Metron factor-1 prevents liver injury without promoting tumor growth and metastasis

Abstract

Hepatocyte growth factor (HGF) is the most powerful hepatotrophic factor identified so far. However, the ability of HGF to promote tumor cell "scattering" and invasion raises some concern about its therapeutic safety. We compared the therapeutic efficacy of HGF with that of Metron Factor-1 (MF-1), an engineered cytokine derived from HGF and the HGF-like factor macrophage stimulating protein (MSP), in mouse models of acute and chronic liver injury. At the same time, we tested the ability of HGF and MF-1 to promote tumor growth, angiogenesis, and invasion in several mouse models of cancer. We show that (1) MF-1 and HGF stimulate hepatocyte proliferation in vitro; (2) MF-1 and HGF protect primary hepatocytes against Fas-induced and drug-induced apoptosis; (3) HGF but not MF-1 induces scattering and matrigel invasion of carcinoma cell lines in vitro; (4) HGF but not MF-1 promotes migration and extracellular matrix invasion of endothelial cells in vitro; (5) MF-1 and HGF prevent CCl(4)-induced acute liver injury as measured by alanine aminotransferase (ALT) levels, histology, terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) analysis, and phospho-histone-3 immunostaining; (6) MF-1 and HGF attenuate liver fibrosis caused by chronic CCl(4) intoxication and promote regeneration as measured by Sirius red staining, alpha-smooth muscle actin immunostaining, and Ki-67 analysis; (7) HGF but not MF-1 promotes tumor growth, angiogenesis, and metastasis in a variety of xenograft models; (8) HGF but not MF-1 promotes intrahepatic dissemination of hepatocarcinoma cells injected orthotopically. These data suggest that MF-1 is as effective as HGF at preventing liver injury and at promoting hepatocyte regeneration, but therapeutically safer than HGF because it lacks proangiogenic and prometastatic activity.