A novel role of hepatic epithelial transforming growth factor-β signaling in cholangiocarcinogenesis

Transforming growth factor-β (TGF-β) signaling regulates a broad range of cellular processes including cell proliferation, differentiation and apoptosis (1). Based on the current knowledge, TGF-β is the main pro-fibrogenic cytokine in the liver that induces fibrosis by activating the hepatic stellate cells (HSCs) (2). However, the role of TGF-β in hepatocarcinogenesis is not as clear as in hepatic fibrogenesis because of the dual functions of TGF-β as both a tumor suppressor and promoter (3). In tumor microenvironment, many cell types are responsive to TGF-β signaling leading to complex effects on cancer initiation and progression. It is now generally accepted that TGF-β acts as a tumor suppressor at early stage of cancer development by inhibiting cell cycle progression and inducing malignant cell apoptosis. However, in late stage, TGF-β acts as a tumor promoter by increasing tumor invasiveness and metastasis. The pro-tumorigenic effect of TGF-β is evident by the induction of a mesenchymal phenotype in epithelial tumor cells, also known as epithelial-to-mesenchymal transition (EMT) after prolonged exposure to TGF-β (4). Indeed, overexpressed TGF-β has been related to increased tumor progression and poor clinical outcomes in different types of cancers (5). Given the critical role of TGF-β in tumor progression, TGF-β has been regarded as a promising target for cancer therapy (6).