our series. The immature pattern characterized by myxoid changes with no inflammation was associated with tumoral budding, desmoplasia, perineural invasion, tumoral depth and metastatic risk.
23
Brown, Victoria Lissa. "The role of p16'I'N'K'4'a and p14'A'R'F tumour suppressor genes in the pathogenesis of cutaneous squamous cell carcinoma". Thesis, Queen Mary, University of London, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.423542.
24
Schwab, Melanie [Verfasser], e Peter [Akademischer Betreuer] Angel. "The Role of the Mucin-Like Glycoprotein Podoplanin in the Progression of Cutaneous Squamous Cell Carcinoma / Melanie Schwab ; Betreuer: Peter Angel". Heidelberg : Universitätsbibliothek Heidelberg, 2019. http://d-nb.info/1201346436/34.
25
García, Díez Irene. "Estudio del perfil genómico y de expresión en carcinomas escamosos cutáneos intraepiteliales e invasivos". Doctoral thesis, Universitat Autònoma de Barcelona, 2021. http://hdl.handle.net/10803/671613.
Abstract (sommario):
El carcinoma escatós cutani (CEC) és el segon tumor maligne cutani més freqüent. La majoria dels CECs es desenvolupen a partir de lesions precursores (queratosis actíniques [QA]). No obstant, només una minoria de QA evolucionen a CECs sense que es coneguin, de forma precisa, els mecanismes que participen en aquesta transformació. Tot i que en la majoria dels casos el pronòstic del CEC és excel·lent, hi ha un petit grup de tumors considerats d’alt risc (metastàtics o localment avançats) que presenten una evolució agressiva i mal pronòstic. En l’actualitat no hi ha biomarcadors fiables en la pràctica clínica que permetin detectar els CECs amb més risc metastàtic. S’ha proposat que l’expressió de PD-L1 per les cèl·lules tumorals podria ser un marcador pronòstic en diferents tumors. Si bé la seva utilitat en el CEC no ha estat prèviament estudiada, diferents assaigs clínics amb nous fàrmacs dirigits enfront de l’eix PD1 / PD- L1 en CECs han mostrat resultats esperançadors. L’objectiu d’aquesta tesi és estudiar els mecanismes moleculars implicats en les diferents etapes de la carcinogènesi del CEC (des de la pell sana fotoexposada [PF] fins al CEC metastàtic) amb la finalitat d’identificar els gens i les vies moleculars implicades en la seva progressió i determinar possibles factors pronòstics. A la primera part d’aquest treball hem estudiat les diferències transcripcionals i genòmiques en PFs, QAs i CECs a partir de 30 mostres aparellades per pacient, analitzades utilitzant plataformes d’arrays. Els resultats obtinguts els hem confirmar per tècniques de RT-qPCR, immunohistoquímica i Western blot. Hem identificat dos factors de transcripció, BNC1 i FOSL1, l’expressió dels quals es troba augmentada en el CEC i que podrien actuar com a gens essencials en la transformació tumoral. La integració de les dades obtingudes en els estudis de transcriptòmica i de genòmica mostra que les alteracions en el número de còpies del gen NEK10 es correlacionaven amb els nivells d’expressió de NEK10. Aquest gen codifica un quinasa relacionada amb el gen NIMA ( “Never in Mitosi gene A”), localitzada en una regió de mida petita a la banda 3p24.1, delecionada en 7 dels 10 CECs estudiats. Mitjançant tècniques d’ immunohistoquímica i de Western blot hem confirmat la pèrdua progressiva de l’expressió de NEK10 des de la PF fins al CEC i la realització d’estudis funcionals ens ha permès demostrar la seva participació en la regulació del cicle cel·lular en cèl·lules epitelials HaCaT. Tot això recolza el paper de NEK10 com a gen supressor tumoral en el CEC. A la segona part d’aquest treball hem estudiat el valor pronòstic dels nivells de PD-L1 en el CEC, analitzant la seva expressió mitjançant immunohistoquímica en 99 CECs primaris amb metàstasis limfàtiques (n = 48) i sense metàstasis (n = 51) i en 24 metàstasis limfàtiques. Hem observat una associació entre l’expressió de PD-L1 en ≥ 1% de les cèl·lules tumorals i la presència de metàstasis limfàtiques, així com amb la recurrència, una mala diferenciació histopatològica i la presència d’invasió perineural. En la majoria dels casos (90%) existia una bona concordança en l’expressió de PD-L1 entre els CEC primaris i les seves metàstasis, amb una tendència cap a una expressió més important en les últimes. No hem trobat diferències entre els tres tipus de mostres analitzades respecte a l’expressió de PD-L1 o de CD8 per les cèl·lules de l’infiltrat peritumoral. Els nostres resultats suggereixen que PD-L1 podria ser un biomarcador útil amb possible valor pronòstic en el CEC.El carcinoma escamoso cutáneo (CEC) es el segundo tumor maligno cutáneo más frecuente. La mayoría de los CECs se desarrollan a partir de lesiones precursoras (queratosis actínicas ([QA]). Sin embargo, sólo una minoría de QAs evolucionan a CECs, sin que se conozcan de forma precisa los mecanismos que participan en dicha transformación. A pesar de que en la mayoría de los casos el pronóstico del CEC es excelente, existe un pequeño grupo de tumores considerados de alto riesgo (metastásicos o localmente avanzados) que presentan una evolución agresiva y mal pronóstico. En la actualidad no existen biomarcadores fiables en la práctica clínica que permitan detectar los CECs con mayor riesgo metastásico. Se ha propuesto que la expresión de PD-L1 por las células tumorales podría ser un marcador pronóstico en distintos tumores, si bien su utilidad en el CEC no ha sido previamente estudiada, distintos ensayos clínicos con nuevos fármacos dirigidos frente al eje PD1/PD-L1 en CECs han mostrado resultados esperanzadores. El objetivo de esta tesis es valorar los mecanismos moleculares implicados en las distintas etapas de la carcinogénesis del CEC (desde la piel sana fotoexpuesta [PF] hasta el CEC metastásico) con la finalidad de identificar los genes y las vías moleculares implicadas en su progresión y determinar posibles factores pronósticos. En la primera parte de este trabajo estudiamos las diferencias transcripcionales y genómicas en PFs, QAs y CECs a partir de 30 muestras apareadas por paciente, analizadas utilizando plataformas de arrays. Los resultados obtenidos se confirmaron por técnicas de RT-qPCR, inmunohistoquímica y Western blot. Identificamos dos factores de transcripción, BNC1 y FOSL1, cuya expresión se hallaba aumentada en el CEC y que podrían actuar como genes esenciales en la transformación tumoral. La integración de los datos obtenidos en los estudios de transcriptómica y de genómica reveló que las alteraciones en el número de copias del gen NEK10 se correlacionaban con los niveles de expresión de NEK10. Este gen codifica una quinasa relacionada con el gen NIMA (“Never in Mitosis gene A”), localizada dentro una región de pequeño tamaño en la banda 3p24.1, delecionada en 7 de los 10 CECs estudiados. Mediante técnicas inmunohistoquímicas y Western blot confirmamos la pérdida progresiva de la expresión de NEK10 desde la PF hasta el CEC y la práctica de estudios funcionales permitió demonstrar su participación en la regulación del ciclo celular en células epiteliales HaCaT. Todo ello apoyaría el papel de NEK10 como gen supresor tumoral en el CEC. En la segunda parte de este trabajo evaluamos el valor pronóstico de los niveles de PD-L1 en el CEC, analizando su expresión mediante inmunohistoquímica en 99 CECs primarios con metástasis linfáticas (n=48) y sin metástasis (n=51) y en 24 metástasis linfáticas. Detectamos una asociación entre la expresión de PD-L1 por ≥ 1% de las células tumorales y la presencia de metástasis linfáticas, así como con la recurrencia, una mala diferenciación histopatológica y la presencia de invasión perineural. En la mayoría de los casos (90%) existía una buena concordancia en la expresión de PD-L1 entre los CEC primarios y sus metástasis, con una tendencia hacia una mayor expresión en las últimas. No encontramos diferencias entre los tres tipos de muestras analizadas con respecto a la expresión de PD-L1 o de CD8 por las células del infiltrado peritumoral. Nuestros resultados sugieren que PD-L1 podría ser un biomarcador útil con posible valor pronóstico en el CEC.”
Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer. Most cSCCs develop from precursor lesions (actinic keratosis [AK]). However, only a minority of AKs will eventually progress into cSCCs and the key mechanisms for this transformation remain unclear. Although in most cases the prognosis of cSCC is excellent, there is a small percentage of tumors with high metastatic risk. Metastatic or locally advanced cSCCs have high mortality, with no effective treatments available. Unfortunately, there is a lack of reliable biomarkers in clinical practice for detecting those cSCCs with the highest metastatic risk. Expression of PD-L1 by tumor cells has been proposed as a prognostic marker in different tumors. While the usefulness of PD-L1 expression in cSCC has not been addressed yet, new drugs aimed to block the PD1/PD-L1 axis are showing encouraging results in clinical trials in cSCC. The objective of this thesis is to evaluate the molecular mechanisms involved in the different stages of cSCC carcinogenesis (from healthy sun-exposed skin to metastatic cSCC) in order to identify the genes and molecular pathways involved, and their putative role as prognostic biomarkers. In the first part of this work we studied the differences in the transcriptome and the genome of sun-exposed skin, AKs and cSCCs of 30 samples matched by patient, using different array platforms. The results obtained were confirmed by quantitative RT-PCR, immunohistochemistry, and Western blot. We detected two transcription factors, BNC1 and FOSL1, whose expression was increased in cSCC and that could contribute to cSCC development. Additionally, a strong correlation between copy numbers and gene expression of NEK10 was identified by integrating the transcriptomic and genomic array data. NEK10 gene encodes a NIMA (“Never in Mitosis gene A”) related kinase, located within a small region in the 3p24.1 band, which was found to be deleted in 7 out of 10 cSCCs studied. By immunohistochemistry and Western blot, we confirmed the progressive loss of NEK10 from sun-exposed skin to cSCC and functional studies demonstrated the role of NEK10 in the regulation of the cell cycle in the epithelial HaCaT cells. These data support the role of NEK10 as a tumor suppressor gene in cSCC. In the second part of this work we evaluated the usefulness of PD-L1 expression, determined by immunohistochemistry, as a prognostic marker in cSCC. PD-L1 expression was analyzed in ninety-nine primary cSCCs with lymphatic metastases (n = 48) and without metastases (n = 51), and 24 metastases. An association between PD-L1 expression by ≥1% of tumor cells and the presence of lymphatic metastases, as well as with recurrence, poor histopathological differentiation and perineural invasion was detected. In most cases (90%), PD-L1 expression remained constant between primary cSCCs and their metastases, with a trend towards a higher expression in the latter. No differences among the three types of samples analyzed with respect to the expression of PD-L1 or CD8 by the cells of the peritumoral infiltrate were found. Our results suggest that PD-L1 could be useful as a prognostic biomarker in cSCC.
