Coexpression of hepatocyte growth factor-Met: An early step in ovarian carcinogenesis?

Abstract

Since autocrine regulation of HGF-Met is implicated in many forms of human cancer, we investigated whether the predisposition to develop ovarian cancer in women with hereditary ovarian cancer syndromes involves changes in the expression of HGF-Met by the tissue of origin of epithelial ovarian cancers, the ovarian surface epithelium (OSE). We compared cultures of normal OSE from women with (FH-OSE) (n = 20) and with no (NFH-OSE) (n=48) family histories of ovarian cancer, SV40 Tag immortalized OSE lines (IOSE, n=5) and ovarian cancer cell lines (n=3). Cultures derived from 21/22 women with NFH-OSE and 13/13 women with FH-OSE expressed Met mRNA initially. After two to three passages, Met was downregulated in 37% of NFH-OSE cultures but persisted in 100% of FH-OSE cultures and ovarian cancer lines, like other epithelial differentiation markers that are stabilized in FH-OSE and neoplasia. HGF and Met mRNA were concomitantly expressed by NFH-OSE from only three of 32 women but in FH-OSE from eight of 13 women, and also in five of five IOSE and two of three ovarian cancer lines. Conditioned media from FH-OSE, but not NFH-OSE, contained immunoreactive HGF and induced cohort migration which was inhibited by neutralizing HGF antibody. Several signaling molecules of the PI3K pathway, including Akt2 and p70 S6K, were constitutively activated in FH-OSE from six of six women but in NFH-OSE from only four of eight women. Exogenous HGF was mitogenic in OSE, and that effect was regulated through the MAP kinase (ERK1/ERK2) and FRAP/p70 S6K pathways. The proliferative response to HGF was greater in NFH-OSE than in FH-OSE cultures. The results show that FH-OSE cultures differ from NFH-OSE by increased stability of Met expression and by HGF secretion. Constitutive phosphorylation of kinases and a diminished growth response to HGF suggest the presence of autocrine regulation in FH-OSE. In analogy with other cell types where an autocrine HGF-Met loop has been implicated in tumorigenic transformation, this change in FH-OSE may play a role in the enhanced susceptibility to ovarian carcinogenesis in women with hereditary ovarian cancer syndromes.