Dissertations / Theses on the topic 'Small Cell Lung Cancer'
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1
Sarvi, Sana. "Small cell lung cancer and cancer stem cell-like cells." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/9542.
Abstract:
Small cell lung cancer (SCLC) is a highly aggressive malignancy with extreme mortality and morbidity. Although initially chemo- and radio-sensitive, almost inevitable recurrence and resistance occurs. SCLC patients often present with metastases, making surgery not feasible. Current therapies, rationally designed on underlying pathogenesis, produce in vitro results, however, these have failed to translate into satisfactory clinical outcomes. Recently, research into cancer stem cells (CSCs) has gained momentum and form an attractive target for novel therapies. Based on this concept, CSCs are the cause of neoplastic tissue development that are inherently resistant to chemotherapy, explaining why conventional therapies can shrink the tumour but are unable to eliminate the tumour completely, leading to eventual recurrence. Here I demonstrate that SCLC H345 and H69 cell lines contain a subset of cells expressing CD133, a known CSC marker. CD133+ SCLC sub-population maintained their stem cell-like phenotype over a prolonged period of culture, differentiated in appropriate conditions and expressed the embryonic stem cell marker Oct-4 indicating their stem-like phenotype. Additionally, these cells displayed augmented clonogenic efficacy, were chemoresistant and tumorigenic in vivo, distinct from the CD133- cells. Thus, the SCLC CD133 expressing cells fulfil most criteria of CSClike definition. The molecular mechanisms associated with CD133+ SCLC chemoresistance and growth is unknown. Up-regulated Akt activity, a known promoter of resistance with survival advantage, was observed in CD133+ SCLC cells. Likewise, these cells demonstrated elevated expression of Bcl-2, an anti-apoptotic protein compared to their negative counterpart explaining CD133+ cell chemoresistance phenotype. Additionally, CD133+ cells revealed greater expression of neuropeptide receptors, gastrin releasing peptide (GRP) and V1A receptors compared to the CD133- cells. Addition of exogenous GRP and arginine vasopressin (AVP) to CD133+ SCLC cells promoted their clonogenic growth in semi-solid medium, illustrating for the first time neuropeptide dependent growth of these cells. A novel peptide (peptide-1) was designed based on the known structure of the substance P analogues that have shown benefit in animal models and in early clinical trials. This compound inhibited the growth of SCLC cells in in vitro with improved potency and stability compared to previous analogues and reduced tumorigenicity in vivo. Interestingly, peptide-1 was more effective in CD133+ cells due to increased expression of neuropeptide receptors on these cells. In conclusion, my results show that SCLC cells retain a sub-population of cells that demonstrate CSC-like phenotype. Preferential activation of Akt and Bcl-2 survival pathways and enhanced expression of neuropeptide receptors contribute to CD133+ SCLC chemoresistance and growth. Therefore, it can be proposed that CD133+ cells are the possible cause of SCLC development, treatment resistance and disease recurrence. Despite being chemoresistant, CD133+ cells demonstrated sensitivity to peptide-1. The identification of such new analogue that demonstrates efficacy towards resistant CD133+ SCLC cells is a very exciting step forward in the identification of a potential new therapy for resistant disease.
2
Kapeleris, Joanna C. "Circulating tumour cells in non-small cell lung cancer." Thesis, Queensland University of Technology, 2022. https://eprints.qut.edu.au/228607/1/Joanna_Kapeleris_Thesis.pdf.
Abstract:
Circulating tumour cells (CTCs) have the potential to transform the management of patients with non-small cell lung cancer (NSCLC). The applications of CTCs can identify clinically actionable targets to predict treatment response and to better understand metastasis. CTCs isolated using microfluidics can be used as prognostic indicators of NSCLC as well as characterizing for markers of immunotherapy (PD-L1), molecular targets (ALK, EGFR). Short term cultures were successfully expanded in 9/70 NSCLC patients and cultured for up to 3 months. Optimization of this novel CTC culture model provides opportunity to identify new therapeutics for NSCLC patients in a precision medicine approach.
3
Wang, Wei. "Modulation of immune cell responses by small cell lung cancer cells." Thesis, King's College London (University of London), 2016. https://kclpure.kcl.ac.uk/portal/en/theses/modulation-of-immune-cell-responses-by-small-cell-lung-cancer-cells(7bdc85c2-acd8-4f13-9d2b-e2ce07d1567b).html.
Abstract:
Small Cell Lung Cancer (SCLC) accounts for 15-20% of all lung cancers and kills at least one person every 2 hours in the UK. There is no effective treatment and overall 2-year survival is less than 5%. Patients with SCLC have poorly understood local and systemic immune defects. Previous studies have shown several important defects in cell-mediated immune responses in patients with SCLC. A better understanding of interactions between SCLC tumour cells and immune cells may lead to the development of novel therapeutic approaches. There is increasing recognition that immunological biomarkers may add to traditional histological analyses and can be exploited in the management of multiple epithelial malignancies. There are currently no such markers used in the management of SCLC. In my PhD project, I have shown that cell lines from different SCLC patients have differential immunosuppressive capabilities. These properties are mediated by the secretion of differing levels of soluble molecules that can suppress the mixed leukocyte reaction (MLR) and CD4+ T cell proliferation, induce IL-10 secretion and differentiation of functional CD4+CD25+CD127+FoxP3+Helios- regulatory T cells (Tregs) from naïve CD4+ T cells. IL-15 is secreted by SCLC cells in culture in proportion to their immunosuppressive capability. Its in vivo relevance is supported by its presence in tumour biopsy samples. The suppressive effect on CD4+ T cell proliferation and the induction of Treg cell population was not affected by blocking IL-10 or TGF-β signalling but was partially reversed by blocking IL-15 activity. Therefore, IL-15 is one, though not the only, soluble molecule produced by SCLC cells to mediate immune suppression by inducing increased population of Treg cells. This may represent a mechanism by which SCLC cells can suppress the immune response. In addition, SCLC cells supressed TNF-α release from monocytes in response to LPS stimulation, down-regulated expression of CD16 and CD86 and upregulated expression of CD163 and CD206 on monocyte-derived macrophages (MDMs) upon activation. This M2-like phenotype poralization was associated with decreased TNF-α and IL-6 production and increased IL-10 secretion. These effects were abrogated by blocking the signalling of bombesin-like peptides (BLPs) that are neuropeptides produced by SCLC cells using a GRP receptor (GRP-R) antagonist. Therefore, the polarization of macrophages to an M2-like phenotype by SCLC cell-derived BLPs may represent another mechanism by which SCLC tumours suppress the immune response. Finally, SCLC tumour biopsies were shown to be infiltrated with various mononuclear immune cells and Treg cells. CD45 and FoxP3 were used as paninflammatory cell and Treg cell markers respectively. An elevated CD45+ infiltrate was predictive of prolonged survival in SCLC independent of age, sex, stage or treatment strategy. An elevated FoxP3+/CD45+ ratio was predictive of a significantly worse prognosis. This study identifies potential mechanisms by which SCLC tumour cells may downregulate local and systemic immune response, and also identifies an independent prognostic marker to predict patient survival in SCLC. Further, IL- 15 and BLPs are potential novel therapeutic targets in SCLC.
4
Oosterhout, Anselmus Gerardus Maria van. "Small cell lung cancer and brain metastasis." Maastricht : Maastricht : Rijksuniversiteit Limburg ; University Library, Maastricht University [Host], 1995. http://arno.unimaas.nl/show.cgi?fid=6643.
5
Seute, Tatjana. "Neurologic complications in small cell lung cancer." Maastricht : Maastricht : Universiteit Maastricht ; University Library, Universiteit Maastricht [host], 2008. http://arno.unimaas.nl/show.cgi?fid=9520.
6
Macaulay, Valentine. "Growth regulation in small cell lung cancer." Thesis, Imperial College London, 1989. http://hdl.handle.net/10044/1/47547.
7
Sikkink, Stephen K. "Genetic pathology of non-small cell lung cancer." Thesis, University of Liverpool, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.250405.
8
Brena, Romulo Martin. "Aberrant DNA methylation in human non-small cell lung cancer." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1172083621.
9
Wong, Wing-sze, and 黃詠詩. "Fusion genes in non-small cell lung cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B43781378.
10
Ng, Sheng Rong. "CRISPR-mediated interrogation of small cell lung cancer." Thesis, Massachusetts Institute of Technology, 2018. http://hdl.handle.net/1721.1/117782.
Abstract:
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2018.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Cataloged student-submitted from PDF version of thesis. Vita.
Includes bibliographical references.
Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine lung carcinoma that remains among the most lethal of solid tumor malignancies. Despite decades of research, treatment outcomes for SCLC remain very poor, highlighting the need for novel approaches to target the disease. Recent genomic sequencing studies have identified multiple recurrently altered genes in human SCLC tumors, many of which remain to be functionally validated. Genetically engineered mouse models (GEMMs) of SCLC have been developed that recapitulate many key features of human SCLC. These models have been used extensively to investigate various aspects of SCLC biology, including tumor initiation, progression and metastasis. The development of the CRISPR-Cas9 system has greatly facilitated genome editing in mammalian cells, leading to its widespread adoption for various applications in cancer biology. We have utilized this system in two complementary ways to investigate the molecular mechanisms involved in SCLC initiation, progression and maintenance. Firstly, we have adapted the CRISPR-Cas9 system for use in GEMMs of SCLC, to enable rapid modeling and functional validation of candidate tumor suppressor genes in vivo. Using this system, we have demonstrated that p107, a member of the retinoblastoma family that is mutated in a significant fraction of human SCLC tumors, is a functional tumor suppressor in SCLC. Notably, loss of p107 in SCLC tumors resulted in significant phenotypic differences compared with loss of its close relative, p130. We also demonstrated that CRISPR-induced mutations can be used to infer lineage relationships between primary and metastatic tumors in the same animal. Secondly, we have performed a CRISPR-based genetic screen, utilizing a custom sgRNA library targeting the druggable genome, to identify novel SCLC-specific genetic vulnerabilities. We found that SCLC cells displayed enhanced sensitivity towards disruption of several key metabolic pathways, including the de novo pyrimidine biosynthesis pathway. Pharmacological inhibition of Dhodh, a key enzyme in this pathway, reduced the viability of SCLC cells in vitro and strongly suppressed SCLC tumor growth in vivo, validating this pathway as a promising therapeutic target in SCLC. Taken together, the work presented here demonstrates the utility of the CRISPR-Cas9 system for performing functional interrogation of SCLC.
by Sheng Rong Ng.
