Regulation of invasion of epithelial ovarian cancer by transforming growthfactor-beta

Objective. The metastatic process in epithelial ovarian cancer is thought t o involve surface shedding and subsequent dissemination of ovarian cancer c ells, facilitated by localized proteolysis at the interface between ovarian cancer cells and peritoneal surfaces. The factors regulating the metastati c process, however, are not well understood. Transforming growth factor-bet a (TGF-beta) is a multifunctional peptide that elicits numerous cellular ef fects pertinent to the metastatic process. The purpose of this study was to evaluate the regulatory role of TGF-beta on metastasis in ovarian cancer. Methods. We evaluated the effect of TGF-beta on the metastatic characterist ics (adhesion, invasion, motility, proteolysis) of five ovarian cancer cell lines (DOV-13 and OVCA 420, 429, 432, and 433), two short-term primary ova rian cancer cell cultures (OVCA 10 and OVCA 208), and five normal ovarian s urface epithelial (NOSE) cell cultures (OSE 133, 185, 186, 188, and 189). T he effect of TGF-beta on invasion and proteolysis was quantified using a mo dified Boyden chamber invasion assay, zymography, a coupled colorimetric ac tivity assay, and an HPLC-based quantitation of synthetic substrate cleavag e. Results. TGF-beta significantly increased invasion in five of seven ovarian cancer cell lines in amounts ranging from 2- to 20-fold. In contrast, TGF- beta significantly decreased invasion in two of five NOSE isolates by 50 to 80% and had no significant effect on invasion in three, TGF-beta treatment increased matrix metalloproteinase (MMP) expression in OVCA 420 and 433 an d DOV-13, resulting in MMP-dependent collagen cleavage and invasive activit y. Addition of the MMP inhibitor GI12947 neutralized the enhancing effect o f TGF-beta on invasion. TGF-beta had no effect on ovarian cancer cell motil ity and only increased adhesion in DOV-13. Conclusions. These data suggest that TGF-beta may enhance the invasiveness of ovarian cancers through induction of MMP activity. (C) 2001 Academic Pre ss.