26
Gastaldi, Cécile. "Études des microARNs dans le développement des carcinomes spinocellulaires cutanés". Thesis, Nice, 2013. http://www.theses.fr/2013NICE4120/document.
Abstract (sommario):
Les carcinomes spinocellulaires cutanés (cSCCs) sont le deuxième type de cancer par ordre de fréquence et sont responsables de 25% des décès dus aux cancers de la peau. Il est donc essentiel de caractériser les mécanismes responsables de la cancérisation de l'épiderme afin de développer de nouveaux traitements. Dans ce contexte, les miRNAs apparaissent comme des cibles de choix pour le développement de futures thérapies anti-tumorales. Toutefois, leur implication dans la physiopathologie des cSCCs est encore peu documentée. Au cours de cette étude, j’ai identifié, par séquençage à haut débit, 112 miRNAs dont l’expression est altérée au cours du développement tumoral dans un modèle murin de carcinogénèse chimique cutanée. J’ai ensuite focalisé mon attention sur le cluster miR-193b/365a et sur miR-708 dont les niveaux diminuent au cours de la progression tumorale, suggérant des fonctions de suppresseurs de tumeur. En accord avec cette hypothèse, l’expression ectopique de ces miRNAs inhibe la prolifération, la survie et la migration de cellules tumorales, alors que le blocage de leur action par des anti-sens stimule ces fonctions cellulaires dans des kératinocytes normaux. L’association d’approches in silico et d’analyses du transcriptome de cellules de cSCC sur-exprimant ces miRNAs m’a permis d’identifier leurs gènes cibles potentiels. J’ai validé KRAS et MAX comme cibles communes de miR-193b et miR-365a, et montré par l’utilisation de siRNAs que la répression de ces cibles mime les effets de ces miRNAs. Ces résultats suggérent que le ciblage de ces gènes pourrait médier en partie les effets suppresseurs de tumeur de miR-193b et de miR-365a dans les cSCCsCutaneous squamous cell carcinomas (cSCCs) are the second most common cancer and are responsible for up to 25% of all skin cancer deaths. It is therefore essential to characterize the mechanisms responsible for epidermis carcinogenesis to develop new treatments. In this context, miRNAs appear to be prime targets for the development of future anti-tumor therapies. However, their involvement in the pathophysiology of cSCCs is still poorly documented. In this study, I identified using Small RNA sequencing, 112 miRNAs whose expression is altered during tumor development in a mouse model of cutaneous two-stage chemical carcinogenesis. Then, I focused my attention on the miR-193b/365a cluster and on miR-708, that are down-regulated during tumorigenesis, suggesting tumor suppressor functions. Consistent with this hypothesis, the ectopic expression of these miRNAs inhibit the proliferation, survival and migration of tumor cells, while blocking their action with antisense oligonucleotides stimulates these cellular functions in normal keratinocytes. Combining in silico target-prediction approaches and transcriptome analyzes of cSCC cells over-expressing these miRNAs, I identified their potential target genes. I validated KRAS and MAX as direct targets of miR-193b and miR-365a, and I showed that repression of these genes using siRNAs mimics the effects of these miRNAs. These results suggest that targeting these genes might mediate, at least in part, the tumor suppressor action of miR-193b and miR-365a in cSCCs
27
Tebcherani, Antonio José. "Painel imunoistoquímico para distinção entre tricoepitelioma e carcinoma basocelular desenvolvido utilizando a técnica do TMA". Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/5/5133/tde-11072012-095546/.
Abstract (sommario):
O diagnóstico das neoplasias cutâneas do folículo piloso, particularmente do tricoepitelioma (TE), frequentemente representa dificuldade diagnóstica com o carcinoma basocelular (CBC). As semelhanças clínicas e histopatológicas somadas aos artefatos de amostragem (amostras exíguas por biopsias incisionais ou parcialmente danificadas por esmagamento ou fulguração) podem provocar situações de dificuldade na diagnose diferencial entre as duas neoplasias. O diagnóstico de certeza é importante, pois o CBC tem caráter agressivo local e, quando não totalmente excisado, infiltra os tecidos adjacentes. O TE é uma lesão benigna, sem capacidade de invasão local, não havendo recomendação de excisão com margem cirúrgica. Vários marcadores imunoistoquímicos têm sido propostos na literatura médica para auxiliar no diagnóstico diferencial entre o TE e o CBC. Esses estudos, entretanto, têm resultados conflitantes que podem estar relacionados à pequena casuística avaliada, que geralmente não excede 50 casos de TE. A técnica do arranjo em matriz de amostras teciduais, tissue microarray (TMA), permite a avaliação de um número grande de amostras teciduais, que podem ser submetidas de modo simultâneo aos procedimentos das reações imunoistoquímicas. O objetivo do presente estudo foi o de submeter uma ampla amostra de TE e CBC, obtida através da técnica de TMA, aos marcadores imunoistoquímicos descritos, com a finalidade de identificar um marcador, ou painel de marcadores, capaz de auxiliar a diferenciação do TE do CBC. Cortes histológicos de quatro blocos de TMA representando espécimes de 162 TE e 328 CBC foram submetidos às reações imunoistoquímicas com os anticorpos CD34, BCL-2, CD 10, antígeno de membrana epitelial (EMA), citoqueratinas (CK) 20 e 15, D2-40 e 34 E12. A fim de facilitar a avaliação dos resultados e padrões de expressão antigênica, os espécimes foram digitalizados para obtenção de lâminas histológicas virtuais. Estas foram analisadas por meio de um programa de computador. Fez-se inicialmente a análise dos resultados de 85 TE e 62 CBC representados no primeiro bloco de TMA. Esta verificação identificou a expressão dos marcadores CD34, CD10, EMA, CK15, CK20 e D2-40 com diferença significativa entre os TE e os CBC. Procedeu-se a seguir a avaliação da imunomarcação de toda a casuística. As análises estatísticas de regressão linear multifatorial e regressão logística multifatorial indicaram os marcadores e padrões de expressão em ordem decrescente de importância: D2 40 positivo em células tumorais periféricas, CK 15 positivo em células tumorais periféricas, CD10 positivo no estroma tumoral, CK 20 positivo em células tumorais periféricas e positividade estromal de CD 34. A regressão logística evidenciou ainda que, na amostra examinada, a presença de três ou quatro desses marcadores, com exceção do CD 34, pode identificar 35,9% dos TE. Nossos resultados, obtidos pelo estudo de casuística expressiva, são concordantes com os achados de outros trabalhos que sugerem que o TE e o CBC são neoplasias que estão em diferentes pontos da mesma linhagem de diferenciação dos tumores basalóides foliculares e que, por este motivo, podem expressar os mesmos marcadores/perfil antigênico epitelial e estromal. Embora o painel de quatro anticorpos acima relatado possa ser de grande ajuda, e até mesmo identificar 35,9% dos TE, os critérios histopatológicos clássicos e clínicos ainda devem ser os principais guias para o diagnóstico diferencial entre o TE e o CBCTrichoepithelioma is a benign neoplasm that shares both clinical and histological features with basal cell carcinoma. It is important to distinguish these neoplasms because they have different clinical behavior and require proper therapeutic planning. Many studies have addressed the use of immunohistochemistry to improve the differential diagnosis of these tumors. These studies present conflicting results when addressing the same markers, probably due to the small number of basaloid tumors that comprised their studies, which generally did not exceed 50 cases. We built a tissue microarray with 162 trichoepithelioma and 328 basal cell carcinoma biopsies and tested a panel of immune markers composed of CD34, CD10, epithelial membrane antigen, BCL-2, cytokeratins 15 and 20 and D2-40. The results were analyzed using multiple linear and logistic regression models. This analysis revealed a model that could differentiate trichoepithelioma from basal cell carcinoma in 35,9% of the cases. The panel of immunohistochemical markers required to differentiate between these tumors was composed of CD10, cytokeratin 15, cytokeratin 20 and D2-40. The results obtained in this work were generated from a large number of biopsies and resulted in the confirmation of overlapping epithelial and stromal immunohistochemical profiles from these basaloid tumors. The results also corroborate the point of view that trichoepithelioma and basal cell carcinoma tumors represent two different points in the same line of differentiation. Despite the use of panels of immune markers, histopathological criteria associated with clinical data certainly remain the best guideline for the differential diagnosis of trichoepithelioma and basal cell carcinoma
28
Silva, Ana Paula da. "Avaliação histopatológica do tratamento do carcinoma espinocelular cutâneo em camundongos usando terapia fotodinâmica mediada por azul de metileno". Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/42/42134/tde-25112014-130952/.
