Mechanisms and clinical significance of TGF-β in hepatocellular cancer progression

Despite progress in treating or preventing viral hepatitis, a leading cause of liver cancer, hepatocellular cancer (HCC) continues to be a major cause of cancer-related deaths globally. HCC is a highly heterogeneous cancer with many genetic alterations common within a patient's tumor and between different patients. This complicates therapeutic strategies. In this review, we highlight the critical role that the Smad-mediated transforming growth factor β (TGF-β) pathway plays both in liver homeostasis and in the development and progression of HCC. We summarize the mouse models that have enabled the exploration of the dual nature of this pathway as both a tumor suppressor and a tumor promoter. Finally, we highlight how the insights gained from evaluating pathway activity using transcriptional profiling can be used to stratify HCC patients toward rational therapeutic regimens based on the differences in patients with early or late TGF-β pathway activity or activated, normal, or inactivated profiles of this key pathway.