title: Antiplatelet therapy prevents hepatocellular carcinoma and improves survival in a mouse model of chronic hepatitis B.
abstract: Chronic infection with hepatitis B virus (HBV) is a major risk factor for the development of hepatocellular carcinoma (HCC). The pathogenesis of HBV-associated HCC involves both viral and host factors. The latter include a functionally inefficient CD8(+) T-cell response that fails to clear the infection from the liver but sustains a chronic necroinflammatory process that contributes to the development of HCC. According to this scenario, amelioration of immune-mediated chronic liver injury may prevent HCC. Because platelets facilitate immune-mediated liver injury by promoting the hepatic accumulation of virus-specific CD8(+) T cells, we evaluated the long-term consequences of antiplatelet therapy in an HBV transgenic mouse model of chronic immune-mediated necroinflammatory liver disease that progresses to HCC. Treatment with aspirin and clopidogrel during the chronic phase of the disease diminished the number of intrahepatic HBV-specific CD8(+) T cells and HBV-nonspecific inflammatory cells, the severity of liver fibrosis, and the development of HCC. Antiplatelet therapy improved overall survival without causing significant side effects. In contrast, the same antiplatelet regimen had no antitumor effect when HCC was induced nonimmunologically by chronic exposure to a hepatotoxic chemical. The unprecedented observation that antiplatelet therapy inhibits or delays immune-mediated hepatocarcinogenesis suggests that platelets may be key players in the pathogenesis of HBV-associated liver cancer and supports the notion that immune-mediated necroinflammatory reactions are an important cause of hepatocellular transformation during chronic hepatitis.
authors: Division of Immunology, Transplantation, and Infectious Diseases, San Raffaele Scientific Institute, 20132 Milan, Italy. sitia.giovanni@hsr.it
authors: Giovanni
authors: G
authors: Sitia
authors: Roberto
authors: R
authors: Aiolfi
authors: Pietro
authors: P
authors: Di Lucia
authors: Marta
authors: M
authors: Mainetti
authors: Amleto
authors: A
authors: Fiocchi
authors: Francesca
authors: F
authors: Mingozzi
authors: Antonio
authors: A
authors: Esposito
authors: Zaverio M
authors: ZM
authors: Ruggeri
authors: Francis V
authors: FV
authors: Chisari
authors: Matteo
authors: M
authors: Iannacone
authors: Luca G
authors: LG
authors: Guidotti
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001241:Aspirin; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D000077144:Clopidogrel; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D019694:Hepatitis B, Chronic / Q000150:complications* / Q000276:immunology* / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D013988:Ticlopidine / Q000031:analogs & derivatives
chemical_list: D008565:Membrane Proteins; D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496512:Ptgs1 protein, mouse; D013988:Ticlopidine; D001241:Aspirin