Targeting the tumor stroma in hepatocellular carcinoma

Abstract

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.