Inflammation-induced hepatocellular carcinoma is dependent on CCR5 in mice

Hepatology. 2013 Sep;58(3):1021-30. doi: 10.1002/hep.26403. Epub 2013 Jul 12.

Abstract

Human hepatocellular carcinoma (HCC) is an inflammation-induced cancer, which is the third-leading cause of cancer mortality worldwide. We investigated the role of the chemokine receptors, CCR5 and CCR1, in regulating inflammation and tumorigenesis in an inflammation-induced HCC model in mice. Multidrug resistance 2 gene (Mdr2)-knockout (Mdr2-KO) mice spontaneously develop chronic cholestatic hepatitis and fibrosis that is eventually followed by HCC. We generated two new strains from the Mdr2-KO mouse, the Mdr2:CCR5 and the Mdr2:CCR1 double knockouts (DKOs), and set out to compare inflammation and tumorigenesis among these strains. We found that in Mdr2-KO mice lacking the chemokine receptor, CCR5 (Mdr2:CCR5 DKO mice), but not CCR1 (Mdr2:CCR1 DKO), macrophage recruitment and trafficking to the liver was significantly reduced. Furthermore, in the absence of CCR5, reduced inflammation was also associated with reduced periductal accumulation of CD24(+) oval cells and abrogation of fibrosis. DKO mice for Mdr2 and CCR5 exhibited a significant decrease in tumor incidence and size.

Conclusions: Our results indicate that CCR5 has a critical role in both the development and progression of liver cancer. Therefore, we propose that a CCR5 antagonist can serve for HCC cancer prevention and treatment.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / deficiency
  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • ATP Binding Cassette Transporter, Subfamily B / physiology
  • Animals
  • Carcinoma, Hepatocellular / epidemiology
  • Carcinoma, Hepatocellular / etiology*
  • Carcinoma, Hepatocellular / physiopathology*
  • Chemokine CCL5 / physiology
  • Disease Models, Animal
  • Disease Progression
  • Hepatitis, Chronic / complications*
  • Hepatitis, Chronic / genetics
  • Incidence
  • Liver / pathology
  • Liver / physiopathology
  • Liver Cirrhosis / complications*
  • Liver Cirrhosis / genetics
  • Liver Neoplasms / epidemiology
  • Liver Neoplasms / etiology*
  • Liver Neoplasms / physiopathology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, CCR1 / deficiency
  • Receptors, CCR1 / genetics
  • Receptors, CCR1 / physiology
  • Receptors, CCR5 / deficiency
  • Receptors, CCR5 / genetics
  • Receptors, CCR5 / physiology*

Substances

  • ATP Binding Cassette Transporter, Subfamily B
  • Ccr1 protein, mouse
  • Chemokine CCL5
  • P-glycoprotein 2
  • Receptors, CCR1
  • Receptors, CCR5