Regulation of Invasion of Epithelial Ovarian Cancer by Transforming Growth Factor-β

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