Abstract (sommario):
A terapia fotodinâmica (TFD) é uma modalidade clínica para tratar uma variedade de neoplasias, doenças de pele e representa um promissor tratamento estético. O presente trabalho avaliou os aspectos histopatológicos e moleculares do tratamento pela TFD mediada por azul de metileno (TFD-AM) no modelo experimental in vivo do Carcinoma Espinocelular Cutâneo (CEC) e na pele sadia de camundongos Swiss. O protocolo da TFD foi de uma única sessão, com aplicação da solução de AM a 1% seguido por irradiação com laser diodo na dose total de 24 J/cm2 nos tecidos tumorais e sadios. Os animais foram sacrificados em dois períodos, 24 horas e 15 dias após TFD. Alterações morfológicas foram pouco marcantes nos tecidos tumorais tratados, entretanto, foram mais pronunciadas nos tecidos sadios. Podemos concluir que os efeitos de uma única sessão da TFD mediada pelo AM na dose aplicada não conferiu melhora no tratamento do CEC. Estes resultados motivam novos estudos com ajustes no protocolo para melhorar a eficácia desta terapia.Photodynamic therapy (PDT) is a clinical method for treating a variety of tumors, skin disorders and represents a promising cosmetic treatment. This study evaluated the histopathological and molecular aspects of the treatment by PDT mediated by methylene blue (PDT-MB) in vivo experimental model of cutaneous squamous cell carcinoma (SCC) and in healthy skin of swiss mice. The PDT protocol was a single session with the application of MB 1% solution followed by irradiation with diode laser at a total dose of 24 J/cm2 in tumor and healthy tissue. The animals were sacrificed at two periods, 24 hours and 15 days after PDT. Morphological changes were less marked in the tumor tissues treated, however, were more pronounced in healthy tissues treated. We can conclude that the effects of a single session of PDT mediated by MB in applied dose conferred no improvement in the treatment of SCC. These results motivate further studies with adjustments in the protocol to improve the effectiveness of this therapy.
29
Guim, Tainã Normanton. "Avaliação da sobrevida e de marcadores histomorfológicos como potenciais fatores prognósticos para carcinoma de células escamosas em cães e gatos". Universidade Federal de Pelotas, 2010. http://repositorio.ufpel.edu.br/handle/ri/2558.
Abstract (sommario):
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Previous issue date: 2010-02-26Squamous cell carcinoma (SCC) is a cutaneous malignant neoplasm commonly observed in dog and cat. Especially in our country, the SCC represents a serious problem, since chronic exposure to ultraviolet radiation is one of the important factors for the development of the disease. In this way, the objective of this study was establish histomorphological markers as prognostic factors and determine the time and the estimated survival of dogs and cats carriers of SCCs. A survey of cases of SCCs in dog and cat diagnosed at the Regional Diagnostic Laboratory from the Federal University of Pelotas, was performed during the period of 1999 to 2009. Fifty samples were obtained from biopsies and/or necropsies. From the studied cases, 24 animals with the disease were followed for a period of one year. In this study, we used the histological grade and survival time of animals as a criterion to prognostic evaluation. The histological parameters evaluated as peritumoral lymphoplasmacytic infiltration, tissue eosinophilia associated with tumor, mitotic index, arrangement, invasion to adjacent tissues, emboli vascular blood and/or lymphatic, desmoplastic reaction and quantification of AgNORs were confronted with the histological grade and the survival time of affected animals. When the histological parameters were compared with survival, a significant relation was observed with the intensity of invasion to adjacent tissues (p <0.05). When confronted with the histological grade, the invasion show significant results only to poorly differentiated SCCs and desmoplasia were statistically significant (p <0.05). In this study, the estimate of survival was 23.4% in one year to animals with or without treatment. From the results obtained, it was concluded that the intensity of invasion is an important predictive prognostic factor for cutaneous SCCs in dogs and cats. Other parameters showed no relation with the histological grade and/or survival, thus, are not considered prognostic factors predictive. The time and the estimate of survival were low and therefore the prognosis for dogs and cats carrier of cutaneous SCCs is unfavorable.
Carcinoma de células escamosas (CCE) é um neoplasma cutâneo maligno comumente observado no cão e no gato. Especialmente em nosso país, o CCE representa um problema sério, uma vez que a exposição crônica à radiação ultravioleta é um dos fatores importantes para o desenvolvimento da doença. Neste sentido, o presente estudo teve como objetivo estabelecer marcadores histomorfológicos como fatores prognósticos e determinar o tempo e a estimativa de sobrevida de cães e gatos portadores de CCEs cutâneos. Foi realizado um levantamento dos casos de CCEs em cães e gatos diagnosticados no Laboratório Regional de Diagnóstico da Universidade Federal de Pelotas, durante o período de 1999 a 2009. Foram recuperadas 50 amostras provenientes de biópsias e/ou necropsias. Do total de casos estudados, 24 animais portadores da doença foram acompanhados durante um período de um ano. Neste estudo, utilizou-se o grau histológico e o tempo de sobrevida como critério de avaliação prognóstica. Os parâmetros histológicos avaliados como: infiltrado linfoplasmacítico peritumoral, eosinofilia tecidual associada a tumores, índice mitótico, arranjo, invasão para tecidos adjacentes, êmbolo vascular sanguíneo e/ou linfático, desmoplasia e quantificação das AgNORs, foram confrontados com o grau histológico e com a sobrevida dos animais acometidos. Quando os parâmetros histológicos foram confrontados com a sobrevida, observou-se relação estatística significativa com a intensidade de invasão para tecidos adjacentes (p<0,05) e, quando confrontados com o grau histológico, a invasão somente para CCEs pouco diferenciados e a desmoplasia foram estatisticamente significativos (p<0,05). No presente estudo, a estimativa de sobrevida para animais portadores de CCEs cutâneos foi 23,4% em um ano, independentemente de terem sido tratados ou não. A partir dos resultados obtidos, concluiu-se que a intensidade de invasão é um fator prognóstico preditivo importante para CCEs cutâneos em cães e gatos. Os demais parâmetros avaliados não mostraram relação com o grau histológico e/ou com a sobrevida, dessa forma, não são considerados fatores prognósticos preditivos. O tempo e a estimativa de sobrevida foram baixos e, portanto, o prognóstico para cães e gatos portadores de CCEs cutâneos é, de um modo geral, desfavorável.
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Simonneau, Marie. "Implication de l'Oncostatine M dans la genèse et le développement des carcinomes épidermoïdes cutanés". Thesis, Poitiers, 2018. http://www.theses.fr/2018POIT1403/document.
Abstract (sommario):
Le carcinome épidermoïde cutané (CEC) est l'un des cancers les plus fréquents et il est résistant aux traitements chimiothérapeutiques classiques. De nombreuses études montrent que selon leur phénotype les cellules du microenvironnement inflammatoire peuvent inhiber (cellules Th1/M1) ou favoriser (cellules Th2/M2) le développement tumoral. En fonction des cytokines présentes dans ce microenvironnement, il est possible de reprogrammer les cellules immunitaires et de les rendre moins permissives au développement tumoral. L’onconstatine M (OSM) est une cytokine aux effets pléiotropes, elle peut favoriser la prolifération, l’invasion tumorale des cellules tumorales et induire une polarisation immunitaire Th2/M2. Nous avons montré que l'OSM a des effets pro-inflammatoires au niveau cutané et qu’elle module le phénotype des kératinocytes normaux mais son rôle dans les CEC n’est pas décrit. Nous avons donc étudié l’implication de l'OSM dans le développement des CEC. Nous avons montré que l'OSM était surexprimée dans les CEC humains ainsi que d'autres cytokines comme l'IL-6, l'IL-1β, l'IFNγ suggérant une polarisation Th1/M1 des cellules du microenvironnement. In vitro, l'OSM induit l’activation de voies de signalisation pro-tumorales (STAT3 - ERK) au niveau de kératinocytes murins malins ainsi que leur prolifération et leur migration. La greffe de ces cellules chez la souris entraine le développement de CEC associés à une surexpression d'OSM. Enfin, l’absence d'OSM entraine une diminution du volume tumoral de 30% et à une réduction de la polarisation M2. Collectivement, ces résultats suggèrent un rôle pro-tumoral de l'OSM dans le développement des CEC et le blocage de cette cytokine pourrait constituer une nouvelle alternative thérapeutiqueCutaneous squamous cell carcinoma (cSCC) is one of the most frequent keratinocyte malignancies worldwide and is chemotherapy resistant. Surgery is the curative treatment but there isn’t any alternative in advanced cSCC. Reprogramming tumor microenvironment and tumor immunosuppressive mechanisms is a new therapeutic approach. Indeed, depending on cytokine expressed in tumor microenvironment, immune cells can inhibit (Th1/M1 cells) or enhance (Th2/M2 cells) tumor development. It was previously showed that Onconstatin M (OSM) had pleiotropic effects on cancer cells. OSM can promote cancer by inducing tumor cells motility, invasiveness or by reprogramming immune cells toward a more permissive phenotype (M2 polarization). Our previous data showed that OSM has proinflammatory effects on skin and modulate normal keratinocyte phenotype both in vitro and in vivo. In this study, we hypothesized that OSM could be involved in cSCC development. We showed that OSM was overexpressed in human cSCC as well as other cytokines such as IL-6, IL-1β, IFNγ whereas IL-4 was decreased, suggesting a Th1/M1 polarization of cSCC microenvironment. In vitro, OSM induced STAT-3 and ERK signalization, modified gene expression, promoted proliferation and migration of malignant keratinocyte PDVC57 cells. PDVC57 cells grafted in skin mice led to cSCC development associated to OSM overexpression by immune infiltrated cells. Finally, we showed that the absence of OSM led to a 30% reduction of tumor size and reduced M2 polarization in tumor microenvironment. Collectively, these results support a pro-tumoral role of OSM in cSCC development and suggest a new therapeutic approach targeting this cytokine
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Strioga, Marius. "Expression of biomarkers, representing immunosuppressive, cytotoxic or immunomodulating properties of CD8h T lymphocytes in the peripheral blood of patients with immunogenic cancer forms". Doctoral thesis, Lithuanian Academic Libraries Network (LABT), 2010. http://vddb.laba.lt/obj/LT-eLABa-0001:E.02~2010~D_20100702_105111-42651.
