title: Peritoneal adhesion and angiogenesis in ovarian carcinoma are inversely regulated by hyaluronan: the role of gonadotropins.
abstract: Ovarian carcinoma is the leading cause of death among gynecologic cancers. Although transformation of the outer ovarian epithelium was linked with ovulation, the disease is significantly more prevalent and severe in postmenopausal women. We postulated that menopause could augment ovarian cancer progression through the effects of gonadotropins on multifocal seeding to the mesothelial layer lining the peritoneum. This seeding is mediated by integrins as well as by CD44 interaction with hyaluronan (HA). Here, we report the effect of gonadotropins on HA synthesis and degradation and on peritoneal adhesion. A significant concentration- and time-dependent induction in expression levels of HA synthases (HASs) and hyaluronidases (Hyals) was observed in vitro on stimulation of human epithelial ovarian carcinoma cells by gonadotropins. Hormonal regulation of HA-mediated adhesion was manifested in vivo as well, by fluorescence microscopy of stained MLS multicellular tumor spheroids. The number of spheroids adhered to the mesothelium of ovariectomized CD-1 nude mice 9.5 hours after intraperitoneal insertion was significantly higher than in nonovariectomized mice. Inhibition of HA synthesis by 6-diazo-5-oxo-1-norleucine (DON) both in spheroids and ovariectomized mice significantly reduced the number of adhered spheroids. Thus, the change in the hormonal environment during menopause assists in HA-dependent adherence of ovarian cancer spheroids onto the peritoneum. However, HA is antiangiogenic and it can significantly suppress tumor progression. Accordingly, angiogenesis of the adhered spheroids was significantly elevated in DON-treated tumors. These results can explain the selective pressure that can lead to simultaneously increased tumor expression of both HASs and Hyals.
authors.affiliation: Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Yael Chagit
authors.initials: YC
authors.lastname: Tzuman
authors.forename: Stav
authors.initials: S
authors.lastname: Sapoznik
authors.forename: Dorit
authors.initials: D
authors.lastname: Granot
authors.forename: Nava
authors.initials: N
authors.lastname: Nevo
authors.forename: Michal
authors.initials: M
authors.lastname: Neeman
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D003980:Diazooxonorleucine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D006062:Gonadotropins / Q000494:pharmacology; D006801:Humans; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000378:metabolism*; D006821:Hyaluronoglucosaminidase / Q000235:genetics / Q000378:metabolism; D017403:In Situ Hybridization; D007986:Luteinizing Hormone / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D010052:Ovariectomy; D010537:Peritoneum / Q000378:metabolism / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000964:Antimetabolites, Antineoplastic; D006062:Gonadotropins; D003980:Diazooxonorleucine; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; D000076002:Hyaluronan Synthases; D006821:Hyaluronoglucosaminidase