Impact of Renin-Angiotensin System in Hepatocellular Carcinoma

H.      Yoshiji; R.      Noguchi; Y.      Ikenaka; K.      Kaji; Y.      Aihara; H.      Fukui

doi:10.2174/156800911795538084

Abstract

Angiogenesis is a complex and critical process essential for supporting the growth of hepatocellular carcinoma (HCC) as well as hepatocarcinogenesis. Recent studies have revealed that renin-angiotensin system (RAS) is involved in many types of cancer including HCC. Some studies have proven that suppression of angiotensin-II (AT-II) by a clinically used angiotensin-converting enzyme inhibitor (ACE-I) significantly attenuated the HCC growth and hepatocarcinogenesis along with down-regulation of a potent angiogenic factor; namely, the vascular endothelial growth factor (VEGF). When used in combination with the clinical available drugs such as interferon (IFN) and vitamin K (VK), ACE-I exerted more potent anti-tumor activities as compared with either single agent in addition to suppression of the intra-tumoral angiogenesis both in experimental models and clinical practice. It is well known that AT-II plays an important role in the insulin resistance (IR), and IR is reportedly involved in the progression of HCC. The combination of ACE-I and branched-chain amino acids (BCAA) exerted a marked chemopreventive effect against HCC under the condition of IR. In addition to AT-II, aldosterone (Ald), which plays a role in the downstream of AT-II, is also involved in the HCC development, and a clinically used selective Ald blocker (SAB) significantly suppressed the HCC growth and hepatocarcinogenesis. Since ACE-I, IFN, VK, BCAA, and SAB are already in widespread clinical use without any serious adverse effects, they may represent a potential new strategy for cancer therapy and chemoprevention against HCC especially in combination with other angiostatic agents.

Keywords: Angiogenesis, angiotensin-converting enzyme, angiotensin-II, hepatocellular carcinoma, vascular endothelial growth factor, aldosterone, nonalcoholic steatohepatitis, radiofrequency ablation, calcium channels blockers, 5-fluorouracil, lectin-reactive -fetoprotein, imatinibmesylate, tyrosine kinase inhibitor