Abstract (sommario):
The aim of the study was to evaluate the expression of immunosuppressive (FOXP3, NKG2A), and cytotoxic (perforin) or cytotoxic / immunomodulating (IFNγ) T-cell properties representing biomarkers in the peripheral blood CD8h T-cell population of patients with advanced renal cell carcinoma (RCC) or high risk cutaneous melanoma and healthy controls by multicolour flow cytometry. Determination of the percentage of functionally competing T-cell subsets (especially immunosuppressive) in the CD8hCD57+ T-cell subpopulation in future may serve as one of parameters enabling to assess the overall status of antitumor immune response and select cancer patients most suitable for antitumor immunotherapy while dismissing those to whom it would be ineffective or even harmful.Darbo tikslas buvo įvertinti imunosupresines (FOXP3, NKG2A), citotoksines (perforin) bei citotoksines / imunomoduliuojančias (IFNγ) savybes atspindinčių žymenų raiškos skirtumus išplitusiu inkstų vėžiu ar didelės rizikos odos melanoma sergančių pacientų periferinio kraujo CD8h T limfocitų populiacijoje, lyginant su kontroline grupe. Skirtingas T limfocitų savybes atspindinčių žymenų raiška buvo tiriama tėkmės citometrijos būdu. Nustatyta, kad inkstų vėžiu ar odos melanoma sergančių pacientų periferiniame kraujyje Įvairių subpopuliacijų (ypač imunosupresinės) nuošimčio nustatymas CD8hCD57+ T limfocitų populiacijoje ateityje gali būti naudingas klinikinėje praktikoje, individualizuojant priešnavikinę imunoterapiją ir selektyviai parenkant tik tuos pacientus, kuriems imuninės sistemos aktyvinimas sukeltų navikinių ląstelių naikinimą, o ne dar labiau gilintų imunosupresiją.
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Strioga, Marius. "Imunosupresines, citotoksines bei imunomoduliuojančias savybes atspindinčių žymenų raiška imunogeniškomis vėžio formomis sergančių pacientų periferinio kraujo CD8h T limfocitų populiacijoje". Doctoral thesis, Lithuanian Academic Libraries Network (LABT), 2010. http://vddb.laba.lt/obj/LT-eLABa-0001:E.02~2010~D_20100702_105125-92547.
Abstract (sommario):
Darbo tikslas buvo įvertinti imunosupresines (FOXP3, NKG2A), citotoksines (perforin) bei citotoksines / imunomoduliuojančias (IFNγ) savybes atspindinčių žymenų raiškos skirtumus išplitusiu inkstų vėžiu ar didelės rizikos odos melanoma sergančių pacientų periferinio kraujo CD8h T limfocitų populiacijoje, lyginant su kontroline grupe. Skirtingas T limfocitų savybes atspindinčių žymenų raiška buvo tiriama tėkmės citometrijos būdu. Nustatyta, kad inkstų vėžiu ar odos melanoma sergančių pacientų periferiniame kraujyje Įvairių subpopuliacijų (ypač imunosupresinės) nuošimčio nustatymas CD8hCD57+ T limfocitų populiacijoje ateityje gali būti naudingas klinikinėje praktikoje, individualizuojant priešnavikinę imunoterapiją ir selektyviai parenkant tik tuos pacientus, kuriems imuninės sistemos aktyvinimas sukeltų navikinių ląstelių naikinimą, o ne dar labiau gilintų imunosupresiją.The aim of the study was to evaluate the expression of immunosuppressive (FOXP3, NKG2A), and cytotoxic (perforin) or cytotoxic / immunomodulating (IFNγ) T-cell properties representing biomarkers in the peripheral blood CD8h T-cell population of patients with advanced renal cell carcinoma (RCC) or high risk cutaneous melanoma and healthy controls by multicolour flow cytometry. Determination of the percentage of functionally competing T-cell subsets (especially immunosuppressive) in the CD8hCD57+ T-cell subpopulation in future may serve as one of parameters enabling to assess the overall status of antitumor immune response and select cancer patients most suitable for antitumor immunotherapy while dismissing those to whom it would be ineffective or even harmful.
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Maubec, Eve. "Prédisposition génétique au mélanome : de la génétique à la recherche clinique". Thesis, Paris 11, 2012. http://www.theses.fr/2012PA11T034.
Abstract (sommario):
Ce travail avait deux objectifs: 1) définir des groupes de patients (pts) susceptibles de bénéficier d’un conseil génétique par l’identification de facteurs prédictifs de l’existence d’une mutation du gène CDKN2A, un des gènes majeurs de prédisposition au mélanome, dans les familles ne comportant que deux cas (Fam_2 cas). 2) la caractérisation épidémiologique et clinique d’entités particulières du mélanome dans l’objectif secondaire de contribuer à l’identification de gènes de prédisposition à ces entités. Les 2 entités étudiées étaient le mélanome cutané (MC) associé au cancer du rein (CR) et les mélanomes muqueux de la sphère ano-génitale (MMAG).Les populations d’étude sont une collection de 293 pts atteints de MC recrutés de façon consécutive sans connaissance à priori de l'histoire familiale et la collection française MELARISK qui comprend ≥ 3000 sujets prélevés appartenant à des familles à cas multiples de mélanomes ou ayant un MC survenant dans un contexte particulier (association à un autre cancer, topographie rare, survenue avant l’âge de 20 ans, MC multiples sporadiques). Nous avons étudié l'effet de 3 facteurs prédictifs potentiels sur la présence d’une mutation de CDKN2A dans une famille en fonction du nombre de pts atteints dans une famille (2 pts versus ≥3 pts). L’étude a été menée dans 483 familles françaises comprenant 387 Fam_2 cas, et 96 familles avec ≥3 pts atteints de mélanome (Fam_3+ cas). Les facteurs étudiés dans la famille un à un puis conjointement étaient : l’âge médian <50 ans au diagnostic de MC, la survenue de ≥1 cas de MC primitifs multiples (MPM) et la survenue de ≥1 cas de cancer du pancréas (CPCP). La fréquence des mutations était plus élevée dans les Fam_3+ cas (32%) que dans les Fam_2 cas (13%). Alors qu’un âge jeune au diagnostic et la survenue de ≥ 1 MPM étaient associés à la présence de mutations de CDKN2A dans les Fam_2 cas, un âge jeune au diagnostic ainsi que la présence de ≥1 cas de CP était associé significativement aux mutations de CDKN2A dans les Fam_3+ cas. L’étude a montré que les caractéristiques cliniques associées aux mutations de CDKN2A varient, en France, pays de faible incidence de mélanome, en fonction du degré d’agrégation familiale. L’identification de facteurs prédictifs de mutations de CDKN2A dans les Fam_2 cas a contribué à définir des sous-groupes de familles (âge jeune au diagnostic, survenue de MPM) dans lesquels la fréquence des mutations de CDKN2A est supérieure à 20% et auxquels il est légitime de proposer un test génétique. L’analyse des deux séries de pts MM+CR et MMAG a permis d’identifier, en les comparant à la série de MC recrutés de manière consécutive, leurs caractéristiques cliniques et histologiques. Dans ces deux séries, nos résultats ont mis en évidence un contexte de prédisposition héréditaire en partie indépendant de CDKN2A. L’étude de l’association MC et CR chez un même patient a eu deux conséquences pratiques: pour les cliniciens ces résultats suggèrent l’intérêt d’un examen dermatologique en cas de CR et l’intérêt de l’échographie abdominale dans le bilan initial d’un MC pour le dépistage du CR; pour la recherche en génétique, cette série a contribué à l’identification d’une mutation germinale dans le gène MITF qui augmente le risque de développer un MC, un CR ou l’association des deux cancers et qui a des propriétés biologiques intéressantes. L’étude des MMAG a montré que ces mélanomes pouvaient être associés à des MC chez un même malade et/ou survenir dans un contexte familial de mélanome. Le corollaire clinique de ces résultats est que l’examen dermatologique de dépistage ou de surveillance doit être à la fois cutané et muqueux dans un contexte familial de mélanome et qu’en cas de MMAG un examen dermatologique des apparentés doit être proposé comme c’est la règle dans les MC. L’absence de mutation de CDKN2A dans ces localisations muqueuses incite à entreprendre des études génétiques pour identifier les gènes impliquésThis thesis had two main objectives: 1) To define groups of patients which may benefit from genetic counseling by identifying predictors of mutations of the CDKN2A gene, a major gene predisposing to cutaneous melanoma (CM) in families with only two cases. 2) Epidemiological and clinical characterization of specific entities of melanoma with the secondary objective of contributing to the identification of susceptibility genes for these entities. Coexistence of CM with renal cell carcinoma and mucosal anogenital melanomas were studied.The study populations are a collection of 293 melanoma patients that were ascertained systematically and the French collection MELARISK which is a collection including over 3000 subjects drawn from families with multiple cases of melanoma or melanoma occurring in a particular context (association with another cancer, rare locations, occurrence before the age of 20, multiple sporadic melanomas).We investigated association of three clinical features with the presence of a CDKN2A mutation in a family by extent of CM family clustering (2 versus ≥3 CM patients among first-degree relatives in a family).The study was conducted in 483 French families including 387 families with two melanoma patients, and 96 families with three or more patients with melanoma. The factors examined individually and in a joint analysis in a family were: median age at diagnosis <50 years, ≥1 patient in a family with multiple primary melanomas (MPM) or with pancreatic cancer. The frequency of CDKN2A mutations was higher in F3+ families (32%) than in F2 families (13%). While early age at melanoma diagnosis and occurrence of MPM in ≥1 patient were significantly associated with the risk of a CDKN2A mutation in F2 families, early age at melanoma diagnosis and occurrence of pancreatic cancer in a family were significantly associated with CDKN2A mutations in F3+ families. Thus this study showed that clinical features associated with CDKN2A mutations vary, in France, a country of low incidence of melanoma, according to the degree of familial clustering. Identifying predictors of CDKN2A mutations in families with two melanoma cases has helped to define subgroups of families (early age at CM diagnosis, and/or ≥1 MPM patient) in which the frequency of CDKN2A mutations is above 20% such that these subgroups of F2 families should be offered genetic testing.The analysis of two series of patients, either patients with melanoma coexisting with renal cell carcinoma or patients with anogenital mucosal melanoma identified their clinical and histological features by comparing them to a series of melanomas that were ascertained systematically. In both series, our results suggested a genetic predisposition at least partly independent of CDKN2A. The study of the c renal cell carcinoma; coexistence of CM and renal cancer in the same patient had two practical consequences for clinicians: it suggests the interest of a dermatologic screening visit in patients with renal cell carcinoma and that abdominal ultrasonography or computed tomography scanning performed at the initial workup and during the follow-up of patients with CM may be of value for the early detection of renal cancer. Regarding genetic research, this series has contributed to the identification of a germline mutation in the MITF gene that increases the risk of developing melanoma, renal cancer or both cancers and has interesting biological properties. The study of anogenital melanoma has shown that these melanomas could be associated with cutaneous melanoma in the same patient and it has also shown a high frequency of family history of melanoma associating mucosal and CM suggesting a shared genetic predisposition. Consequently dermatological screening or monitoring must include examination of both skin and mucosa in families with multiple cases of CM; and in case of a mucosal melanoma, a dermatological examination should be offered to relatives. The genetic mechanism has to be identified
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Colas, Victor. "Modeling and estimation of human skin optical properties using spatially resolved autofluorescence and diffuse reflectance spectroscopy". Electronic Thesis or Diss., Université de Lorraine, 2022. http://www.theses.fr/2022LORR0129.
