Nondegradable Collagen Increases Liver Fibrosis but Not Hepatocellular Carcinoma in Mice

Jacopo Baglieri, Cuili Zhang, Shuang Liang, Xiao Liu, Takahiro Nishio, Sara B. Rosenthal, Debanjan Dhar, Hua Su, Min Cong, Jidong Jia, Mojgan Hosseini, Michael Karin, Tatiana Kisseleva, David A. Brenner

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


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 Colr/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 Colr/r mice or Hepa 1-6 cells were engrafted into WT and Colr/r livers. The effect of hepatic stellate cells (HSCs) from WT and Colr/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 Colr/r mice, but they developed fewer and smaller tumors. Hepa 1-6 cells had reduced tumor growth in the livers of Colr/r mice. Although Colr/r HSCs exhibited a more activated phenotype, Hepa 1-6 growth and malignancy were suppressed in multicellular tumor spheroids and in xenografts containing Colr/r HSCs. Treatment with vitronectin, which mimics the presence of degraded collagen fragments, converted the Colr/r phenotype into a WT phenotype. Although Colr/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.

Original languageEnglish (US)
Pages (from-to)1564-1579
Number of pages16
JournalAmerican Journal of Pathology
Issue number9
StatePublished - Sep 2021
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine


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