TGF-β signaling in liver and gastrointestinal cancers

• TGF-β plays a prominent driving, context-dependent role in liver and gastrointestinal cancers.
• TGF-β pathway members have a broad range of functions (profibrotic, immunomodulatory, tumor supressor, and tumor promoter).
• Mouse models, human genomics and functional studies have provided key insights into this pathway.
• This review focuses on identifying novel strategies targeting this key pathway to improve outcomes for these lethal cancers.

Transforming Growth Factor-β (TGF-β) plays crucial and complex roles in liver and gastrointestinal cancers. These include a multitude of distinct functions, such as maintaining stem cell homeostasis, promoting fibrosis, immune modulating, as a tumor suppressor and paradoxically, as a tumor progressor. However, key mechanisms for the switches responsible for these distinct actions are poorly understood, and remain a challenge. The Cancer Genome Atlas (TCGA) analyses and genetically engineered mouse models now provide an integrated approach to dissect these multifaceted and context-dependent driving roles of the TGF-β pathway. In this review, we will discuss the molecular mechanisms of TGF-β signaling, focusing on colorectal, gastric, pancreatic, and liver cancers. Novel drugs targeting the TGF-β pathway have been developed over the last decade, and some have been proven effective in clinical trials. A better understanding of the TGF-β pathway may improve our ability to target it, thus providing more tools to the armamentarium against these deadly cancers.