Nondegradable Collagen Increases Liver Fibrosis but Not Hepatocellular Carcinoma in Mice

Although hepatocellular cancer (HCC) usually occurs in the setting of liver fibrosis, the causal relationship between liver fibrosis and HCC is unclear. in vivo and in vitro models of HCC involving Col(r/r) mice (that produce a collagenase-resistant type I collagen) or wild-type (WT) mice were used to assess the relationship between type I collagen, liver fibrosis, and experimental HCC. HCC was either chemically induced in WT and Col(r/r) mice or Hepa 1-6 cells were engrafted into WT and Col(r/r) livers. The effect of hepatic stellate cells (HSCs) from WT and Col(r/r) mice on the growth of Hepa 1-6 cells was studied by using multicellular tumor spheroids and xenografts. Collagen type I deposition and fibrosis were increased in Col(r/r) mice, but they developed fewer and smaller tumors. Hepa 1-6 cells had reduced tumor growth in the livers of Col(r/r) mice. Although Col(r/r) HSCs exhibited a more activated phenotype, Hepa 1-6 growth and malignancy were suppressed in multicellular tumor spheroids and in xenografts containing Col(r/r) HSCs. Treatment with vitronectin, which mimics the presence of degraded collagen fragments, converted the Col(r/r) phenotype into a WT phenotype. Although Col(r/r) mice have increased liver fibrosis, they exhibited decreased HCC in several models. Thus, increased liver type I collagen does not produce increased experimental HCC.