Autocrine regulation of growth stimulation in epithelial ovarian carcinoma by urinary-type plasminogen activator
Ovarian epithelial carcinoma is characterized by widespread intraabdominal metastases due to exfoliation of cells from the ovarian surface, peritoneal implantation and proliferation. We have previously demonstrated that ovarian carcinomas (OV CA) overexpress urinarytype plasminogen activator (uPA), leading to an enhanced proteolytic capacity which may facilitate invasion. Furthermore, the uPA receptor (uPAR) is also present on OV CA cells and immunohistochemical analyses of frozen sections of primary tumors demonstrated occupancy of the receptor by uPA in tumor tissues. To determine whether OV CA growth is altered by uPA, the effect of uPA or the amino terminal fragment (ATF, aa 1-135) on OV CA proliferation was analyzed. A 15-35% increase in proliferation was observed in treated OV CA cells relative to controls. In addition, incubation of single-chain uPA (scuPA) with conditioned medium from OV CA cells resulted in cleavage of a 14 kDa fragment from scuPA. Amino terminal sequence analysis identified this fragment as ATF, comprising the uPA growth factor and kringle domains.Time course experiments demonstrated cleavage of scuPA within 15 min of incubation with OV CA conditioned medium. ATF generation was abolished by serine proteinase inhibitors, but not inhibitors of metalloprotemases and was not enhanced by the addition of plasminogen or plasmin. Together these data indicate that uPA, in addition to enhancing the invasive activity of OV CA cells (via increased pericellular proteolysis), also acts as a mitogen for OV CA cells: suggesting a biochemical mechanism by which uPA may contribute to both OV CA invasion and proliferation.
Larsh, S; Kearns, A; Enghild, J; Fishman, D; Bafetti, L; Stack, S
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