title: Inflammatory cytokine tumor necrosis factor alpha confers precancerous phenotype in an organoid model of normal human ovarian surface epithelial cells.
abstract: In this study, we established an in vitro organoid model of normal human ovarian surface epithelial (HOSE) cells. The spheroids of these normal HOSE cells resembled epithelial inclusion cysts in human ovarian cortex, which are the cells of origin of ovarian epithelial tumor. Because there are strong correlations between chronic inflammation and the incidence of ovarian cancer, we used the organoid model to test whether protumor inflammatory cytokine tumor necrosis factor alpha would induce malignant phenotype in normal HOSE cells. Prolonged treatment of tumor necrosis factor alpha induced phenotypic changes of the HOSE spheroids, which exhibited the characteristics of precancerous lesions of ovarian epithelial tumors, including reinitiation of cell proliferation, structural disorganization, epithelial stratification, loss of epithelial polarity, degradation of basement membrane, cell invasion, and overexpression of ovarian cancer markers. The result of this study provides not only an evidence supporting the link between chronic inflammation and ovarian cancer formation but also a relevant and novel in vitro model for studying of early events of ovarian cancer.
authors.affiliation: Laboratory of Gynecologic Oncology, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. josephkwong@cuhk.edu.hk
authors.forename: Joseph
authors.initials: J
authors.lastname: Kwong
authors.forename: Franky Leung
authors.initials: FL
authors.lastname: Chan
authors.forename: Kwong-kwok
authors.initials: KK
authors.lastname: Wong
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Birrer
authors.forename: Kyra M
authors.initials: KM
authors.lastname: Archibald
authors.forename: Frances R
authors.initials: FR
authors.lastname: Balkwill
authors.forename: Ross S
authors.initials: RS
authors.lastname: Berkowitz
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Mok
mesh_terms: D000951:Antigens, Neoplasm / Q000032:analysis; D018394:CA-125 Antigen / Q000032:analysis; D015815:Cell Adhesion Molecules / Q000032:analysis; D018929:Cell Culture Techniques / Q000379:methods; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D000071858:Epithelial Cell Adhesion Molecule; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D005260:Female; D005455:Fluorescent Antibody Technique; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D021621:Imaging, Three-Dimensional; D018836:Inflammation Mediators / Q000494:pharmacology; D046529:Microscopy, Electron, Transmission; D018396:Mucin-1 / Q000032:analysis; D009940:Organoids / Q000166:cytology*; D010048:Ovarian Cysts / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010053:Ovary / Q000166:cytology*; D019718:Receptors, CXCR4 / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D000951:Antigens, Neoplasm; D018394:CA-125 Antigen; C527276:CXCR4 protein, human; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D018836:Inflammation Mediators; C060192:MUC1 protein, human; D018396:Mucin-1; D019718:Receptors, CXCR4; D014409:Tumor Necrosis Factor-alpha