PROTEINASE REQUIREMENTS OF EPIDERMAL GROWTH FACTOR-INDUCED OVARIAN-CANCER CELL INVASION

Aberrant expression or activity of the epidermal growth factor (EGF) r eceptor family of tyrosine kinases has been associated with tumor prog ression and an invasive phenotype. In this study, we utilized 4 ovaria n cancer cell lines, OVCA 432, DOV 13, OVEA6 and OVCA 429, to determin e the effects of EGF on the regulation of proteolytic enzymes and thei r inhibitors, cellular migration and in vitro invasion. Induction of u rinary-type plasminogen activator (u-PA) activity and tissue inhibitor of matrix metalloproteinase (TIMP)-1 was observed in all 4 cell lines . OVCA 432 cells showed strong PAI-1 induction; however, the other 3 l ines displayed substantial baseline PAI-1 expression that was not indu ced by EGF. EGF-dependent stimulation of migration and induction of ma trix metalloproteinase (MMP)-9 (gelatinase B) was observed in OVEA6 an d OVCA 429 cells only. Upon EGF receptor activation, DOV 13, OVEA6 and OVCA 429 cells were induced to invade through an artificial basement membrane (Matrigel); however, no invasion was detected in OVCA 432 cel ls. Cell lines displaying induction of migration and MMP-9 (OVEA6 and OVCA 429) demonstrated robust EGF-induced invasion (5- to 20-fold), an d cell invasion was substantially reduced in the presence of anti-cata lytic MMP-9 antibody. Addition of anti-catalytic u-PA antibody inhibit ed the modest (<2-fold) EGF-induced invasion in a cell line that did n ot express MMP-9 (DOV 13) and in OVEA6 cells that displayed the highes t baseline u-PA activity. Together, our findings indicate that multipl e proteinases are important in ovarian cell invasion and implicate EGF induction of MMP-9 and migration as key components of more aggressive ligand-induced invasion. Int. J. Cancer 78:331-337, 1998, (C) 1998 Wi ley-Liss, Inc.