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

Since autocrine regulation of HGF-Met is implicated in many forms of human cancer, we investigated whether the predisposition to develop ovarian cance r in women with hereditary ovarian cancer syndromes involves changes in the expression of HGF-Met by the tissue of origin of epithelial ovarian cancer s, 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 hi stories of ovarian cancer, SV40 Tag immortalized OSE lines (IOSE, n = 5) an d 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 tw o to three passages, Met was downregulated in 37% of NFH-OSE cultures but p ersisted in 100% of FH-OSE cultures and ovarian cancer lines, like other ep ithelial differentiation markers that are stabilized in FH-OSE and neoplasi a, 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 molecu les of the PI3K pathway, including Akt2 and p70 S6K, were constitutively ac tivated in FH-OSE from six of six women but in NFH-OSE from only four of ei ght women. Exogenous HGF was mitogenic in OSE, and that effect was regulate d through the MAP kinase (ERK1/ERK2) and FRAP/p70 S6K pathways. The prolife rative 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 stabilit y of Met expression and by HGF secretion. Constitutive phosphorylation of k inases and a diminished growth response to HGF suggest the presence of auto crine regulation in FH-OSE. In analogy with other cell types where an autoc rine HGF-R let 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.