Angiogenesis in Hepatocellular Carcinoma: A Potential Target for Chemoprevention and Therapy

Hepatocellular carcinoma (HCC) remains one of the most lethal cancers in the world. Since current treatment options including surgical resection and liver transplantation offer limited therapeutic benefits, there exists a need to evaluate novel therapeutic strategies for the amelioration of HCC. Hepatic tumors are highly vascularized, possessing a rich network of blood vessels and capillaries and there exist an angiogenic component to the tumor growth observed in HCC. Thus, anti-angiogenic therapy has been suggested to possess tremendous therapeutic potential in the treatment of HCC. The process of angiogenesis involves multiple biochemical checkpoints and signaling steps, and thus providing a multitude of opportunities for therapeutic intervention. In this review, we highlight the role of angiogenesis and its use as a therapeutic strategy for HCC. The first part of the article reviews the angiogenic mechanisms with particular emphasis on the multitude of biochemical factors, such as receptors, enzymes and cytokines involved in the complex interplay of new capillary growth. Next, we present the pre-clinical studies which elucidate the anti-angiogenic effects of both dietary and non-dietary agents in animal models of HCC. Of particular interest is the examination of the effects of the antiangiogenic agents on the various angiogenic markers in the hepatic tissue of the animal challenged either with a hepatocarcinogen or xenografted with hepatic neoplastic cells. The review also highlights the clinical investigations carried out in HCC patients to evaluate the therapeutic potential of pharmacological agents with proven anti-angiogenic properties. Finally, the future directions as well as the benefits and potential challenges involved in the use of antiangiogenic pharmacotherapy in the treatment of HCC are also discussed. Keywords: Angiogenesis, anti-angiogenic agents, chemoprevention, hepatocellular carcinoma, treatment, vascular endothelial growth factor, Wnt inhibitory factor 1, Vascular endothelial growth factor, Thrombospondin-1, Tumor necrosis factor, Transforming growth factor, Tissue factor, Transcatheter arterial chemoembolization, Sorafenib HCC assessment randomized protocol, Selenium-enriched malt, Fetal liver kinase