THE ROLE OF HEPATIC MICROENVIRONMENT IN GROWTH AND METASTASIS OF HEPATITIS C VIRUS - INDUCED HEPATOCELLULAR CARCINOMA

Hepatitis viruses are the most commonly implicated risk factors of Hepatocellular Carcinoma (HCC). Hepatitis C virus (HCV)-induce HCC may reflect direct distinct molecular mechanisms, including alteration of normal cellular signaling pathways to stimulate cell growth and transformation. In addition, activated hepatic stellate cells (aHSC) exhibit biological functions that influence the progression of HCC and produce factors that directly participate in the formation of a pro-metastatic microenvironment. We aimed to use the aHSC to improve an animal model of patient derived xenograft (PDX) for HCC and investigate the effects of aHSC on HCV-induced tumor progression.

For testing the effects of the crosstalk between hepatocytes and aHSC on tumor growth and metastasis in vivo, human biopsies of HCC and hepatoma cell lines were mixed with aHSC and injected and transplanted intrahepatically into mice. By monitoring tumor growth and metastasis by PEARL in-vivo imaging system, we show that in the presence of aHSC tumor growth is more effective than without aHSC. To investigate the effects of aHSC in invasion and migration in vitro, hepatoma cell line, both infected and non-infected with HCV, were incubated with conditioned medium of aHSC and evaluated for formation of invadopodia, a key feature of invasive cancer. We demonstrate that hepatoma cell lines infected with HCV and growing in conditioned medium of aHSC show a higher rate of invadopodia formation.

These results suggest that the hepatic microenvironment, specifically aHSC, have an active role in tumor growth and invasion, induce the hepatocytes to become more invasive and metastatic and promote tumor aggressiveness in HCV induce HCC. Thus, targeting aHSC may turn an effective strategy to combat HCC growth and metastasis.