Ph. D.
11
Lawson, Malcolm Hedley. "Determinants of chemoresistance in small cell lung cancer." Thesis, University of Cambridge, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609102.
12
Hodkinson, Philip Simon. "Tumour microenvironment interactions of small cell lung cancer." Thesis, University of Edinburgh, 2009. http://hdl.handle.net/1842/4254.
Abstract:
Small cell lung cancer (SCLC) is characterised by rapid growth, early metastatic spread and poor long-term survival. The tumour is initially sensitive to chemotherapy and thus objective response rates are high. Unfortunately, this response is often short-lived and SCLC recurs with acquired drug resistance, resulting in early patient death. Despite intensive chemo- and radiotherapy regimes survival has not improved significantly in 20 years. Prior research suggests a critical role for the tumour microenvironment in the pathogenesis of other cancers. Therefore, investigating interactions between SCLC cells and components of the tumour stroma may identify novel therapeutic targets. This thesis demonstrates that extracellular matrix (ECM) proteins present in the tumour microenvironment protect SCLC cells in vitro from chemo- and radiotherapy induced cell cycle arrest and apoptosis via cell surface β1 integrins. Pharmacological and genetic inhibition of phosphoinositol-3 kinase signalling abrogates this effect, defining a central role for this pathway in SCLC de novo drug resistance. Furthermore, the protective effect of ECM occurs without alteration in chemotherapy-induced DNA damage allowing SCLC cells to survive with new genetic defects. Integrin-mediated drug resistance has been shown to be important in other tumours and thus development of strategies to inhibit this pathway may yield new anti-cancer treatments. The design of targeted agents to down-regulate integrin-ECM interaction requires an in depth understanding of the intracellular signals that modulate integrin affinity. Two such pathways are investigated in this thesis. 1) H-Ras, a dominant suppressor of integrin affinity, acts in part through phosphorylation of Erk. Data presented here demonstrate that H-Ras also suppresses integrins through a phospholipase-C epsilon (PLCε)-dependent pathway, thus explaining discrepancies in prior data and confirming a physiological role for this recently identified phospholipase. 2) The Notch signalling pathway has been shown to have important roles in both development and cancer. It is shown here that activation of Notch signalling increases β1 integrin affinity and can protect SCLC cells from chemotherapyinduced apoptosis. However the mechanisms appear to be different; Notch-1 modulates integrin activation through the small GTPase R-Ras and Notch-2 promotes SCLC cell survival. These results define a new Notch pathway, a novel integrin modulator and a potential therapeutic target in SCLC cells. In addition to ECM proteins, the tumour microenvironment contains immune cells that may contribute to cancer growth. The cellular composition of the SCLC stroma is poorly understood. The data presented here indicate that the microenvironment of SCLC is infiltrated by lymphocytes and macrophages, the degree of which independently predicts patient survival. This suggests that the host immune system may be able to suppress SCLC growth. It is well recognised that patients with SCLC have defects in cellular immunity which correlate with survival. An in vitro coculture model was used to investigate the underpinning mechanisms, showing SCLC cells can suppress CD4+ T-cell proliferation and macrophage CD86 expression. Furthermore, preliminary data suggest a role for a soluble factor released by SCLC cells that up-regulates CD4+ T-cell production of IL-10. The work in this thesis implies a complex interaction between SCLC cells, ECM and immune cells in the tumour microenvironment. Manipulation of these pathways may have important therapeutic implications. Further investigation is required to understand the mechanisms of this interplay, which may in part be aided by prospective analysis of patient tumour samples and an in vivo model of SCLC.
13
Swinson, Daniel. "Hypoxic markers in non-small cell lung cancer." Thesis, University of Leicester, 2004. http://hdl.handle.net/2381/29476.
Abstract:
Hypoxia is an important factor in the pathogenesis of solid tumours. Hypoxia inducible factors (HIF)-1alpha and HIF-2alpha are transcription factors that in part mediate the cellular response to hypoxia. These transcription factors are involved in the regulation of angiogenesis, anaerobic metabolism, pH homeostasis, erythropoiesis and cell death.;Immunohistochemical (IHC) assays were optimised for HIF-1alpha and one of its transcriptional targets, Carbonic Anhydrase (CA) IX. Attempts to optimise an IHC assay for HIF-2alpha failed to produce reproducible staining. A scoring system was also devised to assess the extent of tumour necrosis (TN) in tumour sections. The expression of these factors was assessed in a retrospective series of patients who had NSCLC tumours resected with curative intent. The expression of EGFR, p53, Bcl-2, MMP-2 and MMP-9 and angiogenesis had previously been assessed.;Extensive TN, perinuclear (p) CA IX and high HIF-1alpha expression were associated with a poor prognosis. PCA IX, stage, gender, MMP-9 and angiogenesis were independent prognostic factors.;The spatial relationship between membranous CA IX expression and TN and tumour microvessels support other studies proposing that CA IX is a marker of tumour hypoxia.;EGFR expression was associated with pCA IX, membranous (m)CA IX and HIF-1alpha expression. In vitro studies demonstrated that prolonged treatment with the EGFR tyrosine kinase inhibitor, ZD 1839 suppressed CA IX expression. These results suggest that activated EGFR may induce CA IX. As such co-expression of these factors may identify patients that are more likely to respond to EGFR targeted therapies.
14
Moka, Nagaishwarya, Manisha Nukavarapu, Jennifer Phemister, and Mckinney Jason. "Small cell lung cancer(SCLC) disguised as Dysphagia." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/asrf/2019/schedule/168.
Abstract:
Common presenting symptoms of Lung cancer are cough, hemoptysis, chest pain, dyspnea, pleurisy. Dysphagia is a very uncommon presenting feature of Lung cancer. Incidence of Dysphagia in Lung cancer is unclear from Literature. Causes of Dysphagia in case of Lung cancer are Anatomically classified as Oropharyngeal and Esophageal. Causes of oropharyngeal dysphagia are oral candidiasis, oropharyngeal Metastasis of Lung cancer. Causes of esophageal dysphagia are Cervical or Mediastinal Lymphadenopathy, Motor dysfunction because of Brain stem Metastasis, Lambert eaton syndrome, Esophageal candidiasis, Radiation esophagitis. Here by we present an Unusual presentation of an aggressive disease, poorly differentiated SCLC presenting as Mid esophageal dysphagia secondary to extrinsic esophageal compression.
65 year old female with past medical history of Diabetes, Hypertension presented with complaints of worsening sub sternal chest pain radiating to back since last 2 days and progressive dysphagia. Pt underwent Left heart catheterization revealing non obstructive coronary artery disease. Modified Barium swallow showed stasis of contrast in mid esophagus, Endoscopy showed extrinsic compression of the proximal esophagus, normal mucosa. Computerized tomography of chest was done for further evaluation, revealing extensive left cervical, mediastinal, left hilar lymphadenopathy causing extrinsic compression of the esophagus and encasement of the left hilar structures. Further evaluation through Bronchoscopic biopsy of her left upper lobe mass reveals poorly differentiated small cell carcinoma. Staging was performed revealing limited stage disease. Started on concurrent chemotherapy with cisplatin, etoposide and radiation. As SCLC is highly responsive to chemotherapy and radiotherapy sensitive patient got symptomatic relief by the end of first cycle.
SCLC is an aggressive lung cancer. As it is a micro metastatic disease in nature at presentation, it’s management is entirely different from Non SCLC. SCLC being an aggressive disease can cause dysphagia in 1-2% during the disease course. SCLC presenting as dysphagia is almost never reported in the literature. Our patient presented with severe dysphagia, described it as “a tennis ball sitting in her food pipe”. Fortunately she presented to the Emergency room with dysphagia and associated chest pain, we were able to make early diagnosis of SCLC, initiate treatment. Delay in the diagnosis lead to rapid progression of disease and poor prognosis. Through our case we wanted to convey that it is very important to obtain meticulous history, keeping broad differentials, which can help improve prognosis. Because not always the presenting features are from the organ of involvement it could be from the contiguous spread or compression.
15
Wong, Wing-sze. "Fusion genes in non-small cell lung cancer." Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B43781378.
16
Wong, Kit-man Sunny, and 王傑民. "Isolation and characterization of cancer stem cells in non-small cell lung cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B47250665.
Abstract:
Tumor heterogeneity has long been observed and recognized as a challenge to
cancer therapy. The cancer stem cell (CSC) model is one of the hypotheses
proposed to explain such a phenomenon. A specific cancer stem cell marker has
not been determined for non-small cell lung cancers (NSCLC), preventing the
definitive evaluation of whether the biology of NSCLC is governed by the CSC
model. This study aimed to analyze the expression of candidate CSC markers and
using the identified putative marker, to isolate CSC and determine the
applicability of the CSC model in NSCLC.
The expression or activities of four putative stem cell markers, CD24, CD44,
CD133 and aldehyde dehydrogenase 1 (ALDH1) were measured by flow
cytometry in eight NSCLC cell lines before and after chemotherapy for 24 hours.
Markers with increased expression after treatment were considered potential CSC
markers and used for isolating tumor cell subpopulations from the untreated cell
lines by fluorescence-activated cell sorting (FACS). Confirmatory analyses using
widely acceptable methodology were performed to test for CSC properties in the marker+ and marker- subpopulations. Isolated subpopulations were further
characterized by functional and phenotypic studies.
