title: A distinct pre-existing inflammatory tumour microenvironment is associated with chemotherapy resistance in high-grade serous epithelial ovarian cancer.
abstract: BACKGROUND
  Chemotherapy resistance is a major determinant of poor overall survival rates in high-grade serous ovarian cancer (HGSC). We have previously shown that gene expression alterations affecting the NF-κB pathway characterise chemotherapy resistance in HGSC, suggesting that the regulation of an immune response may be associated with this phenotype.
  
  
  METHODS
  Given that intrinsic drug resistance pre-exists and is governed by both tumour and host factors, the current study was performed to examine the cross-talk between tumour inflammatory microenvironment and cancer cells, and their roles in mediating differential chemotherapy response in HGSC patients. Expression profiling of a panel of 184 inflammation-related genes was performed in 15 chemoresistant and 19 chemosensitive HGSC tumours using the NanoString nCounter platform.
  
  
  RESULTS
  A total of 11 significantly differentially expressed genes were found to distinguish the two groups. As STAT1 was the most significantly differentially expressed gene (P=0.003), we validated the expression of STAT1 protein by immunohistochemistry using an independent cohort of 183 (52 resistant and 131 sensitive) HGSC cases on a primary tumour tissue microarray. Relative expression levels were subjected to Kaplan-Meier survival analysis and Cox proportional hazard regression models.
  
  
  CONCLUSIONS
  This study confirms that higher STAT1 expression is significantly associated with increased progression-free survival and that this protein together with other mediators of tumour-host microenvironment can be applied as a novel response predictive biomarker in HGSC. Furthermore, an overall underactive immune microenvironment suggests that the pre-existing state of the tumour immune microenvironment could determine response to chemotherapy in HGSC.
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Koti
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Siu
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Canada, Institut du Cancer de Montréal, Montreal, QC H2X 0B9, Canada.
authors.forename: I
authors.initials: I
authors.lastname: Clément
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Bidarimath
authors.affiliation: Department of Pathology and Molecular Medicine, Kingston General Hospital, Kingston, ON K7L3N6, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Turashvili
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Edwards
authors.affiliation: Department of Pathology, Centre Hospitalier de l'Université de Montréal, Montreal, QC H3C 3J7, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Rahimi
authors.forename: A-M
authors.initials: AM
authors.lastname: Mes-Masson
authors.affiliation: 1] Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Canada, Institut du Cancer de Montréal, Montreal, QC H2X 0B9, Canada [2] Department of Medicine, Universite de Montreal, Montreal, QC H3C 3J7, Canada.
authors.forename: A-M M
authors.initials: AM
authors.lastname: Masson
authors.affiliation: Departments of Genetics and Pathology, Faculdade de Medicina de Ribeirão Preto USP, Av. Bandeirantes, 3900 Ribeirão Preto, SP Brazil.
authors.forename: J A
authors.initials: JA
authors.lastname: Squire
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D000077216:Carcinoma, Ovarian Epithelial; D015331:Cohort Studies; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D060787:Neoplasm Grading; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D050794:STAT1 Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D016019:Survival Analysis; D046888:Tissue Array Analysis; D059016:Tumor Microenvironment
chemical_list: D014408:Biomarkers, Tumor; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human
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