title: Sequential molecular and cellular events during neoplastic progression: a mouse syngeneic ovarian cancer model.
abstract: Studies performed to identify early events of ovarian cancer and to establish molecular markers to support of early detection and the development of chemopreventive regimens have been hindered by a lack of adequate cell models. Taking advantage of the spontaneous transformation of mouse ovarian surface epithelial (MOSE) cells in culture, we isolated and characterized distinct transitional stages of ovarian cancer as the cells progressed from a premalignant nontumorigenic phenotype to a highly aggressive malignant phenotype. Transitional stages were concurrent with progressive increases in proliferation, anchorage-independent growth capacity, in vivo tumor formation, and aneuploidy. During neoplastic progression, our ovarian cancer model underwent distinct remodeling of the actin cytoskeleton and focal adhesion complexes, concomitant with downregulation and/or aberrant subcellular localization of two tumor-suppressor proteins E-cadherin and connexin-43. In addition, we demonstrate that epigenetic silencing of E-cadherin through promoter methylation is associated with neoplastic progression of our ovarian cancer model. These results establish critical interactions between cellular cytoskeletal remodeling and epigenetic silencing events in the progression of ovarian cancer. Thus, our MOSE model provides an excellent tool to identify both cellular and molecular changes in the early and late stages of ovarian cancer, to evaluate their regulation, and to determine their significance in an immunocompetent in vivo environment.
authors.affiliation: Department of Immunology/Microbiology, School of Medicine, Wayne State University, Detroit, MI 48201, USA. proberts@med.wayne.edu
authors.forename: Paul C
authors.initials: PC
authors.lastname: Roberts
authors.forename: Emilio P
authors.initials: EP
authors.lastname: Mottillo
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Baxa
authors.forename: Henry H Q
authors.initials: HH
authors.lastname: Heng
authors.forename: Nicole
authors.initials: N
authors.lastname: Doyon-Reale
authors.forename: Lucie
authors.initials: L
authors.lastname: Gregoire
authors.forename: Wayne D
authors.initials: WD
authors.lastname: Lancaster
authors.forename: Raja
authors.initials: R
authors.lastname: Rabah
authors.forename: Eva M
authors.initials: EM
authors.lastname: Schmelz
mesh_terms: D000199:Actins / Q000737:chemistry; D000818:Animals; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D003094:Collagen / Q000737:chemistry; D018031:Connexin 43 / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D019175:DNA Methylation; D004195:Disease Models, Animal; D018450:Disease Progression; D015536:Down-Regulation; D004338:Drug Combinations; D044127:Epigenesis, Genetic; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D020868:Gene Silencing; D007797:Laminin / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D008938:Mitosis; D009369:Neoplasms / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D011509:Proteoglycans / Q000737:chemistry; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013696:Temperature
chemical_list: D000199:Actins; D015820:Cadherins; D018031:Connexin 43; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D012333:RNA, Messenger; C059485:matrigel; D003094:Collagen