Flow cytometry showed amongst the 4 markers, only ALDH1 expression was
significantly enhanced by chemotherapeutic treatment, suggesting ALDH1 could
be a CSC marker. Untreated ALDH1+ cells formed significantly more and larger
cell spheres in non-adherent, serum-free conditions than ALDH1- cells. Likewise,
higher in vitro tumorigenic ability was observed in ALDH1+ subset using colony
formation assay. Furthermore, a higher resistance to cytotoxic drugs was observed
in ALDH1+ compared to ALDH1- cells. In vivo studies also showed ALDH1+ cells
showed higher tumorigenicity than ALDH1- cells; as few as 2,500 ALDH1+ cells
formed tumor in SCID mice which were serially transplantable to 2nd and 3rd
recipients, while no tumor was formed from ALDH- cells with even ten times the
number of cells. Also, expression analysis revealed higher expression of the
pluripotency genes, OCT4, NANOG, BMI1 and SOX9, in ALDH1+ cells. In view
of previous studies reporting CD44 as a CSC marker in lung cancer, double
marker selection of putative CSC was performed to compare ALDH1+CD44+ and
ALDH1-CD44+ subpopulations. Results of the spheroid body formation assay and
cisplatin treatment experiments revealed the ALDH1+CD44+ subpopulation
possessed higher self-renewal ability and chemo-resistance. Cell migration and
invasion assays showed differences between the ALDH1+CD44+ and ALDH1-
CD44+ subpopulations. The significance of these observations require further
investigation.
In conclusion, the result showed that ALDH1 could be a marker for NSCLC stem
cells as evidenced by enhanced self-renewal and differentiation abilities in
ALDH1+ subpopulation. Furthermore, this study observed the presence of at least
two potential stem cell subpopulations in NSCLC cells with differential selfrenewal,
chemotherapy resistance and cell mobility properties. Further
investigations are required to validate these observations and to investigate the
underlying mechanisms. Better understanding of these issues would help to solve
the challenges brought by tumor heterogeneity in lung cancer therapy.published_or_final_version
Pathology
Master
Master of Philosophy
17
Brattström, Daniel. "Angiogenesis related markers in non-small cell lung cancer /." Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl.[distributör], 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3558.
18
陳潔盈 and Kit-ying Loucia Chan. "Expression analysis of Candidate cancer genes in non-small cell lung cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B45011163.
19
Stordal, Britta Kristina. "Regrowth resistance in platinum-drug resistant small cell lung cancer cells." Bill Walsh Cancer Research Laboratories, Royal North Shore Hospital and The University of Sydney, 2007. http://hdl.handle.net/2123/2467.
Abstract:
Doctor of Philosophy (PhD)The H69CIS200 cisplatin-resistant and H69OX400 oxaliplatin-resistant cell lines developed as part of this study, are novel models of low-level platinum resistance. These resistant cell lines do not have common mechanisms of platinum resistance such as increased expression of glutathione or decreased platinum accumulation. Rather, these cell lines have alterations in their cell cycle allowing them to proliferate rapidly post drug treatment in a process known as ‘regrowth resistance’. This alteration in cell cycle control has come at the expense of DNA repair capacity. The resistant cell lines show a decrease in nucleotide excision repair and homologous recombination repair, the reverse of what is normally associated with platinum resistance. The alterations in these DNA repair pathways help signal the G1/S checkpoint to allow the cell cycle to progress despite the presence of DNA damage. The decrease in DNA repair capacity has also contributed to the development of chromosomal alterations in the resistant cell lines. Similarities in chromosomal change between the two platinum resistant cell lines have been attributed to inherent vulnerabilities in the parental H69 cells rather than part of the mechanism of resistance. The H69CIS200 and H69OX400 resistant cells are cross-resistant to both cisplatin and oxaliplatin. This demonstrates that oxaliplatin does not have increased activity in low-level cisplatin-resistant cancer. Oxaliplatin resistance also developed more rapidly than cisplatin resistance suggesting that oxaliplatin may be less effective than cisplatin in the treatment of SCLC. The resistant cell lines have also become hypersensitive to taxol but show no alterations in the expression, polymerisation or morphology of tubulin. Rather, the PI3K/Akt/mTOR pathway is involved in both platinum resistance and taxol sensitivity as both are reversed with rapamycin treatment. mTOR is also phosphorylated in the resistant cell lines indicating that platinum resistance is associated with an increase in activity of this pathway. The mechanism of regrowth resistance in the platinum-resistant H69CIS200 and H69OX400 cells is a combination of activation of PI3K/Akt/mTOR signalling and alterations in control of the G1/S cell cycle checkpoint. However, more work remains to determine which factors in these pathways are governing this novel mechanism of platinum resistance.
20
Stordal, Britta. "Regrowth resistance in platinum-drug resistant small cell lung cancer cells." Connect to full text, 2006. http://hdl.handle.net/2123/2467.
Abstract:
Thesis (Ph. D.)--University of Sydney, 2007.Title from title screen (viewed 10 June 2008). Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the Discipline of Medicine, Faculty of Medicine. Degree awarded 2007; thesis submitted 2006. Includes bibliographical references. Also available in print form.
21
Brattström, Daniel. "Angiogenesis Related Markers In Non-Small Cell Lung Cancer." Doctoral thesis, Uppsala University, Oncology, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3558.
Abstract:
This thesis investigated the predictive and the prognostic powers of angiogenesis related markers in both operable and inoperable non-small cell lung cancer (NSCLC) patients.
In the first and second study, we investigated the serological fractions of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in 2 cohorts of patients with either operable or inoperable NSCLC.
Regarding operable NSCLC, we demonstrated significant correlations between VEGF and tumour volume and overall survival. Regarding bFGF, significant correlations with recurrent disease and survival were demonstrated. VEGF and bFGF correlated to each other and with platelet counts. In multivariate analysis, bFGF proved to be a significantly independent prognostic factor.
Regarding inoperable NSCLC, we demonstrated that patients with elevated bFGF levels before any treatment and during chemotherapy had a significantly poorer survival. During chemotherapy, each rise of one unit of bFGF (ng/L) corresponded to a 4 times increased risk of death. Regarding VEGF, elevated levels after radiotherapy corresponded with better survival. All prognostic information demonstrated in this study concerned patients with a, co-sampled, normal platelet count.
In the third study, three putative markers, HER-2, EGFR and COX-2, suitable for targeted therapies in resected NSCLC were investigated in a panel of 53 tumours and further investigated for a possible correlation with microvessel density. We demonstrated that HER-2 and COX-2 were mainly expressed in adenocarcinomas, whereas EGFR was only expressed in squamous cell carcinomas. COX-2 showed a trend towards a correlation with microvesssel density. The expression profile, HER-2+/EGFR-, was significantly correlated to poorer survival.
In the fourth study, a predictive model for recurrences consisting of p53, CD34 and CD105, and circulating serum fractions of VEGF and bFGF, was investigated. The two endothelial markers correlated with each other. CD105 expression correlated with p53 expression. No other significant correlations between markers could be demonstrated. A significant correlation between p53 overexpression and recurrent disease was demonstrated. The mutational status could not confirm the immunohistochemical correlation between p53 and recurrences.
In conclusion, the present thesis demonstrates that the angiogenic factors VEGF and bFGF analysed in sera have both predictive and prognostic information when measured in operable and inoperable NSCLC. Since HER-2 is overexpressed in NSCLC and linked with prognostic information, this marker might be a suitable target for therapy in NSCLC. Furthermore, in patients with operable NSCLC, p53 expression status was linked with recurrent disease and mean MVD.
22
Lam, Chi-leung David. "Gene expression profiling in non-small cell lung cancer." Click to view the E-thesis via HKUTO, 2007. http://sunzi.lib.hku.hk/hkuto/record/B38585777.
23
Ho, Chung-man. "Non-small cell lung cancer from bench to bedside /." Click to view the E-thesis via HKUTO, 2007. http://sunzi.lib.hku.hk/hkuto/record/B39432592.
24
Berrieman, Helen Katherine. "Resistance to chemotherapy in non-small cell lung cancer." Thesis, University of Hull, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.415803.
25
Furon, Emeline. "Phenotypic variations and chemosensitivity in small cell lung cancer." Thesis, Cardiff University, 2008. http://orca.cf.ac.uk/54491/.
Abstract:
Many complex properties of cancer cells are effectively under selection within the in vivo microenvironment or following therapeutic insult. This critical combination of instability and shifting selection drives the heterogeneity of tumour cell populations in terms of many critical features. Small cell lung cancer (SCLC) is an aggressive, rapidly metastasizing neoplasm with an ability to develop resistance against chemotherapeutic agents. New SCLC therapeutic strategies are urgently needed that contain spreading disease without further compromising tumour chemosensitivity. Variants for attachment to tissue culture plastic of the NCI-H69 cell line, which grows in suspension but generates low frequency appearance of adhesion variants, were enriched, without prejudice for any specific extracellular matrix directed advantage, and then allowed for any proliferation/survival advantage in vitro to impact on the evolution of variation. Two sub-lines were generated representing two stages in variant enrichment. The developed SCLC model, which encompasses elements of variation and heterogeneity, provides opportunities to link in vitro behaviour of SCLC with in vivo characteristics with particular reference to the challenges faced in the management of SCLC such as the accrual of drug resistance. The variant model was characterized using microscopy, flow cytometry and microarray analysis, revealing variation in adherence and morphology impacting on SCLC behaviour, proliferative rate and polysialylation of the neural cell adhesion molecule. The microarray analysis has also revealed new cancer biomarkers that can be explored in clinic studies. This unique SCLC model was used to gain insights into links with chemoresistance. The studies revealed that the variant selection did not result in expansion of a drug resistant clone. Moreover, evidence of clonal evolution/selection was uncovered together with the finding of the absence of CSCs, even in enriched variants, as defined by the classical side population phenotype. The defined PSA expression patterns of the variants allowed for screening of carbohydrates-based agents for polysialylation knock-down.
26
Ohri, Chandra. "The immune response to non-small cell lung cancer." Thesis, University of Leicester, 2010. http://hdl.handle.net/2381/8195.
