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
Hepatocellular carcinoma (HCC) represents about 90% of primary liver cancers and usually develops in patients with underlying liver cirrhosis. One of the major cancer hallmarks of HCC is the process of neoangiogenesis, which is thought to occur early in the carcinogenetic process. Theoretically, angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin II type 1 receptor blockers (ARBs) could have a role in HCC primary prevention since they reduce both neovascularization and the development of liver fibrosis.
The possible role of renin-angiotensin system (RAS) inhibitors in the prevention of HCC is still an attractive field of research, as suggested by the recently published experimental and clinical studies.
To elucidate the role of ARBs and ACE-Is in HCC.
Literature was selected in August 2018, focusing on studies regarding ACE-Is, ARBs and HCCs. For this purpose, an electronic search of the literature was conducted using the online databases PubMed, Cochrane library, Scopus and Web of Science. Eligibility criteria were: (1) prospective or retrospective clinical studies; (2) epidemiological studies; and (3) experimental studies conducted in vivo or in vitro. We conducted the articles selection using a two-step approach, to evaluate whether they matched the eligibility criteria.
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 of overall survival. Among six retrospective observational studies, mainly focused on overall survival, only one demonstrated a prolonged survival in ACE-Is group, whereas the two of them that also evaluated tumor recurrence showed conflicting results. All experimental studies displayed beneficial effects of RAS inhibitors on hepatocarcinogenesis. Numerous experimental studies, conducted either in animals and cell cultures, demonstrated the anti-angiogenetic and anti-fibrotic 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 part of these mechanisms were demonstrated in rodents developing less HCC and preneoplastic lesions after receiving such drugs.
Our systematic analysis of the literature allowed us to partially reinterpret the data supporting the ability of RAS inhibitors to counteract HCC. While there is reasonable research supporting their ability to reduce the HCC recurrence rate, we think that the conclusions of the randomized clinical trials on overall survival underestimated the potential use of these compounds. These conclusions are further supported by the solid experimental data on the anti-angiogenetic activity of RAS inhibitors, which all suggest their clinical use in the prevention of HCC development.
We also proposed enlarging the future research on the relationship between RAS inhibitors and HCC to other possible anti carcinogenetic mechanisms.