Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Feb 27, 2015; 7(2): 165-176
Published online Feb 27, 2015. doi: 10.4254/wjh.v7.i2.165
Targeting the tumor stroma in hepatocellular carcinoma
Femke Heindryckx, Pär Gerwins
Femke Heindryckx, Pär Gerwins, Department of Medical Biochemistry and Microbiology, Biomedical Research Center, Uppsala University, SE-75123 Uppsala, Sweden
Author contributions: Both authors contributed to this work.
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: Femke Heindryckx, PhD, Department of Medical Biochemistry and Microbiology, Uppsala University, Husargatan 3, PO Box 582, SE-75123 Uppsala, Sweden.
Telephone: +46-18-4714442
Received: July 15, 2014
Peer-review started: July 16, 2014
First decision: August 28, 2014
Revised: September 30, 2014
Accepted: November 17, 2014
Article in press: November 19, 2014
Published online: February 27, 2015

Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers worldwide. In ninety percent of the cases it develops as a result of chronic liver damage and it is thus a typical inflammation-related cancer characterized by the close relation between the tumor microenvironment and tumor cells. The stromal environment consists out of several cell types, including hepatic stellate cells, macrophages and endothelial cells. They are not just active bystanders in the pathogenesis of HCC, but play an important and active role in tumor initiation, progression and metastasis. Furthermore, the tumor itself influences these cells to create a background that is beneficial for sustaining tumor growth. One of the key players is the hepatic stellate cell, which is activated during liver damage and differentiates towards a myofibroblast-like cell. Activated stellate cells are responsible for the deposition of extracellular matrix, increase the production of angiogenic factors and stimulate the recruitment of macrophages. The increase of angiogenic factors (which are secreted by macrophages, tumor cells and activated stellate cells) will induce the formation of new blood vessels, thereby supplying the tumor with more oxygen and nutrients, thus supporting tumor growth and offering a passageway in the circulatory system. In addition, the secretion of chemokines by the tumor cells leads to the recruitment of tumor associated macrophages. These tumor associated macrophages are key actors of cancer-related inflammation, being the main type of inflammatory cells infiltrating the tumor environment and exerting a tumor promoting effect by secreting growth factors, stimulating angiogenesis and influencing the activation of stellate cells. This complex interplay between the several cell types involved in liver cancer emphasizes the need for targeting the tumor stroma in HCC patients.

Keywords: Hepatocellular carcinoma, Stellate cells, Cirrhosis, Angiogenesis, Macrophages, Inflammation

Core tip: Hepatocellular carcinoma is a primary liver tumor that usually develops in a background of chronic liver disease and fibrosis. It is the underlying chronic inflammation that creates an environment that not only causes but also enhances the formation and growth of tumors. The stromal compartment-including hepatic stellate cells, macrophages and endothelial cells-actively contribute to tumorigenesis, while the tumor itself influences these cells to create a background that is beneficial for tumor growth. This review focuses on the interplay between stroma and tumor cells, as well as therapeutic strategies that aim to target these complex interactions.