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


CONCLUSIONS
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.
Third Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan.
Terumi
T
Takahara
Feng
F
Xue
Massimiliano
M
Mazzone
Yutaka
Y
Yata
Kazunobu
K
Nonome
Masami
M
Kanayama
Kengo
K
Kawai
Alberto M
AM
Pisacane
Shiro
S
Takahara
Xiao-Kang
XK
Li
Paolo M
PM
Comoglio
Toshiro
T
Sugiyama
Paolo
P
Michieli
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002251:Carbon Tetrachloride / Q000009:adverse effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury; D016207:Cytokines / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D017228:Hepatocyte Growth Factor / Q000494:pharmacology / Q000627:therapeutic use; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D008107:Liver Diseases / Q000473:pathology / Q000517:prevention & control*; D008113:Liver Neoplasms / Q000473:pathology / Q000517:prevention & control*; D008115:Liver Regeneration / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis / Q000473:pathology / Q000517:prevention & control*; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000517:prevention & control; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use
D016207:Cytokines; D011993:Recombinant Fusion Proteins; C529731:metron factor-1; D017228:Hepatocyte Growth Factor; D002251:Carbon Tetrachloride