Abstract (sommario):
Dans le contexte du carcinome cutané, la biopsie optique offre une alternative in-vivo non destructive à la biopsie conventionnelle pour informer le praticien dermatologue de l'état de santé du tissu en profondeur lors de la résection du cancer. Ce dernier est en effet à l'origine de modifications morphologiques et physiologiques de la peau, ce qui explique que les mesures optiques resultantes des interactions lumière/tissus y soient sensibles. Les travaux présentés dans ce manuscrit exploitent les données obtenues l'aide du dispositif de biopsie optique SpectroLive sur une centaine de patients juste avant la résection du cancer par le clinicien. Au contact de la peau, ce dispositif spectroscopique acquiert des signaux de réflectance diffuse (excitation large bande blanche) et d'autofluorescence (émission monochromatique pour exciter les fluorophores endogènes de la peau) résolus spatialement, i.e., pour plusieurs distances de séparation entre la fibre émettrice de lumière est les fibres collectrices en périphérie. Cette résolution spatiale est particulièrement d'intérêt pour la peau, puisque les différentes distances introduites permettent de collecter des photons parcourant les différentes couches en profondeur (épiderme, derme et hypoderme) de l'organe. L'essentiel des travaux présentés ici concerne l'estimation des propriétés optiques de la peau grâce à la résolution du problème inverse à partir de ces acquisitions cliniques. Cela consiste d'abord à établir une simulation de transport de photons fidèle aux caractéristiques (géométriques et spectrales) du dispositif réel avant de construire un modèle multicouche de la peau dans lequel les paramètres optiques (e.g. coefficients d'absorption et de diffusion, le facteur d'anisotropie) et géométriques (e.g. épaisseur des couches) peuvent être estimées par un processus d'optimisation visant à minimiser les différences entre les spectres générés par la simulation et les spectres "cibles" obtenus en clinique. Dans ce but, les contributions principales développées dans ce manuscrit sont d'abord le développement et l'exploitation totale de la simulation, avec notamment une étude visant à caractériser la pénétration des photons détectés aux différentes séparation source/détecteur, et ceci pour différents modèles de peau afin de représenter les différences inter- et intra-individu. Les connaissances acquises avec cette étude de profondeurs sondées sont ensuite utilisées dans la seconde contribution majeure, visant à adapter le processus d'estimations des propriétés optiques à partir des spectres cliniques (problème inverse) à la peau. Enfin, la dernière contribution, plus métrologique, est l'élaboration d'un banc optique à double sphères intégrantes permettant d'obtenir ces mêmes propriétés optiques pour un échantillon ex-vivo, et ainsi permettre la comparaison des estimations issues des deux modalitésIn the context of cutaneous carcinoma, optical biopsy offers a in-vivo non-destructive alternative to conventional biopsy to inform the dermatologist of the state of health of the deep tissue during cancer resection. The latter is indeed at the origin of morphological and physiological modifications of the skin, which explains why the optical measurements resulting from the light/tissue interactions are sensitive to it. The work presented in this manuscript exploits the data obtained with the optical biopsy device extit{SpectroLive} on about a hundred patients just before cancer resection by the clinician. In contact with the skin, this spectroscopic device acquires diffuse reflectance (white broadband excitation) and autofluorescence (monochromatic emission to excite endogenous fluorophores in the skin) spatially resolved signals, extit{i.e.}, for several separation distances between the light emitting fiber and the collecting fibers at the periphery. This spatial resolution is of particular interest for the skin, since the different distances introduced allow the collection of photons traveling through the different layers in depth (epidermis, dermis and hypodermis) of the organ. The main part of the work presented here concerns the estimation of the optical properties of the skin by solving the inverse problem from these clinical acquisitions. This consists first in establishing a photon transport simulation faithful to the characteristics (geometrical and spectral) of the real device before building a multilayer model of the skin in which the optical parameters (e.g. absorption and scattering coefficients, the anisotropy factor) and geometrical parameters e.g. layer thickness) can be estimated by an optimization process aiming at minimizing the differences between the spectra generated by the simulation and the ``target'' spectra obtained in clinic. The main contributions developed in this manuscript are first the development and the full exploitation of the simulation, with in particular a study whose purpose is to characterize the penetration of the photons detected at the various source/detector separations, and this for various skin models in order to represent the inter- and intra-individual differences. The knowledge acquired with this study of probed depths is then used in the second major contribution, aiming at adapting the process of estimating optical properties from clinical spectra (inverse problem) to the skin. Finally, the last contribution, more metrological, is the development of an optical bench with double integrating spheres allowing to obtain these same optical properties for a sample ex-vivo, and thus to allow the comparison of the estimates resulting from the two modalities
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Akinduro, Olufolake A. E. "Autophagy in epidermis". Thesis, Queen Mary, University of London, 2013. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8703.
Abstract (sommario):
Organ‐transplant recipients (OTRs) on a new class of immunosuppressants, rapamycin and its analogues, have reduced cutaneous Squamous Cell Carcinomas (cSCCs). Rapamycin, an mTORC1 inhibitor, is also a known autophagy inducer in experimental models. Autophagy, which literally means self‐eating, is a cell survival mechanism but can also lead to cell death. Therefore, the main hypothesis behind this work is that rapamycin prevents epidermal tumourigenesis by either affecting epidermal mTOR regulation of autophagy and/or selectively affecting epidermal AKT isoform activity. Epidermal keratinocytes move from the proliferating basal layer upwards to the granular layers where they terminally differentiate, forming a layer of flattened, anucleate cells or squames of the cornified layer which provides an essential environmental barrier. However, epidermal terminal differentiation, a specialised form of cell death involving organelle degradation, is poorly understood. The work presented in this thesis shows that analysis of the autophagy marker expression profile during foetal epidermal development, indicates autophagy is constitutively active in the terminally differentiating granular layer of epidermis. Therefore, I hypothesize that autophagy is a mechanism of organelle degradation during terminal differentiation of granular layer keratinocytes. In monolayer keratinocytes, activation of terminal differentiation is accompanied by autophagic degradation of nuclear material, nucleophagy. This suggests that constitutive autophagy is a pro‐death mechanism required for terminal differentiation. In cultured keratinocytes and in epidermal cultures, rapamycinmediated mTORC1 inhibition strongly increases AKT1 activity as well as up‐regulates constitutive granular layer autophagy promoting terminal differentiation. Therefore, autophagy is an important fundamental process in keratinocytes which may be the mechanism by which terminally differentiating keratinocytes of the epidermal granular layer degrade their organelles required for barrier formation. This may have implications for the treatment of patients with barrier defects like psoriasis. In immunosuppressed OTRs, rapamycin may promote epidermal autophagy and AKT1 activity adding to its anti‐tumourigenic properties.
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Khou, Sokchea. "Contribution des neutrophiles infiltrant les tumeurs dans la progression des carcinomes épidermoïdes cutanés : neutrophiles et cancer". Thesis, Université Côte d'Azur (ComUE), 2019. http://theses.univ-cotedazur.fr/2019AZUR4014.
