TGF-β and hepatocellular carcinoma: When a friend becomes an enemy

Hepatocellular carcinoma (HCC) is the third most common cause of cancer death worldwide accounting for more than 700 thousand deaths per year. Most of the HCC develops in a cirrhotic liver, a microenvironment where fibrotic tissue replaces parenchymal cells. Thus, there is a close connection between fibrosis and HCC development. Understanding the cellular and molecular mechanisms involved in this process is a crucial step to advance in novel therapeutic or pharmacological strategies to prevent or improve the course of this malignancy. A key molecular player capable of modulating cell growth and fibrosis is the Transforming Growth Factor-beta (TGF-β). Interestingly, TGF-β seems to act like a switch, since it has dual and opposite roles during early and late phases of cancer development. Therefore to develop therapies that target TGF-β signaling pathway for HCC treatment is important to understand the underlying pathogenetic mechanisms at play with special emphasis in the crosstalk between TGF-β and other signaling pathways. In recent years, a plethora of TGR-β have been developed and some of them are under clinical investigations for testing in patients with advanced HCC. In this review, we summarize recent knowledge about the role of TGF-β signaling pathway in HCC progression.