title: Transmigration of human ovarian adenocarcinoma cells through endothelial extracellular matrix involves alphav integrins and the participation of MMP2.
abstract: The growth of ovarian carcinoma is dependent upon their vascularistion, but the interaction of ovarian cancer cells with the endothelium and their invasion through an endothelial environment remain poorly understood at the molecular level. To investigate adhesive events underlying this process with focusing on the role of alphav integrins and MT1MMP-MMP2 proteinases, we used in vitro models of cocultures of human ovarian adenocarcinoma cell lines (IGROV1 and SKOV3) with human umbilical vein endothelial cells (HUVECs). Immunostaining of HUVECs revealed the network organisation of fibrillar fibronectin (Fn) and pericellular vitronectin (Vn). During coculture, IGROV1 and SKOV3 cells gain access to subendothelial basement membrane of HUVECs and dislocated endothelial Fn without affecting endothelial Vn. Transmigration assays revealed that tumour cells invade Vn and, with an higher efficiency, Fn. Our data also highlighted that ovarian carcinoma cells migrated through the Fn-rich HUVEC-ECM. The expression of MMP2 and MT1-MMP was revealed in tumour cells within an endothelial environment. Furthermore, we found that cell migration through the endothelial ECM was almost totally dependent on alphav integrin function, whereas beta1 integrins were not solicited. In addition, inhibitors of MMP2 activity (alone or combined with anti-alphav integrin MAb) or TSRI265 (which blocks MMP2-alphavbeta3 association) were found to impede this process. Finally, alphav integrins, MT1-MMP and MMP2 were found in ovarian carcinoma cells within the 3-dimensional architecture of intraperitoneal tumour nodes collected from nude mice xenografted with IGROV1 or SKOV3 cell lines or within human tumour tissues. alphav integrins therefore appear as essential to the migration properties of human ovarian carcinoma cells, especially in an endothelial environment, with MMP2 participating to this process.
authors.affiliation: ERRMECe, EA 1391, UFR Sciences et Techniques, Cergy-Pontoise, France.
authors.forename: Johanne
authors.initials: J
authors.lastname: Leroy-Dudal
authors.forename: Christine
authors.initials: C
authors.lastname: Demeilliers
authors.forename: Olivier
authors.initials: O
authors.lastname: Gallet
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Pauthe
authors.forename: Soizic
authors.initials: S
authors.lastname: Dutoit
authors.forename: Rémy
authors.initials: R
authors.lastname: Agniel
authors.forename: Pascal
authors.initials: P
authors.lastname: Gauduchon
authors.forename: Franck
authors.initials: F
authors.lastname: Carreiras
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement; D002478:Cells, Cultured; D018920:Coculture Techniques; D003094:Collagen / Q000737:chemistry; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D005353:Fibronectins / Q000737:chemistry / Q000378:metabolism; D005470:Fluorometry; D006801:Humans; D007150:Immunohistochemistry; D039564:Integrin alphaV / Q000378:metabolism*; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D007797:Laminin / Q000737:chemistry; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D011509:Proteoglycans / Q000737:chemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014471:Umbilical Veins / Q000166:cytology; D019096:Vitronectin / Q000737:chemistry / Q000378:metabolism
chemical_list: D004338:Drug Combinations; D005353:Fibronectins; D039564:Integrin alphaV; D039302:Integrin alphaVbeta3; D007797:Laminin; D061965:Matrix Metalloproteinase Inhibitors; D011509:Proteoglycans; D019096:Vitronectin; C059485:matrigel; D003094:Collagen; D020778:Matrix Metalloproteinase 2