Abstract (sommario):
Les carcinomes cutanés constituent les cancers les plus fréquents chez l’homme et leur incidence est en constante croissance. Il en existe deux principaux types : les carcinomes baso-cellulaires et les carcinomes épidermoïdes. Les facteurs de risque sont principalement l’exposition aux rayons UV et l’immunosuppression. Ils sont traités par chirurgie ou par radiothérapie mais peuvent parfois évoluer vers des formes incurables. De nouvelles alternatives thérapeutiques sont donc nécessaires. L’immunothérapie est une récente révolution dans le traitement des cancers qui vise à réactiver l’immunité des patients cancéreux. Les carcinomes cutanés pourraient en bénéficier car ils se développent lors de situations d’immunosuppression. L’immunosurveillance implique à la fois les cellules immunitaires et le microenvironnement tumoral comme le stroma. Lorsque les réponses anti-tumorales, notamment médiées par les lymphocytes T CD8+ sont efficaces, on parle de phase d’élimination. Puis vient une phase d’équilibre où la tumeur reste stable et enfin, lors de la phase finale d’échappement, des mécanismes d’immunosuppression permettent à la tumeur de croître. Les neutrophiles, des cellules immunitaires de type myéloïde, sont recrutées très rapidement aux sites d’inflammation et au sein des cancers. Une méta-analyse récente sur 39 types de cancers humains a pu associer ces cellules aux plus mauvais pronostiques cliniques. Elles sont impliquées dans des fonctions anti-tumorales et pro-tumorales. Cette polarisation semble induite respectivement par l’interféron de type I et le TGF-β. Leur rôle lors de cancers et en particulier dans les carcinomes cutanés reste encore largement incompris. Notre objectif a été de caractériser les fonctions des neutrophiles et leur contribution au développement des carcinomes épidermoïdes. Pour cela, nous avons utilisé premièrement, un modèle de carcinogénèse cutanée chimio-induite. La tumorigénèse est séquentielle et donc très représentative du carcinome cutané chez l’homme. Dans ce modèle, nous observons une infiltration massive des neutrophiles au stade précancéreux et cancéreux. Une analyse de l’expression génique des neutrophiles isolés des lésions précancéreuses et cancéreuses et des peaux environnant ces lésions a été réalisée, qui montre une signature génique spécifique des neutrophiles des lésions, comparée aux peaux environnantes. Des comparaisons d’expression génique différentielle illustrent que les neutrophiles des lésions possèdent des fonctions pro-tumorales comparés aux neutrophiles des peaux.Deuxièmement, nous avons mis en place un modèle de greffe intradermique d’une lignée de carcinome épidermoïde. Une déplétion spécifique des neutrophiles retarde significativement la croissance tumorale, ce qui confirme le caractère pro-tumoral des neutrophiles. Nous avons caractérisé les mécanismes mis en jeu, qui incluent la génération de ROS et iNOS favorisant la croissance tumorale et une suppression de l’activation et de la prolifération des lymphocytes T CD8+ anti-tumoraux. Les neutrophiles produisent de l’arginase 1 qui dégrade l’arginine et inhibe la prolifération des lymphocytes T. Par ailleurs, l’environnement tumoral induit l’expression de PD-L1 en surface des neutrophiles et de PD1 en surface des lymphocytes T CD8+ et CD4+. Ceci suggère que l’interaction PD-L1/PD1 contribue à l’immunosuppression. De plus, une corrélation positive et significative a été observée entre la taille des tumeurs et la fréquence des neutrophiles exprimant PD-L1 au sein de ces tumeurs. Au vu de ces résultats, il semble intéressant d’évaluer les immunothérapies bloquant l’interaction PD-L1/PD1 dans le traitement des carcinomes cutanés. Ces traitements pourraient être combinés avec ceux qui bloquent le recrutement ou les fonctions des neutrophiles. Il reste à évaluer si la fréquence de neutrophiles exprimant PD-L1 peut être un bon marqueur de prédiction de la réponse aux immunothérapies anti-PD-L1 ou anti-PD1Non-melanoma skin carcinomas are the most frequent cancers in Human and their incidence is constantly increasing. Two main types exist: the cutaneous basal cell carcinoma (cBCC) and the cutaneous squamous cell carcinomas (cSCC). Risk factors include sun radiation and immunosuppression. These cancers are mainly treated with surgery and radiotherapy but they can reach an incurable stage. For this reason, novel therapeutic alternatives are needed. At present, immunotherapies constitute a revolution in the treatment of cancers. Its mechanism of action relies on the stimulation of the immune system of cancer patients, so that they develop efficient anti-tumoral immune responses. cSCC may benefit from this type of treatment as they generally develop in the context of an immunosuppression. Immune surveillance involves both immune cells and the tumor microenvironment, in particular the stroma. During the elimination phase, the anti-tumoral responses, mediated mainly by CD8+ T lymphocytes, are efficient. Then, there is an equilibrium phase in which the tumor is stable before the escape phase, when the tumor can evade immune surveillance and grow. Our research interest focused on neutrophils, a subset of myeloid cells that are very rapidly recruited to the sites of inflammation and inside tumors. A recent meta-analysis of 39 human malignancies showed that neutrophils are associated with the worst clinical outcome. Neutrophils harbor both anti- and pro-tumoral functions. This polarization seems to be dependent on type I interferon and TGF-β, respectively. It remains to establish the exact role played by neutrophils in cancer and specifically in skin carcinomas. The aim of our research was to further characterize the functions and the contribution of neutrophils to the development of cutaneous squamous cell carcinomas. We first used a chemically-induced skin carcinoma mouse model that recapitulates the different stages of skin carcinoma development in Human. In this model, we saw a massive infiltration of neutrophils at the precancerous and cancerous stages. We performed transcriptomic analysis of highly purified neutrophil populations from precancerous, cancerous lesions and from the surrounding skin controls. These data revealed a specific gene signature in neutrophils from lesions compared to surrounding skins. Differential gene expression analysis identified a pro-tumoral phenotype for neutrophils infiltrating lesions compared to skins. In a second approach, we studied the growth of a cSCC cell line grafted in the dermis of mice. Specific depletion of neutrophils significantly delayed tumor growth, thus indicating that neutrophils were pro-tumoral. Mechanisms of action included the production of ROS and NO that favor tumor growth and the immune suppression of anti-tumoral responses mediated by tumor-associated CD8+ T cells. In the tumor, neutrophils produced arginase 1 which catalyzes the degradation of arginine, thus inhibiting the proliferation of CD8+ T cells. In addition, we found that the tumor microenvironment induced PD-L1 expression at the cell surface of neutrophils and concomitantly, PD1 on CD8+ and CD4+ T cells. These results suggested that PD-L1/PD1 interaction triggers immune suppression and contributes to SCC progression. Indeed, a positive and significant correlation was observed between tumor size and frequencies of PD-L1-expressing neutrophils inside tumors. Collectively, these results suggest that it is relevant to assess immunotherapies that block PD-L1/PD1 interaction for the treatment for cSCC. These approaches could be combined with treatments that aim to block the recruitment or inhibit neutrophils. Moreover, it remains to evaluate whether the frequency of PD-L1-expressing neutrophils could constitute a good predictive marker of the response to anti-PD-L1 and anti-PD1 immunotherapies
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ARFI, CATHERINE. "Exerese en deux temps des carcinomes cutanes etendus de la face : etude retrospective de 87 patients". Nantes, 1994. http://www.theses.fr/1994NANT247M.
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PIREDDU, ROSA. "Nanosized systems for efficient delivery of antitumoral and anti-inflammatory drugs". Doctoral thesis, Università degli Studi di Cagliari, 2015. http://hdl.handle.net/11584/266618.
Abstract (sommario):
The purpose of the present PhD thesis was to study two different nanosized systems, liposomes and nanosuspensions. Liposomes were develop with the aim to improve the Triiodothyronine (T3) delivery to hepatic cancer cells and nanosuspensions were proposed to enhance dermal bioavailability of Diclofenac acid, a potent nonsteroidal anti-inflammatory drug (NSAID) with a very low aqueous solubility. T3, is a thyroid hormone normally synthesized and secreted by the thyroid gland and through interaction with its nuclear receptors (TRs) plays an essential role in morphogenesis and differentiation. However, there is increasing evidence for its role in hepatocellular carcinoma (HCC) suppression. Three different liposome systems, such as, conventional, Stealth (PEGylated) and Lf-modified-Stealth liposomes were successfully prepared, by the film hydration method, and characterized. Liposomes showed a mean diameter ranging between 86 and 126 nm and a PI lower than 0.28, as shown by PCS measurements. Liposomes cell interactions and cellular uptake were evaluated in three different HCC target cells (FaO, HepG2 and SKHep) by confocal microscopy using liposomes labeled with the lipophilic marker Rho-PE and loaded with the hydrophilic probe CF. Finally, in vitro cytotoxicity studies were carried out by using MTT assay to evaluate the toxicity of the liposome delivery system and to test the effect of T3 when incorporated into liposomes. These studies provides the great potential of liposomes as suitable carrier for T3 delivery to hepatoma cells. Internalization studies performed using Lf-modified-liposomes labeled with the lipophilic marker Rho-PE and loaded with the hydrophilic probe CF clearly demonstrated the effective internalization of both hydrophilic and lypophilic markers. Lf-liposome might markedly enhance the specific cell binding and cellular uptake in hepatoma cells due to the mediating of Lf that could bind to multiple receptors on cell surface such as ASGP-R with high affinity. From our data, emerges that liposome delivery system may insure a specific and sustained drug delivery, a reduced therapeutic dose and, in particular, should avoid deleterious side effects of T3 treatment. Overall, our results showed that liposomes are good candidates as liver delivery system of T3 since cell viability tests performed by using hepatoma cell lines demonstrated a very low toxicity of all three lyposome formulations. On the other hand, nanocrystal formulations, containing two different diclofenac acid crystal forms, were developed with the aim to improve dermal drug bioavailability. Nanosuspensions were obtaining using wet media milling technique and were characterized in terms of size distribution, morphology, zeta potential, differential scanning calorimetry and X-ray diffraction powder. The ability of the nanocrystals to improve dermal drug bioavailability was investigated in vitro using Franz diffusion vertical cells and newborn pig skin, in comparison with diclofenac acid coarse suspensions and a commercial topical formulation containing diclofenac sodium. Nanocrystals exhibited a mean diameter ranging between 279 and 315 nm and a PI lower than 0.25, as shown by PCS measurements. The XRDP and DSC analysis clearly indicated that the preparation process did not modify the diclofenac polymorphic forms. In vitro transdermal delivery experiments showed an improved skin deposition and permeation of the nanocrystals compared to coarse suspensions and diclofenac sodium commercial topical formulation. These results highlight the fundamental role of the crystal size on drug solubility and, thus, on the ability of a poorly soluble drug to cross the skin and accumulate in the deeper skin layers. Afterwards, the aims of the work were to develop Diclofenac acid (DCF) nanosuspensions obtained by the addition of a permeation enhancer, Transcutol (TRC), in the aqueous stabilizer solution and to study the effect of Transcutol on the transdermal permeation and skin accumulation of DCF nanocrystals. DCF-TRC-nanosuspensions, prepared using the wet media milling technique, were characterized in terms of size distribution, morphology, zeta potential, differential scanning calorimetry, X-ray diffraction powder and Fourier transform infrared spectroscopy.The influence of Transcutol concentration on skin penetration ability of DCF nanosuspensions was evaluated by in vitro skin penetration and permeation studies using Franz diffusion vertical cells and newborn pig skin, in comparison with DCF nanosuspension without TRC, DCF coarse suspension and a commercial topical formulation containing diclofenac sodium. Nanosuspensions with Transcutol exhibited a mean diameter of ∼350 nm and a polydispersity index ranging between 0.21 and 0.26, values greater than those of the nanosuspension without TRC. In vitro permeations studies showed that the increase of TRC in the nanosuspension formulations decreased the DCF skin delivery probably because the higher average diameter values of TRC nanosuspensions could decrease the DCF dissolution velocity with respect to nanosuspension without TRC. Moreover, although TRC is considered a powerful solubilizing agent, the increase of its concentration in the nanosuspension formulations determined the DCF solubility decrease. In light of these results, in the last part of this thesis nanocrystals of diclofenac (DCF) are proposed as a novel approach to treat skin inflammation, and their efficacy was validated in an animal model. Diffusion of DCF through mouse skin was investigated ex vivo, and the topical anti-inflammatory potential of the DCF nanosuspension was assessed in vivo by testing their activity against common inflammatory endpoints: inhibition of chemically induced oedema and leucocyte infiltration (reflected in myeloperoxidase–MPO-activity). TPA (12-O-tetradecanoylphorbol-13-acetate) is commonly used to induce inflammation in animal models. The therapeutic efficacy of the nanosuspension was
compared with those of a DCF coarse suspension and a commercial topical preparation containing diclofenac diethylamine, Voltaren Emulgel®. In vivo and ex vivo results have proven the superior anti-inflammatory efficacy of the nanocrystal suspension and its actual ability to localize the drug in the site of inflammation, compared to a commercial product (Voltaren). In conclusion, this study highlights the great potential of using nanocrystal suspensions as an effective strategy to improve topical bioavailability of poorly water-soluble drugs as well as a valid therapeutic approach.