Abstract:
Non-small cell lung cancer (NSCLC) is responsible for more deaths worldwide than any other cancer. Currently, 5-year survival for patients with stage IA disease is just 67%. Chemotherapy offers no cure at present for patients with NSCLC. It is now recognised that the immune system plays a significant role in both tumour modulation and progression. Therefore, a better understanding of immune responses to NSCLC may lead to the development of novel therapies. In these studies, I have investigated, using immunohistochemistry, the microlocalisation of macrophage and mast cell phenotypes (as well as mast cell degranulation), TNFα expression, non-macrophage expression of markers associated with macrophage phenotypes, chemokine receptors and markers of apoptosis and cellular proliferation in surgically resected NSCLC tissue. These studies have demonstrated for the first time in NSCLC that there are two major macrophage phenotypes, M1 and M2, and that the cytotoxic M1 phenotype predominates in the islets of patients with extended survival. The presence of high numbers of mast cells in the islets, irrespective of phenotype, also predicts extended survival. In addition, TNFα expression in tumour islets was found to be an independent predictor of increased survival but its expression in tumour stroma was an independent predictor of poor survival. Also, patients with increased tumour islet expression of markers associated with cytotoxic macrophages (HLA-DR, iNOS, MRP 8/14 and TNFα) by non-macrophage cells was associated with extended survival. Patients with increased expression of CXCR3 and CCR1 in their tumour islets also had extended survival suggesting that these chemokine receptors may be involved in a pathway attracting cytotoxic components of the immune system into tumour islets. In summary, these studies highlight the importance of microlocalisation and phenotype of immune cells in determining whether they play a pro- or anti-tumorigenic role in NSCLC.
27
Ho, Chung-man, and 何重文. "Non-small cell lung cancer: from bench to bedside." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B39432592.
28
Lam, Chi-leung David, and 林志良. "Gene expression profiling in non-small cell lung cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B38585777.
29
Bryant, Jennifer. "Neuroendocrine and epithelial markers of small cell lung cancer." Thesis, University of Manchester, 2015. https://www.research.manchester.ac.uk/portal/en/theses/neuroendocrine-and-epithelial-markers-of-small-cell-lung-cancer(c7c51e2c-6443-4021-b2ff-469966cd10b6).html.
Abstract:
Small cell lung cancer (SCLC) is an extremely aggressive disease characterized by early metastasis and acquired resistance to therapy. SCLC is distinguished by its neuroendocrine (NE) component; the role of which is not fully understood in metastasis and response to therapy. Patients respond exceptionally well to first round chemotherapy; however, relapse with therapy-resistant tumours is virtually inevitable. Hypoxic regions within tumours can contribute towards metastasis and therapy resistance, highlighting hypoxia-targeted therapy as a novel approach for improving treatment for SCLC patients. Tumours are highly phenotypically heterogeneous, raising debate over the roles played by each cell type. Analysis of NE and epithelial markers in SCLC cell lines highlighted this inter-tumour heterogeneity. Further heterogeneity is displayed in SCLC xenograft tumours that show areas of dual epithelial and NE marker expression as well as regions negative for both markers. Irradiating xenograft tumours enhanced heterogeneity of the NE marker, pro-opiomelanocortin (POMC), which is ectopically secreted by a subset of SCLC tumours. Examining changes in marker expression post-therapy could provide vital information regarding transitions that can serve to guide therapy. SCLC is a highly metastatic disease. The role of the NE phenotype in human SCLC is not fully understood, but is considered essential for metastasis in murine models. Sub-cutaneous, intravenous and intra-splenic injection were carried out and resulted in no metastasis, spontaneous tumour generation and peripheral liver tumour growth, respectively. POMC expression was present and extremely heterogeneous within the liver, suggesting that NE properties are maintained in metastases; however, further work is necessary to develop a more consistent metastatic model that can be used to assess responses to therapy in a more clinically relevant setting. SCLC tumours proliferate rapidly and outgrow their nutrient and oxygen supplies, resulting in hypoxic conditions. Here, carbonic anhydrase IX (CA IX) becomes up-regulated in order to maintain pH levels suitable for survival. The specific CA IX inhibitor, S4, induces hypoxia-specific cell death in vitro and impairs tumour growth in vivo. This response is further accentuated by combining S4 with single or repeated cisplatin doses. Combination treatment reduced gene expression of S-phase kinase-associated protein (Skp2), associated with cisplatin resistance. CA IX inhibition combined with cisplatin chemotherapy therefore presents a novel treatment for SCLC tumours that could reduce therapy resistance. In summary, heterogeneity is extremely important when choosing treatment options for SCLC and must be considered when basing treatment on single biopsies. NE and epithelial markers are present within sub-cutaneous and liver tumours; however, a reliable multi-organ metastatic model is necessary to fully appreciate the role of these markers in the spread of SCLC. Hypoxic regions within sub-cutaneous xenograft tumours upregulate CA IX. Inhibition of this enzyme resulted in impaired tumour growth, particularly when used together with cisplatin. Combining CA IX inhibition with cisplatin presents a much-needed novel therapy for SCLC.
30
Agrawal, Vishesh. "Quantitative Imaging Analysis of Non-Small Cell Lung Cancer." Thesis, Harvard University, 2016. http://nrs.harvard.edu/urn-3:HUL.InstRepos:27007763.
Abstract:
Quantitative imaging is a rapidly growing area of interest within the field of bioinformatics and biomarker discovery. Due to the routine nature of medical imaging, there is an abundance of high-quality imaging linked to clinical and genetic data. This data is particularly relevant for cancer patients who receive routine CT imaging for staging and treatment purposes. However, current analysis of tumor imaging is generally limited to two-dimensional diameter measurements and assessment of anatomic disease spread. This conventional tumor-node-metastasis (TNM) staging system stratifies patients to treatment protocols including decisions regarding adjuvant therapy. Recently there have been several studies suggesting that these images contain additional unique information regarding tumor phenotype that can further aid clinical decision-making.
In this study I aimed to develop the predictive capability of medical imaging. I employed the principles of quantitative imaging and applied them to patients with non-small cell lung cancer (NSCLC). Quantitative imaging, also termed radiomics, seeks to extract thousands of imaging data points related to tumor shape, size and texture. These data points can potentially be consolidated to develop a tumor signature in the same way that a tumor might contain a genetic signature corresponding to mutational burden. To accomplish this I applied radiomics analyses to patients with early and late stage NSCLC and tested these for correlation with both histopathological data as well as clinical outcomes.
Patients with both early and late stage NSCLC were assessed. For locally advanced NSCLC (LA-NSCLC), I analyzed patients treated with preoperative chemoradiation followed by surgical resection. To assess early stage NSCLC, I analyzed patients treated with stereotactic body radiation therapy (SBRT). Quantitative imaging features were extracted from CT imaging obtained prior to chemoradiation and post-chemoradiation prior to surgical resection. For patients who underwent SBRT, quantitative features were extracted from cone-beam CTs (CBCT) at multiple time points during therapy. Univariate and multivariate logistic regression were used to determine association with pathologic response. Concordance-index and Kaplan-Meier analyses were applied to time dependent endpoints of overall survival, locoregional recurrence-free and distant metastasis.
In this study, 127 LA-NSCLC patients were identified and treated with preoperative chemoradiation and surgical resection. 99 SBRT patients were identified in a separate aim of this study. Reduction of CT-defined tumor volume (OR 1.06 [1.02-1.09], p=0.002) as continuous variables per percentage point was associated with pathologic complete response (pCR) and locoregional recurrence (LRR). Conventional response assessment determined by diameter (p=0.213) was not associated with pCR or any survival endpoints. Seven texture features on pre-treatment tumor imaging were associated with worse pathologic outcome (AUC 0.61-0.66). Quantitative assessment of lymph node burden demonstrated that pre-treatment and post-treatment volumes are significantly associated with both OS and LRR (CI 0.62-0.72). Textural analyses of these lymph nodes further identified 3 unique pre-treatment and 7 unique post-treatment features significantly associated with either LRR, DM or OS. Finally early volume change showed associated with overall survival in CBCT scans of early NSCLC.
Quantitative assessment of NSCLC is thus strongly associated with pathologic response and survival endpoints. In contrast, conventional imaging response assessment was not predictive of pathologic response or survival endpoints. This study demonstrates the novel application of radiomics to lymph node texture, CBCT volume and patients undergoing neoadjuvant therapy for NSCLC. These examples highlight the potential within the rapidly growing field of quantitative imaging to better describe tumor phenotype. These results provide evidence to the growing radioimics literature that there is significant association between imaging, pathology and clinical outcomes. Further exploration will allow for more complete models describing tumor imaging phoentype with clinical outcomes.
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Holgersson, Georg. "Prognostic Factors in Non-Small Cell Lung Cancer (NSCLC)." Doctoral thesis, Uppsala universitet, Experimentell och klinisk onkologi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-327925.
Abstract:
Background: Non-small cell lung cancer (NSCLC) is the cancer disease with the highest mortality globally. About 75% of NSCLC patients are diagnosed in an advanced stage where surgical treatment is not possible. For patients with locally advanced disease without distant metastases, the treatment of choice is curatively intended radiotherapy. However, this treatment has considerable side effects and many patients relapse. To individualize the treatment strategy for these patients, it is essential to have as much prognostic information as possible. The aim of this thesis was to investigate the prognostic significance of histology and pre-treatment hematopoietic blood parameters. Material and Methods: Data were collected retrospectively for NSCLC patients treated between 1990 and 2000 with curatively intended radiotherapy. The data were obtained by manually searching patient records from all radiation oncology departments in Sweden. The prognostic significance of histology, and pre-treatment levels of hemoglobin (Hgb), white blood cells (WBC) and platelets (Plt) were analyzed in relation to overall survival using univariate and multivariate statistical methods. These prognostic factors were further analyzed in a chemoradiation patient cohort and in a cohort of patients with recurrent NSCLC treated with palliative docetaxel, or the insulin-like growth factor 1 receptor (IGF-1R) modulator AXL1717. Results: In the cohort of NSCLC patients treated between 1990 and 2000, squamous cell carcinoma (SCC) histology and pre-treatment anemia (Hgb <110 g/L), leukocytosis (WBC > 9.0 x109/L), and thrombocytosis (Plt >350 x109/L) were independent prognostic factors for shorter overall survival. However, in the chemoradiation cohort only thrombocytosis retained independent prognostic significance in a multivariate analysis. In the cohort of patients with recurrent disease treated with palliative systemic therapy, only leukocytosis was significantly associated with worse survival. Conclusions: Routine pre-treatment hematopoietic blood parameters—together with other prognostic factors such as disease stage and performance status—can provide decision-making support when individualizing treatment of NSCLC. The prognostic role of histology is unclear and further research is warranted to determine its significance.
