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Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Aug 14, 2016; 22(30): 6841-6850
Published online Aug 14, 2016. doi: 10.3748/wjg.v22.i30.6841
Cancer-associated fibroblasts in hepatocellular carcinoma
Norio Kubo, Kenichiro Araki, Hiroyuki Kuwano, Ken Shirabe
Norio Kubo, Kenichiro Araki, Ken Shirabe, Department of Hepatobiliary and Pancreatic Surgery, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
Hiroyuki Kuwano, Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
Author contributions: Shirabe K designed research; Araki K and Kuwano H analyzed the literature; Kubo N wrote the paper.
Supported by Research Program on Hepatitis from Japan Agency for Medical Research and development, AMED.
Conflict-of-interest statement: Authors declare no conflict of interests for this article.
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: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Kenichiro Araki, MD, PhD, Department of Hepatobiliary and Pancreatic Surgery, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan. karaki@gunma-u.ac.jp
Telephone: +81-27-2208224 Fax: +81-27-2208230
Received: March 28, 2016
Peer-review started: April 2, 2016
First decision: May 12, 2016
Revised: June 9, 2016
Accepted: July 6, 2016
Article in press: July 6, 2016
Published online: August 14, 2016
Abstract

The hepatic stellate cells in the liver are stimulated sustainably by chronic injury of the hepatocytes, activating myofibroblasts, which produce abundant collagen. Myofibroblasts are the major source of extracellular proteins during fibrogenesis, and may directly, or secreted products, contribute to carcinogenesis and tumor progression. Cancer-associated fibroblasts (CAFs) are one of the components of the tumor microenvironment that promote the proliferation and invasion of cancer cells by secreting various growth factors and cytokines. CAFs crosstalk with cancer cells stimulates tumor progression by creating a favorable microenvironment for progression, invasion, and metastasis through the epithelial-mesenchymal transition. Basic studies on CAFs have advanced, and the role of CAFs in tumors has been elucidated. In particular, for hepatocellular carcinoma, carcinogenesis from cirrhosis is a known fact, and participation of CAFs in carcinogenesis is supported. In this review, we discuss the current literature on the role of CAFs and CAF-related signaling in carcinogenesis, crosstalk with cancer cells, immunosuppressive effects, angiogenesis, therapeutic targets, and resistance to chemotherapy. The role of CAFs is important in cancer initiation and progression. CAFtargeted therapy may be effective for suppression not only of fibrosis but also cancer progression.

Keywords: Cancer associated fibroblast, Hepatic stellate cell, Hepatocellular carcinoma, Immunosuppression, Therapeutic target

Core tip: Cancer-associated fibroblasts (CAFs) are one of the most crucial components of the tumor microenvironment that promote the carcinogenesis, proliferation and invasion of cancer cells by secreting various growth factors and cytokines. In hepatocellular carcinoma (HCC), cirrhosis caused by chronic inflammation was considered the main reason for carcinogenesis, and field cancerization was explained by the epigenetic changes in fibroblasts in tissues surrounding the tumor. In this review, we discuss the findings from current literature on the role of CAFs in HCC. CAF-targeted therapy may be effective for suppression not only fibrosis but also cancer progression.