Activation of cultured rat hepatic stellate cells by tumoral hepatocytes

Hepatocellular carcinoma (HCC) is the main type or primary liver cancer, an d it develops from hepatocytes. The stroma of HCC is infiltrated by myofibr oblasts. In other settings, such as liver fibrosis, myofibroblasts are deri ved mainly from the activation of hepatic stellate cells (HSC). In this stu dy, we investigated whether tumoral hepatocytes were able to activate HSC. HSC were isolated from normal rats and were plated in dishes coated with Ma trigel, to prevent their spontaneous activation. HSC were exposed to condit ioned medium (CM) from the rat HCC lines Fao and H5. Tumor cell CM elicited major morphologic changes, such as spreading and generation of cytoplasmic processes. Fao and H5 CM increased HSC proliferation to 1.60 and 1.76 time s control values, respectively. The expression of alpha-smooth muscle actin was low or undetectable in control cells and was markedly increased by bot h tumor cell CM but not by normal rat hepatocyte CM. Desmin expression was also enhanced. Gelatinase A secretion was significantly increased 1.20-fold by Fao CM and 1.55-fold by H5 CM. Expression of beta-type platelet-derived growth factor receptor mRNA was increased 5.8-fold by H5 GM but was decrea sed to 13% of control levels by Fao CM. HSC activation by tumor cell CM was not prevented by urokinase or matrix metalloproteinase inhibitors, suggest ing that Matrigel degradation was not central to the activation process. Fi nally, a blocking antibody to transforming growth factor-beta 1 did not imp ede Fao CM-induced activation but significantly blocked the increase in mat rix metalloproteinase-2 expression induced by H5 CM. Our results show that tumoral rat hepatocyte CM is able to induce the activation of rat HSC in cu lture. The lack of induction of beta-type platelet-derived growth factor re ceptor mRNA by Fao CM indicates that, in some cases, tumor-induced activati on differs from classic fibrosis-type activation. Our data thus suggest tha t HSC recruitment and activation in HCC could be under the control of tumor cells.