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Xinarianos, George. "Genetic alterations in non-small cell lung carcinomas." Thesis, University of Liverpool, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.343688.
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Chan, Kit-ying Loucia. "Expression analysis of Candidate cancer genes in non-small cell lung cancer /." View the Table of Contents & Abstract, 2007. http://sunzi.lib.hku.hk/hkuto/record/B38480360.
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Baker, Amanda F., Neale T. Hanke, Barbara J. Sands, Liliana Carbajal, Janet L. Anderl, and Linda L. Garland. "Carfilzomib demonstrates broad anti-tumor activity in pre-clinical non-small cell and small cell lung cancer models." BioMed Central, 2014. http://hdl.handle.net/10150/610318.
Abstract:
BACKGROUND: Carfilzomib (CFZ) is a proteasome inhibitor that selectively and irreversibly binds to its target and has been approved in the US for treatment of relapsed and refractory multiple myeloma. Phase 1B studies of CFZ reported signals of clinical activity in solid tumors, including small cell lung cancer (SCLC). The aim of this study was to investigate the activity of CFZ in lung cancer models. METHODS: A diverse panel of human lung cancer cell lines and a SHP77 small cell lung cancer xenograft model were used to investigate the anti-tumor activity of CFZ. RESULTS: CFZ treatment inhibited both the constitutive proteasome and the immunoproteasome in lung cancer cell lines. CFZ had marked anti-proliferative activity in A549, H1993, H520, H460, and H1299 non-small cell lung cancer (NSCLC) cell lines, with IC₅₀ values after 96 hour exposure from <1.0 nM to 36 nM. CFZ had more variable effects in the SHP77 and DMS114 SCLC cell lines, with IC₅₀ values at 96 hours from <1 nM to 203 nM. Western blot analysis of CFZ-treated H1993 and SHP77 cells showed cleavage of poly ADP ribose polymerase (PARP) and caspase-3, indicative of apoptosis, and induction of microtubule-associated protein-1 light chain-3B (LC3B), indicative of autophagy. In SHP77 flank xenograft tumors, CFZ monotherapy inhibited tumor growth and prolonged survival, while no additive or synergistic anti-tumor efficacy was observed for CFZ + cisplatin (CDDP). CONCLUSIONS: CFZ demonstrated anti-proliferative activity in lung cancer cell lines in vitro and resulted in a significant survival advantage in mice with SHP77 SCLC xenografts, supporting further pre-clinical and clinical investigations of CFZ in NSCLC and SCLC.
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譚郭雅欣 and Gloria Tam. "Non-small cell lung cancer clinical trials on new medicines." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B41711956.
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Daly, Maria Catherine. "Chromosome 3 deletion mapping in human small cell lung cancer." Thesis, University of Cambridge, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.304095.
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Tai, Lai-shan. "Molecular genetic characterizations of human non-small cell lung cancer." Click to view the E-thesis via HKUTO, 2005. http://sunzi.lib.hku.hk/hkuto/record/B31375315.
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Casadevall, Aguilar David. "Heterogeneity of biomarker expression in non-small cell lung cancer." Doctoral thesis, Universitat Autònoma de Barcelona, 2017. http://hdl.handle.net/10803/457975.
Abstract:
L’èxit de de la medicina de precisió en oncologia depèn, en gran mesura, d’una adequada selecció dels pacients que rebran teràpies dirigides contra dianes específiques del seu tumor. Per poder seleccionar els pacients, és indispensable disposar de biomarcadors amb valor predictiu que informin les decisions terapèutiques.
MET i PD-L1 són dos receptors de membrana rellevants en la biologia del carcinoma pulmonar no microcític (CPNM). MET és un oncogen i l’activació de la seva via es troba relacionada amb múltiples processos pro-tumorals com són la proliferació i la motilitat cel·lulars, així com la invasió d’estructures veïnes. PD-L1 és una molècula clau en la resposta immunitàries, i la seva sobre-expressió en els tumors està relacionada amb la capacitat de les cèl·lules tumorals d’evitar el seu reconeixement i destrucció per part del sistema immunitari. Actualment, existeixen teràpies específiques dirigides contra aquestes molècules. L’estratègia més emprada per seleccionar els pacients que se’n poden beneficiar és la determinació de l’expressió d’ambdues molècules en teixit tumoral. Tanmateix, el valor de MET i de PD-L1 com a biomarcadors predictius i el mètode pel qual s’han de determinar és subjecte de debat.
Estudis recents han detectat un alt grau d’heterogeneïtat genòmica en mostres tumorals en CPNM. Aquesta heterogeneïtat podria afectar de forma rellevant la classificació de pacients basada en l’expressió de biomarcadors. A més, aquest fet seria especialment rellevant en el cas del CPNM, ja que l’estudi de biomarcadors es fa generalment en mostres petites de teixit, provinents de biòpsies o citologies obtingudes mitjançant tècniques mínimament invasives. L’objectiu principal dels treballs presentats en aquesta tesi és estudiar l’heterogeneïtat de l’expressió de MET i PD-L1 en mostres de CPNM.
Amb aquesta finalitat, hem analitzat mostres tumorals procedents de pacients tractats quirúrgicament de CPNM a l’Hospital del Mar. De cada tumor, hem seleccionat múltiples àrees geogràficament separades, les quals hem analitzat de forma independent. En l’estudi en que hem avaluat MET hem seleccionat quatre àrees per cada pacient, mentre que en l’estudi de PD-L1 n’hem seleccionat dues. En cada àrea tumoral, hem mesurat l’expressió de MET i de PD-L1 mitjançant mètodes d’immunohistoquímica i d’hibridació in situ fluorescent (FISH). Finalment, hem comparat l’expressió de MET i de PD-L1 entre diferents àrees tumorals.
En el cas de MET, hem trobat discordances entre diferents àrees tumorals en un 20-40% per immunohistoquímica i en un 25-50% per FISH. En el cas de PD-L1, aquesta discordança ha estat major si es valora només l’expressió en limfòcits infiltrants de tumor (17-27%) que si es valora en cèl·lules tumorals (10-19%). A més, un 36% dels casos amb amplificació del gen que codifica PD-L1 determinada per FISH presenten aquesta amplificació només en una de les dues àrees analitzades.
En conjunt, els nostres resultats suggereixen que l’expressió d’ambdós biomarcadors és heterogènia, tant si es mesura mitjançant immunohistoqumímica com mitjançant FISH. Aquesta heterogeneïtat pot tenir un impacte potencial en la classificació de tumors basada en l’expressió de biomarcadors i per tant, pot suposar una dificultat afegida a l’hora de desenvolupar teràpies dirigides per pacients amb CPNM.The success of precision medicine in oncology is dependent to a large extent on an adequate selection of patients who will receive targeted therapies aimed at specific molecular traits of their tumor. In order to be able conduct such patient selection, predictive biomarkers that can inform therapeutic decisions are essential. MET and PD-L1 are two relevant membrane receptors for non-small cell lung cancer (NSCLC) biology. MET is an oncogene the activation of which is involved in multiple pro-tumorigenic processes such as cell proliferation, motility and invasion. PD-L1 is a key molecule that acts during the immune response, and its overexpression in tumors is thought to mediate the ability of tumor cells to avoid immune cell recognition and destruction. Currently, there are specific therapies directed against these molecules. The most commonly used strategy to select the patients that will benefit from such drugs is the analysis of the expression of both molecules in tumor tissue. However, the value of MET and PD-L1 as predictive biomarkers and the method by which it should be determined is a subject of debate. Recent studies have detected a high degree of genomic heterogeneity in NSCLC tumor samples. This heterogeneity could significantly affect biomarker-based patient classification especially in the case of NSCLC, since biomarker studies are usually performed in small biopsies or cytology samples obtained through minimally invasive techniques. The main objective of the work presented in this thesis is to study the heterogeneity of the expression of MET and PD-L1 in NSCLC samples. For this purpose, we have analyzed tumor samples from NSCLC patients that had undergone surgical treatment at Hospital del Mar. Of each tumor, we have selected multiple geographically separate areas, which we analyzed independently. In the study evaluating MET, we selected four tumor areas per patient, while in the study evaluating PD-L1 we selected two areas. In each tumor area, we measured the expression MET and PD-L1 using immunohistochemical and fluorescence in situ hybridization methods (FISH). Finally, we compared the expression of MET and PD-L1 in different tumor areas. Regarding MET, we have found discordances between different tumor areas in 20-40% of cases using immunohistochemistry and in 25-50% of cases using FISH. Regarding PD-L1, this discrepancy was greater if we evaluated PD-L1 expression in tumor infiltrating lymphocytes (17-27%) than if we did so only in tumor cells (10-19%). Moreover, 36% of the cases with amplification of the gene coding for PD-L1 determined by FISH presented gene amplification only in one of the two areas analyzed. Overall, our results suggest that the expression of both biomarkers is heterogeneous, whether measured by immunohistochemistry or by FISH. This heterogeneity can have a potential impact on the classification of tumors based on the expression of biomarkers and, therefore, could represent a hurdle for the development of targeted therapies for NSCLC patients.
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Tong, Wing-yee. "Studies on non-small cell lung cancer with EGFR mutation /." View the Table of Contents & Abstract, 2005. http://sunzi.lib.hku.hk/hkuto/record/B31495333.
