TGF-β signaling in liver and gastrointestinal cancers

Abstract

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.

Keywords: Cancers; GI cancers; Liver cancer; TGF-β signaling.

Figure 1. TGF-β signaling in tumor suppression and promotion

TGF-β achieves its tumor suppressive and promoting effects through several mechanisms. An important suppressor mechanism is through regulation of cell proliferation. TGF-β upregulates the expression of p21 and p15 to inhibit cyclin-dependent kinase (CDK) and downregulates the expression of c-Myc and ID to drive cell proliferation. TGF-β also exerts its tumor promoting effect through induction of EMT by Smad3 and Smad4 upregulation; Examples of evasion of the immune system are by suppression of granzyme A, B, perforin, FAS ligand and IgA; angiogenesis by promotion of MMP2, MMP9, VEGF and CTCT; and metastasis.