title: Exposure of fallopian tube epithelium to follicular fluid mimics carcinogenic changes in precursor lesions of serous papillary carcinoma.
abstract: OBJECTIVE
  Ovulation-related inflammation is suspected to have a causal role in ovarian carcinogenesis, but there are no human models to study the molecular pathways. Our aim is to develop such an ex-vivo model based on human fallopian tube (FT) epithelium exposed to human follicular fluid (FF).
  
  
  METHODS
  FT epithelium was dissociated from normal surgical specimens. FF was obtained from donors undergoing in-vitro fertilization. The cells were cultured on collagen-coated Transwells and incubated with FF for various periods of time. The transcriptomic changes resulting from FF treatment were profiled using Affymetrix expression arrays. Specific characteristics of the FT pre-cancerous lesions were studied using immunohistochemistry, immunofluorescence, RT-PCR and XTT assay.
  
  
  RESULTS
  We show that FF exposure causes up-regulation of inflammatory and DNA repair pathways. Double stranded DNA breaks are induced. There is a minor increase in cell proliferation. TP53, which is the hallmark of the precursor lesion in-vivo, is accumulated. Levels of expression and secretion of Interleukin-8 are significantly increased.
  
  
  CONCLUSIONS
  Our model addresses the main non-genetic risk factor for ovarian cancer, namely the impact of ovulation. This study demonstrates the biological implications of in-vitro exposure of human FT epithelial cells to FF. The model replicates elements characterizing the precursor lesions of ovarian cancer, and warrants further investigation of the linkage between repeated exposure to ovulation-related damage and accumulation of neoplastic changes.
authors.affiliation: Sheba Cancer Research Center, Chaim Sheba Medical Center, Ramat Gan 52621, Israel.
authors.forename: K
authors.initials: K
authors.lastname: Bahar-Shany
authors.affiliation: Sheba Cancer Research Center, Chaim Sheba Medical Center, Ramat Gan 52621, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv 69978, Israel.
authors.forename: H
authors.initials: H
authors.lastname: Brand
authors.affiliation: Sheba Cancer Research Center, Chaim Sheba Medical Center, Ramat Gan 52621, Israel.
authors.forename: S
authors.initials: S
authors.lastname: Sapoznik
authors.affiliation: Sheba Cancer Research Center, Chaim Sheba Medical Center, Ramat Gan 52621, Israel.
authors.forename: J
authors.initials: J
authors.lastname: Jacob-Hirsch
authors.affiliation: IVF Unit and Reproduction Lab, Department of Obstetrics and Gynecology, Chaim Sheba Medical Center, Ramat-Gan 52621, Israel.
authors.forename: Y
authors.initials: Y
authors.lastname: Yung
authors.affiliation: Department of Gynecologic Oncology, Chaim Sheba Medical Center, Ramat Gan 52621, Israel.
authors.forename: J
authors.initials: J
authors.lastname: Korach
authors.affiliation: Department of Gynecologic Oncology, Chaim Sheba Medical Center, Ramat Gan 52621, Israel.
authors.forename: T
authors.initials: T
authors.lastname: Perri
authors.affiliation: Institutional Tumor Banks, Chaim Sheba Medical Center, Ramat Gan 52621, Israel.
authors.forename: Y
authors.initials: Y
authors.lastname: Cohen
authors.affiliation: Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv 69978, Israel; IVF Unit and Reproduction Lab, Department of Obstetrics and Gynecology, Chaim Sheba Medical Center, Ramat-Gan 52621, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Hourvitz
authors.affiliation: Sheba Cancer Research Center, Chaim Sheba Medical Center, Ramat Gan 52621, Israel; The Dr. Pinchas Borenstein Talpiot Medical Leadership Program 2012, Institute of Oncology, Chaim Sheba Medical Center, Ramat Gan 52621, Israel. Electronic address: Keren.Levanon@sheba.health.gov.il.
authors.forename: K
authors.initials: K
authors.lastname: Levanon
mesh_terms: D000328:Adult; D000368:Aged; D063646:Carcinogenesis; D002291:Carcinoma, Papillary / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004249:DNA Damage; D004848:Epithelium / Q000473:pathology; D005185:Fallopian Tube Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005187:Fallopian Tubes / Q000473:pathology*; D005260:Female; D015571:Follicular Fluid / Q000737:chemistry*; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D046228:Microarray Analysis; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016896:Treatment Outcome
keywords: Biomarkers; Carcinogenesis; Fallopian tube; Follicular fluid; Ovarian cancer; Ovulation