Hepatocyte Growth Factor Induces Rat Ovarian Surface Epithelial Cell Mitosis or Apoptosis Depending on the Presence or Absence of an Extracellular Matrix

Abstract

The present studies showed that sequential treatment with equine CG (eCG) and hCG not only induced an increase in ovarian weight, but also caused an estimated 4.6-fold increase in the number of ovarian surface epithelial cells. In addition, eCG-hCG treatment increased ovarian hepatocyte growth factor (HGF) messenger RNA levels. These studies also demonstrated that rat primary ovarian surface epithelial cells as well as a cell line derived from rat ovarian surface epithelium (i.e. ROSE-179 cells) do not express the LH (hCG) receptor. Both of these cells express c-Met, the receptor for HGF. To assess the effects of hCG and HGF on ovarian surface epithelial cell mitosis, ROSE-179 cells were cultured for 24 h in serum-supplemented medium on either glass or the synthetic fibronectin-like extracellular matrix protein, pronectin (RGD). The cells were then cultured for 24 h in serum-free medium in the presence or absence of hCG or HGF. The numbers of cells at 2, 24, and 48 h of culture were determined. The percentage of apoptotic cells was assessed by in situ DNA staining at 48 h of culture. In the serum-supplemented medium in the presence or absence of RGD, the number of ROSE-179 cells doubled. In serum-free medium, cell proliferation was reduced, and the percentage of apoptotic nuclei ranged between 10-15% regardless of the substrate. Neither mitosis nor apoptosis was influenced by hCG in the presence or absence of RGD. For ROSE-179 cells cultured in serum-free medium on RGD, HGF induced mitosis, resulting in a 2.8 +/- 0.2-fold increase in cell number compared with the 24 h control values. On a glass substrate in serum-free medium, HGF did not induce mitosis, but increased the percentage of apoptotic nuclei. Time-lapse photographic analysis revealed that on RGD, cells undergoing HGF-induced mitosis showed a transient reduction in cell contact. On glass, HGF caused many cells to completely lose contact and separate from each other. Collectively, these data suggest that in vivo gonadotropins stimulate HGF expression and ovarian surface epithelial cell proliferation. Based on in vitro studies, it is likely that the mitogenic action of hCG is mediated by HGF. However, HGF only induces mitosis in the presence of an extracellular matrix.

Cyclic changes of the ovarian surface epithelium in the rat

“…In this context, it can be expected that isolated OSE cells are unresponsive to reproductive hormones, just as the in vivo OSE in areas covering regressing corpora lutea or ovarian stroma. Several growth factors such as hepatocyte growth factor (HGF) (Hess et al 1999), and stem cell factor (SCF) (Parrot et al 2000), have been reported to regulate OSE cell proliferation in vitro. The expression of receptors for these growth factors in the OSE (Hess et al 1999, Parrot et al 2000, suggests that autocrine and paracrine routes are likely to be involved.…”

“…As the ovary is under the control of gonadotropins and steroids, these hormones are strong candidates to regulate the OSE. The potential for gonadotropins and steroids to regulate OSE cell proliferation is suggested by the demonstration of receptors for these hormones in the OSE of several species (HildPetito et al 1988, Zheng et al 1996, Pelletier et al 2000, Kuroda et al 2001, Okada et al 2002, although interspecies variations have been reported (Hess et al 1999, Pelletier et al 2000. In general, in vivo studies have reported that gonadotropins (Davies et al 1999, Hess et al 1999, Stewart et al 2004) and estrogens (Adams andAuersperg 1983, Bai et al 2000) stimulate OSE cell proliferation.…”

Hepatocyte Growth Factor Sensitizes Human Ovarian Carcinoma Cell Lines to Paclitaxel and Cisplatin

“…Nonetheless, HGF had been shown to induce apoptosis in a sarcoma cell line and in liver carcinoma models (21)(22)(23)(24). Furthermore, HGF induces death of ovarian surface epithelial cells when extracellular matrix or intercellular contacts are lacking (29,30). However, in all of these cases, HGF had a cytotoxic effect per se.…”

Phosphatidylinositol 3-kinase-dependent, MEK- independent proliferation in response to CaR activation

“…Because OSE cells are the cell type responsible for ovarian tumors, an understanding of the proliferative pathways used by these cells is of obvious importance. Although OSE cells show a proliferative response to a variety of stimuli, including follicle-stimulating hormone (2), hepatocyte growth factor (13), and elevated calcium (14,18), the relative importance of distinct signal transduction pathways in mediating the proliferation of OSE cells is not known.…”