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Cox, Giles. "Angiogenesis and matrix metalloproteinases in non-small cell lung cancer." Thesis, University of Leicester, 2000. http://hdl.handle.net/2381/29608.
Abstract:
The aim of this study was to evaluate potential invasive and metastatic pathways in order to develop a biological prognostic model for operable NSCLC. Initially an immunohistochemical study of angiogenesis, growth factor receptors (EGFR, c-erbB-2), regulators of apoptosis (p53, Bcl-2) and matrix metalloproteinases and their inhibitors (MMP-2, MMP-9 and TIMP-2) was performed in a retrospective series of resected NSCLC tumours. Chalkley counting of CD34-immunostained microvessels was used as an indirect measure of angiogenesis. A high Chalkley count was an independent marker of poor outcome. Bcl-2 expression correlated with good prognosis suggesting that loss of Bcl-2 expression may indicate more severe molecular dedifferentiation resulting in a more aggressive phenotype. MMP-2, MMP-9 and TIMP-2 were frequently demonstrated in both tumour cells and the surrounding stroma. Tumour cell MMP-9 expression was independently associated with poor prognosis and significantly correlated with EGFR immunoreactivity. A stage-independent prognostic model using the immunohistochemical markers CD34, EGFR, MMP-9 and Bcl-2 performed on routinely processed tissue was developed. This model identified patients at particular risk of recurrence after resection who could receive adjuvant treatment with either traditional cytotoxic chemotherapy or potentially individualised therapy with more targeted therapeutic agents. In vitro studies demonstrated that EGF up-regulated MMP-9 mRNA expression in 4/5NSCLC cell-lines with no effect on MMP-2, MTI-MMP, TIMP-1 or TIMP-2 mRNA expression. These results suggest EGFR is involved in the specific up-regulation of MMP-9 and supports the use of novel therapies including MMP inhibitors and EGFR tyrosine kinase antagonists in the treatment of NSCLC.
41
Tai, Lai-shan, and 戴麗珊. "Molecular genetic characterizations of human non-small cell lung cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2005. http://hub.hku.hk/bib/B31375315.
42
Tong, Wing-yee, and 唐穎儀. "Studies on non-small cell lung cancer with EGFR mutation." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2005. http://hub.hku.hk/bib/B45010432.
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Koch, Andrea. "Clinical Aspects of Inflammation in Non-small Cell Lung Cancer." Doctoral thesis, Linköpings universitet, Internmedicin, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-68749.
Abstract:
Lung cancer is the most common cause of cancer death worldwide, with about 1.2 million deaths every year. In Sweden, about 3500 new cases are diagnosed every year. The majority of patients presents with advanced non-small cell lung cancer (NSCLC) and is treated with palliative intent. Standard treatment in these patients in performance status 0-2 is combination chemotherapy. Radiotherapy may be added for palliative purposes. Median survival time with such treatment is 6-10 months. New treatment strategies are urgently needed. There is growing evidence for a link between cancer and inflammation and consequently, inflammation may be a possible target for the treatment of lung cancer. The aim of this thesis was to study clinical aspects of inflammation in non-small cell lung cancer. A central issue was to adapt the projects as close to clinical routine as possible. In a retrospective study of 289 patients (paper I), we investigated the prognostic value of Creactive protein (CRP), a nonspecific marker of systemic inflammation, and smoking in patients with advanced NSCLC treated with palliative first-line chemotherapy. We found that patients with elevated CRP values (≥10 mg/ml) and current smokers at onset of treatment had inferior survival compared to patients with normal CRP values and patients who were not smoking. CRP and smoking status were independent prognostic factors and provided additional information to established prognostic factors such as stage of disease and performance status. The expression of COX-2, an important enzyme involved in inflammation, was prospectively analysed in 53 patients with cytologically diagnosed lung cancer (paper II). The study showed that the analysis of COX-2 expression in cytological material is technically easy to perform with routine diagnostic methods and results in good quality slides. There was great variation in the proportion of COX-2 positive cells between the patients as well as in the intensity of staining between individual cells in many single cases. The major project (paper III) of this thesis was the CYCLUS study, an academic, randomised, double-blind, phase III trial. The scientific question was if addition of the COX-2 inhibitor celecoxib to first-line palliative chemotherapy would prolong survival in patients with advanced NSCLC. 316 patients were included at 13 centres in Sweden. There was no survival difference between the treatment arms. Celecoxib appeared to have more favourable effect on survival in women than in men, but the differences were not significant. Small but not statistically significant differences in global quality of life and pain were seen favouring the celecoxib group. No increased incidence of cardiovascular events was observed in the celecoxib group.
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Brauneis, Alison Dooley. "Investigating the initiation and progression of small cell lung cancer." Thesis, Massachusetts Institute of Technology, 2011. http://hdl.handle.net/1721.1/63063.
Abstract:
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2011.Cataloged from PDF version of thesis.
Includes bibliographical references.
Small cell lung cancer (SCLC) comprises 18% of all lung cancer cases and is an aggressive disease with a five-year survival rate of less than 5%, mainly due to the advanced nature of the disease at the time of diagnosis. Despite the need to better understand this disease, the genetic lesions that contribute to SCLC remain poorly characterized. To investigate the genetic aberrations that occur in SCLC, we analyzed the copy number alterations in tumors and metastases arising in a mouse model of SCLC (mSCLC), driven by conditional inactivation alleles of two tumor suppressor genes, Trp53 and Rbl. We identified frequent, high-level amplification of a novel, protooncogenic transcription factor Nuclear Factor I/B (Nfib in mouse, NFIB in human), which frequently occurred coincident with amplification of a previously characterized oncogene, L-myc (Mycl). Functional studies revealed cooperation between Nfib and Lmyc in cellular transformation. Comparative genomics identified NFIB amplifications in human SCLC and uncovered a role for NFIB in regulating cell viability and proliferation. We also examined the effect of lung injury on SCLC initiation and progression utilizing naphthalene, a chemical that ablates the cells that line the bronchioles of the lung. The pulmonary neuroendocrine cells, the putative cell of origin of SCLC, are refractory to naphthalene-mediated injury. We demonstrated that naphthalene-mediated injury prior to tumor initiation in the mouse model of SCLC induced more advanced mSCLC lesions and decreased tumor latency. Throughout the course of this thesis work, we successfully utilized a mouse model of SCLC to interrogate the initiation of SCLC as well as to define the genetic alterations that occur in SCLC tumors and metastases. This work has led to the identification of candidate genes that promote tumor progression and to a better understanding of the process of tumor initiation. We anticipate that these findings will not only enhance our understanding of SCLC, but may lead to the development of therapeutics used to treat this aggressive disease.
by Alison L. Dooley.
Ph.D.
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Kouverianou, Eleni. "Galectin-3 regulation of non small cell lung cancer growth." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/17891.
Abstract:
Galectin-3 is a β-galactoside binding lectin expressed in tumour cells and macrophages and has been associated with increased malignancy in a variety of cancers. Previous work has shown that galectin-3 is an important regulator of macrophage function, promoting an alternative (M2) phenotype which potentiates chronic inflammation and fibrosis. Tumour associated macrophages (TAMs) adopt an M2 phenotype and are thought to promote tumour growth by down regulating T cell effector function and promoting angiogenesis. This project examines the hypothesis that host galectin-3 promotes lung cancer growth and spread. In order to test this hypothesis, Lewis Lung Carcinoma tumour growth and metastasis was investigated in strain matched mice either expressing or deficient in galectin-3. The Lewis Lung Carcinoma cell line (LLC1) is a spontaneous lung carcinoma line, derived from C57BL/6 mice, which readily forms tumours when transplanted. Furthermore, LLC1 cells were stably transfected with a Luciferase expressing vector in order to assist detection of tumour growth and metastasis in vivo. An orthotopic model of LLC1 growth suggested that galectin-3-/- animals do not support lung carcinoma growth and spread. This finding was confirmed by a subcutaneous model of cancer growth, where it was found that wild type animals display a higher proportion of macrophages expressing a prototypic M2 marker around tumour sites compared to galectin-3-/- animals. M2-promoting cytokine transcripts were also reduced in galectin-3-/- mice. Additionally, tumours of wild type mice were more invasive and presented more mature blood vessels compared to galectin-3-/- mice. To specifically address the role of recruited cells on tumour growth, metastasis and the inflammation profile around tumour sites, in relation to galectin-3 expression, bone marrow cells (BMCs) were transplanted from wild type to galectin-3-/- mice and vice versa. It was shown that galectin-3 positive BMCs restore the wild type phenotype of tumour growth in galectin-3-/- mice, while galectin-3 deficient BMCs impair tumour growth in wild type animals. Furthermore, macrophage ablation experiments demonstrated incapacity for tumour establishment in the absence of macrophages. A series of experiments investigating reported inhibition of galectin-3 by modified citrus pectin (MCP) via competitive inhibition did not provide conclusive results. MCP had no effect in vivo, but was able to inhibit LLC1 cell growth in vitro. Most importantly though, results were inconclusive as to whether galectin-3 binds MCP. Some ligand displacement was seen, but direct binding of the molecules could not be shown. In general, the results obtained demonstrate a strong pro-tumoural effect of galectin-3 on growth, tissue invasion and metastasis of LLC1 tumours via an increased proportion of Ym1-expressing macrophages around tumour sites. It was shown that macrophages are key cells for tumour initiation and that BMC phenotype in relation to galectin-3 expression determines the phenotype of tumour development in subcutaneous and orthotopic LLC1 models. Therefore, galectin-3 has a strong regulatory effect on tumour phenotype and could present a key target in the management of lung carcinomas.
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Usó, Marco Marta. "ANALYSIS OF IMMUNOREGULATORY BIOMARKERS IN NON-SMALL CELL LUNG CANCER." Doctoral thesis, Universitat Politècnica de València, 2015. http://hdl.handle.net/10251/51283.
