Lysophosphatidic acid promotes matrix metalloproteinase (MMP) activation and MMP-dependent invasion in ovarian cancer cells

Ovarian cancer is an highly metastatic disease characterized by ascites for mation and diffuse i.p. adhesion, invasion, and metastasis. Levels of lysop hosphatidic acid (LPA) are elevated in the plasma of patients with ovarian carcinoma, including 90% of patients with stage I disease, suggesting that LPA mag promote early events in ovarian carcinoma dissemination. Expression of matrix metalloproteinases (MMPs) is also upregulated in ovarian cancer tissues and ascites, and numerous studies have provided evidence for a dire ct role of MMPs in i.p. invasion and metastasis. Using three-dimensional ty pe I collagen cultures or immobilized beta (1) integrin subunit-specific an tibodies, we previously demonstrated that beta (1) integrin clustering prom otes activation of proMMP-2 and processing of membrane type 1 MMP in ovaria n cancer cells (S, M. Ellerbroek et al., Cancer Res., 59: 1635-1641, 1999). In the current study, the effect of LPA on MMP expression and invasive act ivity was investigated. Treatment of ovarian cancer cells with pathophysiol ogical levels of LPA increased cellular adhesion to type I collagen and bet a (1) integrin expression. A significant up-regulation of MMP-dependent pro MMP-2 activation was observed in LPA-treated cells, leading to enhanced per icellular MMP activity. As a result of increased MMP activity, haptotactic and chemotactic motility, in vitro wound closure, and invasion of a synthet ic basement membrane were enhanced. These data indicate that LPA contribute s to metastatic dissemination of ovarian cancer cells via up-regulation of MMP activity and subsequent downstream changes in MMP-dependent migratory a nd invasive behavior.