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

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.