Abstract:
[EN] Lung cancer is the leading cause of cancer-related death worldwide, and is the third most common cancer type; it can be classified into two subgroups based on histology: non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). The 5-year survival still remains poor and despite the existence of several distinct tumour phenotypes, therapeutic decisions are mainly based on clinical features such as stage or performance status. This highlights the need for new diagnostic and prognostic biomarkers in different types of samples (such as blood, fresh-frozen tissue or formalin-fixed, paraffin-embedded samples).
The field of tumour immunology has changed in the last decade, and it is now accepted that the immune system plays a pivotal role in cancer. Although the immune cells that infiltrate the tumour microenvironment are potentially capable of eliminating tumour cells, they cannot prevent tumour development and progression. Tumours acquire mechanisms to regulate their immune microenvironment such as the release of a series of factors to subvert normal reaction mechanisms, the modulation of co-stimulatory pathways, also known as immune checkpoints, and the induction and attraction of suppressor cells (myeloid-derived suppressor cells, tumour-associated macrophages, and regulatory T cells). The potential effect of the patient's immune system on clinical outcome is important for the identification of prognostic markers as well as markers that predict treatment responses. The study of immune-related markers, especially those implicated in immunoregulatory processes, could provide valuable prognostic information that could help in many applications in future clinical practice.
Thus, the objective of this thesis is to characterise cancer immunoregulation biomarkers and to evaluate the possible correlation between these biomarkers and clinicopathological and prognostic variables in patients with NSCLC by the use of well-tested and accurate techniques such as quantitative PCR and immunohistochemistry. Furthermore, this study will provide information about the immunological features of the tumour microenvironment in NSCLCs.[ES] El cáncer de pulmón es una de las principales causas de muerte relacionada con cáncer en el mundo, siendo el tercer tipo de cáncer más común. El cáncer de pulmón no microcítico (CPNM) representa casi el 85% de todos los cánceres de pulmón y la supervivencia a los 5 años va desde el 50% en estadios IA hasta el 15% en estadios IIIA. Hasta el momento, no se han descubierto biomarcadores capaces de predecir la progresión de la enfermedad en pacientes tanto en estadios resecables como en estadios avanzados, por lo que existe una clara necesidad de realizar estudios centrados en la búsqueda de biomarcadores pronósticos y diagnósticos en los diferentes tipos de muestra disponibles, como por ejemplo sangre, tejido fresco y tejido parafinado. El campo de la inmunología tumoral ha cambiado en la última década y actualmente se sabe que el sistema inmune juega un papel clave en cáncer. Las células inmunes que infiltran el tumor son un componente más del microambiente tumoral. Pese a que son potencialmente capaces de eliminar los antígenos tumorales, estas células no pueden evitar la formación y progresión tumoral. Esto es debido a que el tumor adquiere diversos mecanismos de regulación del microambiente tumoral con el objetivo de escapar del ataque del sistema inmune, como por ejemplo liberación de factores que impiden el correcto funcionamiento de los mecanismos de reacción inmune, modulación de vías co-estimuladoras y reclutamiento y activación de células inmunoreguladoras como las células T reguladoras, las células mieloides supresoras y los macrófagos asociados a tumores. El estudio de marcadores relacionados con la respuesta inmune y concretamente con los procesos de inmunoregulación puede proporcionarnos información pronóstica y predictiva relevante sobre los pacientes con cáncer. Por todo ello, el principal objetivo de esta tesis doctoral es analizar la presencia de marcadores relacionados con la inmunoregulación y evaluar su posible correlación con las variables clínico-patológicas y pronósticas en pacientes con CPNM mediante el uso de técnicas fiables y aplicables en la práctica clínica como la PCR cuantitativa y la inmunohistoquímica. Así mismo, esto nos permitirá conocer en mayor profundidad las características inmunológicas del microambiente tumoral en pacientes con CPNM.
[CAT] El càncer de pulmó és una de les principals causes de mort relacionades amb càncer al món, sent a més a més el tercer tipus de càncer més comú. El càncer de pulmó no microcític (CPNM) representa el 85% de tots els casos de càncer de pulmó aproximadament i la supervivència als 5 anys continua sent molt baixa. Fins el moment, no s'han descobert biomarcadors capaços de predir la progressió de la malaltia tant en pacients en estadis inicials com en estadis avançats. Per aquest motiu, existeix una clara necessitat de realitzar estudis centrats en la recerca de biomarcadors pronòstics i predictius en els diferents tipus de mostres disponibles, com per exemple sang, teixit fresc i teixit parafinat. El camp de la immunologia tumoural ha canviat en l'última dècada i actualment se sap que el sistema immune exerceix un paper clau en el càncer. Les cèl¿lules immunològiques que infiltren el tumour són un component més del microambient tumoural. Malgrat que aquestes cèl¿lules són potencialment capaces d'eliminar el antígens tumourals, s'ha evidenciat que no poden previndre la formació i progressió tumoural. Una de les raons per les quals s'observa aquest fenomen és que el tumour adquireix diversos mecanismes de regulació del microambient tumoural. Aquests mecanismes es basen en l'alliberació de factors que impedeixen el correcte funcionament del sistema immune, la modulació de vies coestimuladores i el reclutament i activació de cèl¿lules immunoreguladores com poden ser les cèl¿lules T reguladores, les cèl¿lules mieloides supressores i els macròfags associats a tumour. L'estudi de marcadors relacionats amb la resposta immune i més concretament amb els processos d' immunoregulació pot proporcionar informació pronòstica i predictiva rellevant sobre els pacients amb càncer. Per tot això, el principal objectiu d'aquesta tesi doctoral és analitzar la presència de marcadors relacionats amb la immunoregulació i avaluar la seva possible correlació amb les variables clinicopatològiques i pronòstiques de pacients amb CPNM mitjançant l'ús de tècniques fiables i aplicables a la pràctica clínica com són la PCR quantitativa i la immunohistoquímica. Així mateix, aquestes anàlisis ens permetran conèixer amb major profunditat les característiques immunològiques del microambient tumoural de pacients amb CPNM.
Usó Marco, M. (2015). ANALYSIS OF IMMUNOREGULATORY BIOMARKERS IN NON-SMALL CELL LUNG CANCER [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/51283
TESIS
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Deskin, Brian J. "Histone deacetylase 6 functions in non-small cell lung cancer." Thesis, Tulane University, 2017. http://pqdtopen.proquest.com/#viewpdf?dispub=10195328.
Abstract:
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide in both men and women. Of relevance to our research presented herein are the Transforming growth factor β (TGF-β) signaling pathways and the heat shock response in the context of NSCLC. Dysregulation of TGF-β signaling often results in disease and is a common feature of many cancers including NSCLC where it governs cell fate and epithelial plasticity through the epithelial-to-mesenchymal transition (EMT). Another key feature of oncogenic TGF-β signaling is the crosstalk with other oncogenic pathways, like the NOTCH signaling pathway, which aids to restrict differentiation and modulates proliferation. Our research identified a mechanistic link between histone deacetylase 6 (HDAC6) and TGF-β1-induced Notch1 signaling. When HDAC6 is knocked down with siRNA or its deacetylase function is pharmacologically inhibited TGF-β1 activation of Notch signaling is abrogated. Within this paradigm we identified a protein complex consisting of HDAC6, heat shock protein 90 (HSP90), and the Notch1 receptor. In response to TGF-β1 stimulation, HDAC6 rapidly deacetylates HSP90 at lysine 294 which corresponds with cleavage and activation of Notch1.
Our investigations also uncovered a unique feature of HSP90 function in NSCLC. Activation of the heat shock response triggers activation of Notch1 signaling. We demonstrated that HDAC6 regulates this heat shock-induced Notch1 signaling through modulation of HSP90 function of cytoplasmic sequestration of the key transcription factor that governs the heat shock response, heat shock factor 1 (HSF1). Brief exposure of NSCLC cells to 42°C activates heat shock-induced Notch1 signaling, knockdown of HDAC6 with siRNA or pharmacological inhibition of HDAC6 abrogated this induction. In our investigations employing this combined strategy of targeting both HDAC6 and HSP90 we discovered that this treatment had an additive effect to enhance apoptotic markers and inhibit cell cycle progression in NSCLC cells. Individual HDAC6 or HSP90 inhibition slowed tumorigenesis and enhanced apoptosis of NSCLC in vivo. Taken altogether, our research identifies HDAC6 and HSP90 as regulators of key oncogenic pathways required for EMT and that combined inhibition of both these targets is a rational strategy to selectively kill NSCLC cells.
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Tam, Gloria. "Non-small cell lung cancer clinical trials on new medicines." Click to view the E-thesis via HKUTO, 2008. http://sunzi.lib.hku.hk/hkuto/record/B41711956.
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Acheampong, Emmanuel. "Assessment of circulating tumour cells in lung cancer patients." Thesis, Edith Cowan University, Research Online, Perth, Western Australia, 2022. https://ro.ecu.edu.au/theses/2554.
Abstract:
Lung cancer is among the most prevalent forms of cancer and remains the leading cause of cancer-associated deaths globally. Traditionally, lung cancers are classified as either non-small cell lung cancer (NSCLC) (85%) or small cell lung cancer (SCLC) (15%). About 60% of all cases are diagnosed at an advanced stage, at which the 5-year survival is only 4%. Anti-programmed cell death-1 and its ligand 1 (anti-PD-1/PD-L1) therapies have significantly improved the outcomes for lung cancer patients in recent years. However, prognosis and understanding of an individual patient’s lung cancer are often limited by tumour accessibility. Tissue biopsies are invasive, costly, and technically challenging procedures, posing risks to the patient. Circulating tumour cells (CTCs) are very attractive tumour surrogates that could serve as “liquid biopsy” with the advantage to be a low–to–null invasive and real-time approach compared to conventional tissue biopsies. Increasing evidence suggests that CTCs counts can serve as a prognostic biomarker for lung cancers. Notably, phenotypic, and molecular characterisation of CTCs may offer important clinical information for guiding personalised medicine.
