Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 7, 2018; 24(33): 3695-3708
Published online Sep 7, 2018. doi: 10.3748/wjg.v24.i33.3695
Updates on the hepatocyte growth factor/c-Met axis in hepatocellular carcinoma and its therapeutic implications
Javier A García-Vilas, Miguel Ángel Medina
Javier A García-Vilas, Department of Pediatrics, University of Alberta, Edmonton T6G 2S2, Canada
Miguel Ángel Medina, Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, Andalucía Tech, Universidad de Málaga, Málaga 29071, Spain
Miguel Ángel Medina, Unidad 741 de CIBER “de Enfermedades Raras” (CIBERER), Málaga 29071, Spain
Miguel Ángel Medina, Institute of Biomedical Research in Málaga, Málaga 29071, Spain
Author contributions: Both authors equally contributed to this paper with conception and design of the study, literature review and analysis, drafting and critical revision and editing, and final approval of the version.
Supported by grants BIO2014-56092-R (MINECO and FEDER), No. P12-CTS-1507 (Andalusian Government and FEDER); and funds from group BIO-267 (Andalusian Government). The “CIBER de Enfermedades Raras” is an initiative from the ISCIII (Spain).
Conflict-of-interest statement: No potential conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Miguel Ángel Medina, PhD, Full Professor, Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, Andalucía Tech, Universidad de Málaga, Boulevar Louis Pasteur 31, Málaga 29010, Spain.
Telephone: +34-952-137132
Received: May 3, 2018
Peer-review started: May 4, 2018
First decision: May 16, 2018
Revised: June 28, 2018
Accepted: July 16, 2018
Article in press: July 16, 2018
Published online: September 7, 2018

Hepatocellular carcinoma (HCC) is the fifth most common cancer and is the second leading cause of cancer death. Since the diagnosis of HCC is difficult, in many cases patients with HCC are diagnosed advanced stage of development. Hepatocyte growth factor (HGF)/c-mesenchymal-epithelial transition receptor (c-Met) axis is a key signaling pathway in HCC, either via canonical or non-canonical pathways. Available treatments against HCC based upon HGF/c-Met inhibition can increase patient lifespan, but do not reach the expected therapeutic benefits. In HCC, c-Met monomers can bind other receptor monomers, activating several noncanonical signaling pathways, leading to increased cell proliferation, invasion, motility, and drug resistance. All of these processes are enhanced by the tumor microenvironment, with stromal cells contributing to boost tumor progression through oxidative stress, angiogenesis, lymphangiogenesis, inflammation, and fibrosis. Novel treatments against HCC are being explored to modulate other targets such as microRNAs, methyltransferases, and acetyltransferases, which are all involved in the regulation of gene expression in cancer. This review compiles basic knowledge regarding signaling pathways in HCC, and compounds already used or showing potential to be used in clinical trials.

Keywords: Hepatocellular carcinoma, Hepatocyte growth factor/c-MET, Tumor microenvironment, c-Met canonical and non-canonical pathways

Core tip: Hepatocellular carcinoma (HCC) is a tumor usually arising from previous hepatic diseases as cirrhosis and chronic hepatitis B and C infections. Several studies have shown that a key factor for HCC oncogenesis is chronic inflammation. Inflammation induces changes in the gene expression pattern in surrounding cells. These changes provide an environment with a high level of cytokines, promoting hepatocyte transformation to tumor cells. New therapies against HCC are focused on regulating stromal cells within the tumor microenvironment to avoid HCC progression.