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ROCA, ROUSSEAUX FREDERIQUE. "Actualites en cryochirurgie : que penser d'un nouveau cryogene, le protoxyde d'azote, dans le traitement des carcinomes cutanes ? apport de l'echographie cutanee, mode b, comme nouvelle methode de controle". Reims, 1992. http://www.theses.fr/1992REIMM033.
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Pyczek, Joanna. "Hedgehog signaling in cutaneous squamous cell carcinoma". Doctoral thesis, 2017. http://hdl.handle.net/11858/00-1735-0000-002E-E330-0.
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Laert, José Artur Veiga. "Revisão sistemática: tratamento do carcinoma espinocelular cutâneo avançado". Master's thesis, 2019. http://hdl.handle.net/10316/89850.
Abstract (sommario):
Trabalho Final do Mestrado Integrado em Medicina apresentado à Faculdade de MedicinaINTRODUÇÃO: O carcinoma espinocelular cutâneo (CECc) é o segundo tipo mais comum de neoplasia da pele e a sua incidência tem vindo a aumentar ao longo das últimas décadas. A maioria dos CECc pode ser tratada com procedimentos simples, no entanto o tratamento da doença avançada está mal definido e, pela sua raridade, existem poucos ensaios clínicos disponíveis. Esta revisão sistemática tem como objetivo sumarizar as opções de tratamento disponíveis, focando nos avanços mais recentes. MÉTODOS: Foram realizadas pesquisas nas bases de dados PubMed e Embase utilizando palavras-chave relacionados com o CECc avançado. Aplicando critérios específicos de inclusão e exclusão, a seleção dos artigos foi efetuada com base na leitura do título e/ou resumo. Também se consideraram elegíveis as recomendações internacionais sobre o tema.RESULTADOS: Obtiveram-se 80 artigos publicados entre 2010 e 2018. Cirurgia, radioterapia e quimioterapia, isoladas ou em associação, têm sido considerados o tratamento padrão do CECc avançado. A deteção de mutações das vias de proliferação celular abriu as portas ao uso das terapêuticas dirigidas a alvos moleculares, nomeadamente os inibidores do EGFR. A elevada carga mutacional torna estes tumores suscetíveis de responder à imunoterapia.DISCUSSÃO: Os resultados obtidos com cirurgia, radioterapia e quimioterapia são condicionados pelo grau de evolução da doença, sendo a sua aplicação limitada pelas comorbilidades dos doentes. Os inibidores do EGFR estão associados a respostas objetivas relevantes, embora de curta duração. Em relação à imunoterapia, os estudos iniciais sobre os inibidores do PD-1 mostram uma taxa de resposta significativa. CONCLUSÃO: A escassez de estudos controlados para confirmar a eficácia e segurança das terapêuticas disponíveis dificulta uma estandardização do tratamento baseada em evidência robusta. Apesar das novas opções terapêuticas, o CECc avançado permanece uma doença de mau prognóstico.
INTRODUCTION: Cutaneous squamous cell carcinoma is the second most common type of skin neoplasm and its incidence has been increasing over the last decades. Most cases can be treated with simple procedures, but the treatment of advanced disease is poorly defined and, due to its rarity, there are few clinical trials available. This systematic review aims to summarize the available treatment options, focusing on the most recent advances in this field.METHODS: A search was performed on PubMed and Embase databases using keywords related to advanced cutaneous squamous cell carcinoma. Applying specific inclusion and exclusion criteria, the selection of the articles was done based on the reading of the title and/or summary. International recommendations on the subject were also considered eligible.RESULTS: A total of 80 articles published between 2010 and 2018 have been found. Surgery, radiation therapy and chemotherapy, alone or in association, have been considered the standard treatment for advanced cutaneous squamous cell carcinoma. Detection of mutations in cell proliferation pathways has opened the doors to the use of targeted therapies, namely EGFR inhibitors. The high mutational burden serves as a rational basis for the use of immune checkpoint inhibitors.DISCUSSION: The results obtained with surgery, radiotherapy and chemotherapy are conditioned by the degree of the disease, and its application is limited by the patients comorbidities. EGFR inhibitors are associated with a significant rate of disease control, but the response is generally short-lived. Regarding immunotherapy, initial studies on PD-1 inhibitors show a significant response rate.CONCLUSION: Considering the few controlled studies to confirm the efficacy and safety of different treatments, it is still not possible to design an evidence-based standard management of this disease. Advanced cutaneous squamous cell carcinoma is a disease with poor prognosis despite the new therapies.
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Hsiang-YunWang e 王湘韻. "PEI-mediated Anti-cancer Gene Delivery to Cutaneous Squamous Carcinoma Cell". Thesis, 2012. http://ndltd.ncl.edu.tw/handle/54803070449885568583.
Abstract (sommario):
碩士國立成功大學
臨床藥學與藥物科技研究所
100
Cutaneous squamous cell carcinoma (SCC) is the second most common form of skin cancer. The incidence of this type of skin cancer has increased greatly for the past decade. The treatment for treatment of squamous cell carcinoma include surgery, radiotherapy, chemotherapy, immunotherapy and gene therapy. Human WWOX gene, encoding the WWOX/FOR/WOX1 family proteins, is mapped to a fragile site on chromosome 16q23.2. WOX1 protein is considered as a candidate tumor suppressor protein. TP53 gene is located on the short arm of chromosome 17p13.1. It is well-known that p53 protein is important for cellular response to a wide variety of stressful stimulation. During the development of skin cancer, loon-term ultraviolet radiation (UVR) exposure can alter gene activity in keratinocytes, resulting notably p53 mutantion. The technology of gene delivery plays an important role in the evelopment of gene therapy. Several methods have been developed to transfer DNA into cells for gene therapy. One of the non-invasive gene delivery methods is the use of gene vectors or carriers. Polyethylenimine (PEI) is a cationic polymer-based gene carrier,. Many researches demonstrated that PEI can transfer genes into different kind of cells under different transfection conditions. The aim of this study was to examine the feasibility of using PEI as gene carrier to deliver WWOX gene TP53 gene to squamous cell carcinoma. The PEI/DNA complexes of different N/P ratios were characterized by gel retardation assay. Transfection efficiency, degree of cell apoptosis and protein expression were analyzed in SCC cells and HaCaT cells, in order to determine optimal transfection conditions for PEI/DNA complexes to be used in in vivo experiments. Results of gel retardation assay showed that WWOX gene formed complexes with PEI when N/P ratios were greater than 4:1. It was demonstrated that transfection efficiency were related to the amount of DNA, but not to DNA types in both cell lines, and transfecton efficiency of PEI was lower than that of Lipofectamine. In SCC-15 cells, degree of apoptosis induced by WWOX gene were not related with DNA types. However, degree of apoptosis induced by p53 gene were dose-dependent. On the other hand, degree of apoptosis induced by both WWOX gene and p53 gene in HaCaT cell was associated with DNA content but not with DNA types. Degree of apoptosis induced by PEI/DNA complex was more prominent than lipo/DNA complex in HaCaT cells, while they were comparable in SCC-15 cells. Based on the above data, vector/DNA 2μg/mL (N/P ratio 8:1) was selected for the following evaluation. The results displayed that WWOX protein expression was significantly increased in comparison with control groups in both cell lines. For HaCaT cell, protein expression level was comparable between PEI and Lipo as vectors, while in SCC-15 Cell, protein expression level by PEI-mediated gene delivery was greater than Lipo. Direct injection of vector/DNA complexes into tumor-bearing mice demonstrated that PEI/WWOX pEGFPC1, PEI/WWOX-pEGFPC1+ PEI/p53-pDsRedN1, Lipo/WWOX-pEGFPC1 and PEI/p53-pDsRedN1 complexes significantly inhibited tumor growth in comparison to the control. Among these groups, the effect from PEI/WWOX-pEGFPC1 complex was the most prominent. In summary, the current study demonstrated that both WWOX gene and p53 gene can be effectively delivered to squamous cell carcinoma by PEI and Lipofectamine and effectively reduced tumor size in vivo. The effect of PEI was comparable to Lipofectamine in terms of transfection efficiency, apoptotic effect and protein expression, with the advantages of easy accessibility and cost-effectiveness. It is concluded PEI with WWOX gene and p53 gene complexes is a potential therapeutics for squamous cell carcinoma. Keywords：Squamous cell carcinoma (SCC), WWOX gene, p53 gene, gene delivery, polyethylenimine(PEI)
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Frydenlund, Noah. "Neurotrophin receptors in select cutaneous malignancies with a propensity for perineural invasion". Thesis, 2015. https://hdl.handle.net/2144/16317.
