The tumor microenvironment in hepatocellular carcinoma: current status and therapeutic targets

Abstract

A growing body of literature highlights the cross-talk between tumor cells and the surrounding peri-tumoral stroma as a key modulator of the processes of hepatocarcinogenesis, epithelial mesenchymal transition (EMT), tumor invasion and metastasis. The tumor microenvironment can be broadly classified into cellular and non-cellular components. The major cellular components include hepatic stellate cells, fibroblasts, immune, and endothelial cells. These cell types produce the non-cellular components of the tumor stroma, including extracellular matrix (ECM) proteins, proteolytic enzymes, growth factors and inflammatory cytokines. The non-cellular component of the tumor stroma modulates hepatocellular carcinoma (HCC) biology by effects on cancer signaling pathways in tumor cells and on tumor invasion and metastasis. Global gene expression profiling of HCC has revealed that the tumor microenvironment is an important component in the biologic and prognostic classification of HCC. There are substantial efforts underway to develop novel drugs targeting tumor-stromal interactions. In this review, we discuss the current knowledge about the role of the tumor microenvironment in pathogenesis of HCC, the role of the tumor microenvironment in the classification of HCC and efforts to develop treatments targeting the tumor microenvironment.

Figure 1. Regulators of stellate cell activation and their roles in liver fibrosis and carcinogenesis

Stellate cells and CAF activated by several factors induce proliferation, invasion and metastasis in hepatocellular carcinoma. TGF-β plays a critical role in liver fibrosis and tumorigenesis through the epithelial-mesenchymal transition.

Figure 2. Modulation of TGF-β signaling by Hepatitis B or C

TGF-β normally suppresses cell proliferation and induces cell apoptosis through the activation of the pSmad3C mediated p21 ^WAF1 pathway and down regulation of anti-apoptotic proteins. HBx proteins and HCV impair pSmad3C/p21 ^WAF1 tumor suppressive pathways and activate JNK/pSmad3L oncogenic pathways, which in turn activate c-myc and related oncogenic pathways. This also leads to increased angiogenesis via VEGF, vascular invasion through the activation of β1 integrin, and promotion of EMT.