Published online May 28, 2019. doi: 10.3748/wjg.v25.i20.2524
Peer-review started: January 23, 2019
First decision: February 21, 2019
Revised: March 6, 2019
Accepted: March 24, 2019
Article in press: March 25, 2019
Published online: May 28, 2019
Neoangiogenesis is one of the key pathogenetic mechanisms in hepatocellular carcinoma (HCC). Modulation of the renin-angiotensin system (RAS) by angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) seems to be a possible adjuvant therapy for HCC, due to the anti-angiogenic and anti-fibrogenic activity of these drugs.
To elucidate the role of ARBs and ACE-Is in HCC.
We performed an electronic search of the literature using the most accessed online databases (PubMed, Cochrane library, Scopus and Web of Science), entering the query terms "angiotensin-converting enzyme inhibitors" OR "ACE inhibitors" OR "ACE-I" AND "hepatocarcinoma*" OR "hepatocellular carcinoma; moreover "angiotensin II type 1 receptor blockers" OR "ARBs" AND "hepatocarcinoma*" OR "hepatocellular carcinoma". Eligibility criteria were: (1) prospective or retrospective clinical studies; (2) epidemiological studies; and (3) experimental studies conducted in vivo or in vitro. Abstracts, conference papers, and reviews were excluded a priori. We limited our literature search to articles published in English, in peer-reviewed journals.
Thirty-one studies were selected. Three interventional studies showed that ACE-Is had a significant protective effect on HCC recurrence only when used in combination with vitamin K or branched chain aminoacids, without a significant increase in overall survival. Of six retrospective observational studies, mainly focused on overall survival, only one demonstrated a prolonged survival in the ACE-Is group, whereas the two that also evaluated tumor recurrence showed conflicting results. All experimental studies displayed beneficial effects of RAS inhibitors on hepatocarcinogenesis. Numerous experimental studies, conducted either on animals and cell cultures, demonstrated the anti-angiogenetic and antifibrotic effect of ACE-Is and ARBs, thanks to the suppression of some cytokines such as vascular endothelial growth factor, hypoxia-inducible factor-1a, transforming growth factor-beta and tumor necrosis factor alpha. All or parts of these mechanisms were demonstrated in rodents developing fewer HCC and preneoplastic lesions after receiving such drugs.
In humans, RAS inhibitors - alone or in combination - significantly suppressed the cumulative HCC recurrence, without prolonging patient survival, but some limitations intrinsic to these studies prompt further investigations.
Core tip: All experimental studies strongly support the ability of renin-angiotensin system (RAS) inhibitors to counteract carcinogenesis essentially by inhibiting angiogenesis and possibly fibrogenesis in chemically-induced or xeno-transplanted hepatocarcinomas, whereas additional pathogenetic mechanisms using animal models that mimic the progression of liver disease in humans and have been barely considered. In all randomized clinical trials, RAS inhibitors - in combination with other therapies - significantly reduced cumulative hepatocarcinoma recurrence. However, the data on patient survival obtained by these studies and several observational studies are not conclusive. The beneficial effect of the early use of RAS inhibitors on the progression of cirrhosis toward hepatocarcinoma cannot be excluded.