Abstract (sommario):
Perineural invasion (PNI) in cutaneous squamous cell carcinoma (cSCC) and desmoplastic melanoma (DM) may be a negative prognostic finding, and likely contributes to increased rates of local recurrence. The biological mechanisms underlying PNI remain unclear, although several lines of evidence implicate neurotrophins and their receptors. Expression of the high affinity nerve growth factor (NGF) receptor TrkA has been shown to be associated with PNI in numerous malignancies, although literature in cutaneous neoplasms is sparse. Given this, we sought to ascertain the incidence of PNI in a cohort cSCCs using double immunostaining (DIS), and to investigate PNI's relationship with TrkA expression and established histopathologic prognosticators. In DMs we investigated the relationship between TrkA and PNI. In DM we additionally analyzed expression of the low affinity NGF receptor (p75NGFR) and the presence of a functional polymorphism in the glial cell line-derived neurotrophic factor (GDNF) receptor RET (RETp) as they relate to PNI.
In this IRB approved study, cSCCs from the head and neck (H&N) and 53 from non-H&N areas were immunohistochemically analyzed for PNI (DIS with S100 and p63) and TrkA expression. For DM, 43 cases were immunohistochemically evaluated for TrkA and p75NGFR expression while RETp was detected by direct DNA sequencing. The presence of each was correlated with histologically observed PNI.
In cSCCs, comparing H&N versus non-H&N areas; using hemotoxylin and eosin (H&E) PNI was detected in 11% versus 6% of cases respectively and using DIS, in 23% versus 15% respectively, with significant disagreement between both methods (𝜅=0.47, p=0.002). There was a 2.33 fold increase in PNI detection with DIS compared to H&E (95%CI: 1.12-4.87; p=0.02). TrkA expression was 2.9 times more frequently observed in cSCCs from the H&N compared to those from non-H&N areas (p=0.01). Regardless of site, TrkA expression was associated with decreased degree of differentiation (OR=6.46, p=0.0006) and high-risk morphologic variants (OR = 6.53, p=0.002). TrkA expression was not significantly associated with PNI (p=0.33).
In DM, PNI was present in 67% of cases. On univariate analysis; p75NGFR was associated with PNI (expression detected in 79% of PNI-positive cases compared to 36% of PNI-negative cases, p=0.005), increased Breslow's depth and greater Clark's Level (p= 0.007 and p= 0.01 respectively). RETp was noted in 28% of cases but was not significantly associated with PNI (p=0.27) or other histopathologic variables. TrkA expression was absent in all cases. PNI was associated with increased Breslow's depth and Clark's Level (p=0.01 and p=0.009 respectively). Controlling for the association between p75NGFR and depth, p75NGFR remained associated with an increased propensity for PNI (OR=4.68, p=0.04).
In conclusion, increased PNI detection with DIS in cSCCs underscores the adjunctive utility of immunohistochemistry in microstaging. Although unlikely to play a role in the development of PNI, TrkA's association with cSCCs from H&N and select histopathologic parameters suggests a role for the NGF-TrKA axis in tumorogenesis while its absent expression in DM suggests that expression is lineage-related. Lastly, In DM, p75NGFR expression is significantly associated with PNI and a more locally aggressive phenotype.
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Pinho, António Álvaro Pereira de. "Association of Human Papillomavirus with Cutaneous Squamous Cell Carcinoma and Basal Cell Carcinoma: a systematic review and meta-analysis". Master's thesis, 2018. https://hdl.handle.net/10216/111949.
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Pinho, António Álvaro Pereira de. "Association of Human Papillomavirus with Cutaneous Squamous Cell Carcinoma and Basal Cell Carcinoma: a systematic review and meta-analysis". Dissertação, 2018. https://repositorio-aberto.up.pt/handle/10216/111949.
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Khizanishvili, Natalia. "The role of Hedgehog signaling and its interaction with EGFR-pathway in cutaneous squamous cell carcinoma". Doctoral thesis, 2020. http://hdl.handle.net/21.11130/00-1735-0000-0005-1427-9.
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Batista, Cheila Daniela Andrade. "Imunoterapia no Tratamento do Carcinoma Espinhocelular Avançado". Master's thesis, 2021. http://hdl.handle.net/10316/98402.
Abstract (sommario):
Trabalho Final do Mestrado Integrado em Medicina apresentado à Faculdade de MedicinaO carcinoma espinhocelular apresenta uma incidência crescente e mortalidade significativa quando em estado avançado, razão pela qual o seu tratamento tem especial relevância. O CEC avançado representa os tumores localmente avançados (irressecáveis) ou metastáticos, em que a excisão cirúrgica não permite a cura, determinando outras abordagens terapêuticas. Até recentemente, a quimioterapia tinha o papel preponderante, ainda que limitado, devido aos efeitos adversos graves. Entretanto surgiram os inibidores EGFR, anticorpos dirigidos ao recetor do fator de crescimento epidérmico, que têm uma atividade limitada comparativamente à quimioterapia, apesar de um perfil de toxicidade mais benéfico. A radioterapia e a eletroquimioterapia são também opções consideráveis mas nem sempre aplicáveis. Assim, foi necessário desenvolver alternativas mais seguras e eficazes no tratamento de doentes em estado avançado.Nas últimas décadas, surgiu um novo paradigma terapêutico, com base em anticorpos monoclonais e pequenos inibidores moleculares que bloqueiam vias de sinalização envolvidas na patogénese tumoral e no checkpoint imunitário. A supressão da imunomodulação negativa é, assim, um dos grandes pilares atuais da imunoterapia. De facto, o CEC é dos cancros que possui um maior número cumulativo de mutações, carga mutacional esta que se reflete na boa resposta à imunoterapia.Entre os diferentes imunoterápicos, destacam-se os inibidores PD-1. Estes fármacos têm afinidade para o recetor-1 de morte celular programada (PD-1), impedindo a sua ligação aos ligandos PD-L1 e PD-L2 expressos pelas células tumorais, o que causaria a inibição funcional das células T. Deste modo, a resposta citotóxica antitumoral é potenciada, controlando a proliferação tumoral. Estes fármacos apresentam um perfil de toxicidade bastante favorável.Em 2018, assiste-se à aprovação, pelas FDA e EMA, do primeiro inibidor PD-1 destinado ao tratamento de CEC avançado, o cemiplimab. Recentemente, em 2020, foi também aprovado pela FDA o pembrolizumab. Outros fármacos desta categoria estão atualmente a ser testados.No futuro, será importante o estudo dos indicadores preditores de resistência ou de boa resposta a estes agentes, tal como a carga mutacional. Também a utilidade da imunoterapia nos indivíduos transplantados deve ser um importante objeto de investigação, assim como a combinação da imunoterapia com outras abordagens, inclusive a nível neoadjuvante / adjuvante.A imunoterapia veio abrir novas portas no tratamento do CEC avançado, apresentando um boa relação benefício-risco, sendo da maior importância a análise de todo o seu potencial.
Cutaneous squamous cell carcinoma (cSCC) has an increasing incidence and significant mortality when at advanced stage, which is why its treatment is particularly relevant. Advanced cSCC represents locally advanced (unresectable) or metastatic tumors, in which surgical excision does not allow a cure, determining other therapeutic approaches.Until recently, chemotherapy had a predominant role, albeit limited, due to serious side effects. Meanwhile, EGFR inhibitors, antibodies directed to the epidermal growth factor receptor, have a limited activity compared to chemotherapy, despite a more beneficial toxicity profile. Radiotherapy and electrochemotherapy are also considerable options, but not always applicable. Thus, it was necessary to develop safer and more effective alternatives in the treatment of advanced patients.In the last few decades, a new therapeutic paradigm has emerged, based on monoclonal antibodies and small molecular inhibitors that block signaling pathways involved in tumor pathogenesis and the immune checkpoint. The suppression of negative immunomodulation is thus one of the great pillars of immunotherapy today. In fact, CEC is one of the cancers that has a greater cumulative number of mutations, which is reflected in the good response to immunotherapy.Among the different immunotherapeutic agents, PD-1 inhibitors stand out. These drugs have an affinity for the programmed cell death receptor-1 (PD-1), preventing their binding to the PD-L1 and PD-L2 ligands expressed by tumor cells, which would cause functional inhibition of T cells. Thus, antitumor cytotoxic response is enhanced, controlling tumor proliferation. These drugs have a very favorable toxicity profile.In 2018, FDA and EMA approved the first PD-1 inhibitor for the treatment of advanced cSCC, cemiplimab. Recently, in 2020, pembrolizumab was also approved by FDA. Other drugs in this category are currently being tested.In the future, it will be important to study the predictive indicators of resistance or good response to these agents, such as the mutational burden. Also, the usefulness of immunotherapy in transplanted individuals should be an important research goal, as well as the combination of immunotherapy with other approaches, including at the neoadjuvant / adjuvant level.Immunotherapy has opened new doors in the treatment of advanced CPB, presenting a good risk-benefit ratio, and the analysis of its full potential is of utmost importance.