Abstract
The processes of ovarian cancer dissemination are characterized by altered local proteolysis, cellular proliferation, cell attachment, and invasion, suggesting that the urokinase-type plasminogen activator (uPA) and its specific inhibitor (plasminogen activator inhibitor type-1 (PAI-1)) could be involved in the pathogenesis of peritoneal dissemination. We showed previously that expression of uPA and PAI-1 in the human ovarian cancer cell line HRA can be down-regulated by exogenous bikunin (bik), a Kunitz-type protease inhibitor, via suppression of transforming growth factor-beta1 (TGF-beta1) up-regulation and that overexpression of the bik gene can specifically suppress the in vivo growth and peritoneal dissemination of HRA cells in an animal model. We hypothesize that the plasminogen activator system in mesothelial cells can be modulated by HRA cells. To test this hypothesis, we used complementary techniques in mesothelial cells to determine whether uPA and PAI-1 expression are altered by exposure to culture media conditioned by HRA cells. Here we show the following: 1) that expression of PAI-1, but not uPA, was markedly induced by culture media conditioned by wild-type HRA cells but not by bik transfected clones; 2) that by antibody neutralization the effect appeared to be mediated by HRA cell-derived TGF-beta1; 3) that exogenous TGF-beta1 specifically enhanced PAI-1 up-regulation at the mRNA and protein level in mesothelial cells in a time- and concentration-dependent manner, mainly through MAPK-dependent activation mechanism; and 4) that mesothelial cell-derived PAI-1 may promote tumor invasion possibly by enhancing cell-cell interaction. This represents a novel pathway by which tumor cells can regulate the plasminogen activator system-dependent cellular responses in mesothelial cells that may contribute to formation of peritoneal dissemination of ovarian cancer.
Highlights
Bikunin,1 a Kunitz-type protease inhibitor, known as urinary trypsin inhibitor, is proposed as a main participant
We showed previously that expression of urokinase-type plasminogen activator (uPA) and PAI-1 in the human ovarian cancer cell line HRA can be down-regulated by exogenous bikunin, a Kunitz-type protease inhibitor, via suppression of transforming growth factor-1 (TGF-1) up-regulation and that overexpression of the bik gene can suppress the in vivo growth and peritoneal dissemination of HRA cells in an animal model
We investigated the mechanism(s) by which TGF-1, which is produced by ovarian cancer cells, mediates the adhesion and invasive behavior of tumor cells through an overproduction of PAI-1 from peritoneal mesothelial cells
Summary
Bikunin (bik), a Kunitz-type protease inhibitor, known as urinary trypsin inhibitor, is proposed as a main participant. TGF- stimulates PAI-1 secretion in various cell lines and in vivo [13,14,15] In considering these data, we asked whether the PA system expressed by mesothelial cells could be involved in the pathogenesis of peritoneal dissemination by ovarian cancer. In this study we determined whether culture media conditioned by human ovarian cancer cell line HRA induced uPA and PAI-1 expression in cultured human peritoneal mesothelial cells and dermal fibroblast cells as a control, either by incubation with culture medium conditioned by the bikϩ clones or the controls (wild-type HRA cells and the luciferase transfected (lucϩ) clones). Our results demonstrate that culture medium conditioned by wild-type cells, rather than bikϩ clones, increases PAI-1 expression of cultured mesothelial cells at least via a TGF-1-mediated MAPK pathway and that TGF-1 enhances tumor cell adhesion and subsequent invasion via overexpression of PAI-1. These findings suggest that altered expression of PAI-1 by the mesothelium could influence the processes of peritoneal dissemination in ovarian cancer cells
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