Phenotypic Switch from Paracrine to Autocrine Role of Hepatocyte Growth Factor in an Androgen-Independent Human Prostatic Carcinoma Cell Line, CWR22R

Abstract

Support mechanisms involved in growth of androgen-independent prostate cancer are primarily unknown. Hepatocyte growth factor (HGF)/Met has been suggested to be one of them based primarily on immunohistochemical studies. We conducted a series of experiments to assess the role of the HGF/Met system in an androgen-dependent human prostate carcinoma, CWR22 and its androgen-independent derivative, CWR22R. We found that action of HGF changed from paracrine to autocrine in progression to androgen-independent state. CWR22 tumors did not express HGF but expressed Met, whereas prostate stromal cells expressed HGF at a high level. Growth of CWR22 was stimulated either by addition of HGF to the culture or by the presence of prostate stromal cells. On the other hand, CWR22R cells expressed both HGF and Met. Knockdown of Met expression by RNA interference method suppressed the growth of CWR22R cells. Our data suggest that HGF is intimately involved in growth of human prostate cancer and that progression from the androgen-dependent to the androgen-independent state is associated with an adaptive switch in support mechanism from paracrine to autocrine. Our data offer one mechanism to account for androgen-independent human cancer growth. Prostate cancer is the most common cancer and the second most common fatal cancer in men in the United States.

The Androgen Receptor Negatively Regulates the Expression of c-Met: Implications for a Novel Mechanism of Prostate Cancer Progression

“…Interestingly, we only observed a slight effect on c-Met expression by the AR shRNA in CWR22Rv1 cells. In addition, a higher level of cMet expression in CWR22Rv.1 cell line than its parental line CWR22 had been reported (42). In transient transfection experiments, we also observed that increasing expression of Sp1 proteins ectopically in prostate cancer cells can attenuate the repressive effect of AR on c-Met expression (data not shown).…”

BMS-777607, a Small-Molecule Met Kinase Inhibitor, Suppresses Hepatocyte Growth Factor–Stimulated Prostate Cancer Metastatic Phenotype In vitro

“…How such constitutive c-Met activation is acquired remains elusive. In some studies, the existence of a HGF/c-Met autocrine loop has been suggested (36,38), but others indicate that PC-3 cells do not express HGF (16,39). Clearly, elucidating the mechanism of c-Met activation in the absence of exogenous ligand in the PC-3 model would provide important information about the potential therapeutic application of Met inhibitors in cancer patients whose tumors possess cells with constitutively activated c-Met.…”

Antibodies Neutralizing Hepsin Protease Activity Do Not Impact Cell Growth but Inhibit Invasion of Prostate and Ovarian Tumor Cells in Culture

“…In this respect, the recent studies demonstrating that active hepsin can catalyze the conversion of pro-HGF to the c-met binding ligand, HGF (27,28), as confirmed here using the modified activated hepsin protein, point to a possible role for hepsin in the activation of tumorpromoting factors. There is considerable evidence that c-met and HGF are involved in metastatic prostate cancer (30), and development of an autocrine loop for HGF/c-met has been proposed as one of the mechanisms leading to androgenindependent tumors (31). The coexpression of hepsin with HGF and c-met in metastatic cancers may be key in the activation of the HGF/c-met pathway in late stage prostate tumors.…”