Abstract
Chronic liver disease caused by infections or dietary toxins may result in liver fibrosis, cirrhosis and, eventually, hepatocellular carcinoma (HCC). The only curative treatments for patients with advanced liver disease are partial surgical resection and liver transplantation. However, organ shortage as well as an increasing organ demand call for early treatment of liver disease and prevention of fibrosis on high risk individuals. Stellate cells of the liver seem to be responsible for the fibrogenic response through the activation of an autocrine loop involving the chemokine receptor, CCR5. Since this receptor is also one of the main ports of entry for the human immunodeficiency virus (HIV), several CCR5 inhibitors are being used in the clinic to reduce viral load. We used one of these inhibitors, maraviroc (MVC), in a mouse model of diet-induced HCC to investigate whether this intervention would reduce disease progression. This diet was deficient in choline and was supplemented with ethionine in the drinking water (CDE diet). Animals receiving the CDE diet presented higher mortality, higher levels of markers for liver injury such as transaminases, alkaline phosphatase, and bilirubin, developed severe hepatic fibrosis, and were affected by numerous tumors by week 16, when compared with control mice receiving a regular diet. In addition, many cytokines, chemokines, and other matrix components including CCL2, CCL3, CCL4, CCL5, CCR5, CXCL10, IL-12, TGF-b1, or MMP9, were elevated by the CDE diet. Animals which received the CDE diet but were simultaneously treated with MVC presented significantly higher survival, less liver fibrosis, lower levels of liver injury markers and chemokines, and lower tumor burden than their counterparts receiving only the hepatotoxic diet. Animals treated with MVC on top of a normal control diet did not show any evidence of toxicity or any morphological change when compared with non-treated mice. This study suggests that MVC, a well tolerated and clinically characterized drug, may be used as a preventative treatment for HCC. Clinical studies are needed to demonstrate the efficacy of this drug, or other CCR5 inhibitors, in patients with high risk of developing HCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-173. doi:1538-7445.AM2012-LB-173
