title: Inflammation-induced hepatocellular carcinoma is dependent on CCR5 in mice.
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.
authors.affiliation: Goldyne Savad Institute of Gene Therapy, Human Biology Research Center, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Neta
authors.initials: N
authors.lastname: Barashi
authors.forename: Ido D
authors.initials: ID
authors.lastname: Weiss
authors.forename: Ori
authors.initials: O
authors.lastname: Wald
authors.forename: Hanna
authors.initials: H
authors.lastname: Wald
authors.forename: Katia
authors.initials: K
authors.lastname: Beider
authors.forename: Michal
authors.initials: M
authors.lastname: Abraham
authors.forename: Shiri
authors.initials: S
authors.lastname: Klein
authors.forename: Daniel
authors.initials: D
authors.lastname: Goldenberg
authors.forename: Jonathan
authors.initials: J
authors.lastname: Axelrod
authors.forename: Eli
authors.initials: E
authors.lastname: Pikarsky
authors.forename: Rinat
authors.initials: R
authors.lastname: Abramovitch
authors.forename: Evelyne
authors.initials: E
authors.lastname: Zeira
authors.forename: Eithan
authors.initials: E
authors.lastname: Galun
authors.forename: Amnon
authors.initials: A
authors.lastname: Peled
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000453:epidemiology / Q000209:etiology* / Q000503:physiopathology*; D018946:Chemokine CCL5 / Q000502:physiology; D004195:Disease Models, Animal; D018450:Disease Progression; D006521:Hepatitis, Chronic / Q000150:complications* / Q000235:genetics; D015994:Incidence; D008099:Liver / Q000473:pathology / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000150:complications* / Q000235:genetics; D008113:Liver Neoplasms / Q000453:epidemiology / Q000209:etiology* / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054389:Receptors, CCR1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D019713:Receptors, CCR5 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D018946:Chemokine CCL5; D054389:Receptors, CCR1; D019713:Receptors, CCR5; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C515301:Ccr1 protein, mouse