The studies in this dissertation assessed the potential of CTCs to provide information that could aid the management of lung cancer patients. We carried out a series of investigations covering a systematic review and meta-analysis of programmed cell death ligand-1 (PD-L1) expression on tumour samples and CTCs, a methodological study to improve phenotypic characterisation of CTCs for PD-L1 expression and its application in the clinical settings, and a study using singlecell genomics to uncover novel subpopulations of CTCs.
The first chapter of the thesis includes an introduction to lung cancer and a thorough review of the literature on immunotherapy in lung cancer as well as CTCs. Chapter 2 describes a comprehensive review and meta-analysis of PD-L1 expression on tumour cells in SCLC from 27 studies enrolling a total of 27,292 patients. Our results revealed that the prevalence of PD-L1 expression in SCLC tumour cells was heterogeneous across studies. This heterogeneity was significantly moderated by factors such as cut-off values used for scoring PD-L1 staining by immunohistochemistry, and assessment of PD-L1 staining patterns as membranous and/or cytoplasmic. Following these findings, Chapter 3 covers a study carried out to address the feasibility to quantify PD-L1 expression on CTCs in SCLC patients. We develop an EpCAM targeting magnetic bead-based CTC isolation method as a surrogate for the CellSearch method, as this is the gold standard for CTC enumeration and the most used SCLC CTC isolation platform in the clinical setting. Using our immunomagnetic isolation technique, we compared detection rates of CTCs to those isolated using the microfluidic CTC enrichment device - Parsortix system, which separates cells by size exclusion. Detected CTCs were used to assess PD-L1 expression. We identified a subpopulation of EpCAM-negative SCLC CTCs, indicating that epitope-independent methods can detect additional CTCs missed by EpCAM basedcapture. The study also demonstrated that PD-L1 expression can be quantified on CTCs detected in SCLC patients.
In parallel, we questioned whether blood is the alternative for PD-L1 expression in NSCLC patients based on several published studies that have assessed PD-L1 expression on CTCs in NSCLC patients. The review in Chapter 4 indicates that the analysis of PD-L1 on CTCs is feasible and PD-L1 expression could be detected before and after first-line therapy. However, there was limited evidence of whether PD-L1 expression on CTCs could predict response to anti-PD-1/PDL1 treatment.
Chapter 5 describes a study in NSCLC patients to improve the detection of relevant CTC phenotypes and interrogate them for PD-L1 expression. We simultaneously identified circulating cells with epithelial origin and cells with mesenchymal features in patients with NSCLC by combining the Parsortix system with a modified sequential fluorescent quenching and restaining protocol. Nevertheless, none of the detected circulating cells expressed PD-L1 protein. Furthermore, a subset of mesenchymal-featured cells was confirmed as cancer cells via whole genome amplification (WGA) and low-pass whole-genome sequencing (LP-WGS) which revealed copy number alterations (CNAs) in several genomic regions.
Lastly, the general discussion underscores how specific CTCs enrichment techniques are required for lung cancers according to their phenotypic characteristics. The results question the potential of CTCs for evaluating PD-L1 expression and the need for systematic clinical validation. Finally, the prospect of CTC genomic analysis is highlighted as it provides an opportunity to timely recognise patients harbouring deleterious alteration and new treatment targets. We conclude by proposing future directions building upon the findings presented in this thesis.
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Bingula, Rea. "Non-small cell lung cancer, immunity and microbiota : laying ground for the gut-lung-lung cancer axis in human subjects." Thesis, Université Clermont Auvergne (2017-2020), 2019. http://www.theses.fr/2019CLFAS009.
Abstract:
Le cancer du poumon est la principale cause de décès par cancer dans le monde. En dépit de la variété de traitements disponibles, tels que la chirurgie, la chimiothérapie, la radiothérapie et l’immunothérapie, la survie moyenne à 5 ans est de 60 %. L’une des raisons sous-jacente est une très grande variabilité de réponse au traitement, expliquée par les antécédents génétiques du patient et depuis peu par son microbiote. Le terme « microbiote » regroupe les bactéries, les archées, les champignons, les virus et les protistes qui colonisent notre organisme. Des études utilisant des modèles animaux montrent que le microbiote intestinal joue un rôle crucial dans la réponse de l’hôte au traitement, via la stimulation du système immunitaire. Dans ce contexte, plusieurs « axes de communication » entre le site intestinal et les sites tumoraux distaux commencent à émerger, y compris l’axe « intestin-poumon ». Cependant, le microbiote pulmonaire, qui pourrait directement influencer la réponse tumorale et interagir avec le microbiote intestinal, est pour l’heure peu caractérisé. Afin de développer cette idée d’un axe « intestin, poumon et cancer du poumon », nous avons inclus dans notre étude 18 patients atteints d’un cancer du poumon non à petites cellules (CBNPC) admissibles à la chirurgie. Nous avons analysé leurs microbiotes par séquençage à haut débit à partir de quatre échantillons différents de poumon (tissu sain, tissus péritumoral et tumoral et fluide de lavage broncho-alvéolaire LBA) mais également à partir d’échantillons de salive et de fèces. Nous avons également analysé plusieurs marqueurs immunitaires (infiltration lymphocytaire des tumeurs, profils Th et neutrophiles, cytokines dans le LBA et le sang), des marqueurs inflammatoires et enfin les acides gras à chaînes courtes dans les fèces. Une caractérisation détaillée de ces quatre types d’échantillons de poumons nous a permis de montrer que le microbiote du LBA présente une communauté nettement distincte de celle du tissu pulmonaire. Les tumeurs des lobes inférieurs prédisant le plus mauvais pronostic, nous avons décidé d’étudier le lien entre l’emplacement des tumeurs et la composition du microbiote. Les microbiotes du tissu péritumoral et du LBA ont été identifiés comme étant les plus impactés en terme d’abondance et de diversité ; la tumeur est quant à elle moins impactée. Cependant nous avons observé que le phylum des Firmicutes, décrit comme étant élevé dans les maladies pulmonaires obstructives chroniques, est plus abondant dans le microbiote des lobes inférieurs du poumon. Par conséquent, nous pouvons émettre l’hypothèse que l’augmentation des Firmicutes et les variations importantes du microbiote dans le tissu péritumoral pourraient être associés à une agressivité accrue des tumeurs du lobe inférieur. Nous avons ensuite démontré que la présence de ganglions lymphatiques (GL) métastatiques, marqueur d’un pronostic négatif dans le NSCLC, influence considérablement le microbiote local de par le profil respiratoire du tissu. Nous avons en effet observé que les bactéries anaérobies étaient plus abondantes dans les tumeurs en présence de LN métastatiques. Les bactéries aérobies sont quant à elles plus représentées dans les tumeurs sans GL métastatiques. Nous avons cependant observé la situation inverse dans les tissus extratumoraux. L’hypothèse avancée est celle d’une migration bactérienne en fonction des préférences de conditions de croissance, directement liées aux caractéristiques de la tumeur. Ceci nous permet de proposer plusieurs biomarqueurs pour la détection de GL métastatique, facilitant ainsi leur détection sans imposer de biopsie. Enfin, nous montrons que le microbiote du LBA est d’avantage associé à la réponse immunitaire locale et est indépendant de la présence de GL métastatique. Les recherches à venir porteront sur l’exploration de l’interaction entre le microbiote pulmonaire, l’immunité systémique et le microbiote intestinalLung cancer is the main cause of death by cancer worldwide. Despite the variety of available treatments, including surgery, chemotherapy, radiotherapy, and immune therapy, the average 5-year survival is 60%. One of the underlying reasons is a very high variability in patients’ susceptibility to treatment, explained by genetic background and since recently – our microbiota. The term microbiota includes bacteria, archaea, fungi, viruses and protists that inhabit our organism. The studies in animal models show that the gut microbiota (focused on bacteria) has a crucial role in host’s responsiveness to therapy through the stimulation of immune system. In this light, several “communication axes” between the gut and distal tumour sites have started to develop, including the “gut-lung” axis. However, the resident microbiota in the lungs that could directly influence the tumour response and interact with the gut microbiota has been scarcely characterised. To enable further development of the idea of the “gut-lung-lung cancer” axis, we included 18 non-small cell lung cancer (NSCLC) patients eligible for surgery and analysed the microbiota from four different lung samples (non-malignant, peritumoural and tumour tissue and bronchoalveolar lavage fluid; BAL), saliva and faeces by high-throughput sequencing. We also analysed several immune markers, as lymphocytic tumour infiltrate, Th and neutrophil profiles and cytokines in BAL and blood, and inflammatory markers in faeces along with short-chain fatty acids. Focusing first on the lungs, we show that BAL microbiota represents a significantly distinct community compared to lung tissue microbiota by providing detailed characterisation of the four different lung samples. Since tumours in lower lobes are reported as the ones with the worse prognosis, we investigated how the lobe location affected the microbiota composition. Peritumoural tissue and BAL microbiota were identified as the most affected in both abundance and diversity, and tumour as the least affected. However, phylum Firmicutes, previously reported as elevated in chronic obstructive pulmonary disease compared to controls, was found more abundant in microbiota from lower lung lobes. Therefore, we propose that both increase in Firmicutes and extensive changes in peritumoural tissue could be associated to increased aggressiveness of the lower lobe tumours. Next, we show that the presence of metastatic lymph nodes (LN), negative prognostic marker in NSCLC, significantly influence the local tissue microbiota in relation to its respiratory profile. We reported that anaerobic bacteria were more abundant within the tumour in the presence of metastatic LN, and aerobic bacteria within the one without it. Moreover, exactly inverse was observed for the same bacteria in extratumoural tissues. Along with migratory hypothesis depending on the bacterial preference for growth conditions shaped by tumour’s features, we propose several biomarkers for detection of metastatic LN that might facilitate their detection without imposing LN biopsy. Finally, we showed that BAL microbiota is the most associated to the local immune response and independent of the presence of metastatic LN. Future research will focus on the exploration of the interaction between the lung microbiota, systemic immunity and the gut microbiota