TGF-β Signaling in Liver, Pancreas, and Gastrointestinal Diseases and Cancer

Abstract

Genetic alterations affecting transforming growth factor-β (TGF-β) signaling are exceptionally common in diseases and cancers of the gastrointestinal system. As a regulator of tissue renewal, TGF-β signaling and the downstream SMAD-dependent transcriptional events play complex roles in the transition from a noncancerous disease state to cancer in the gastrointestinal tract, liver, and pancreas. Furthermore, this pathway also regulates the stromal cells and the immune system, which may contribute to evasion of the tumors from immune-mediated elimination. Here, we review the involvement of the TGF-β pathway mediated by the transcriptional regulators SMADs in disease progression to cancer in the digestive system. The review integrates human genomic studies with animal models that provide clues toward understanding and managing the complexity of the pathway in disease and cancer.

Keywords: Cancers; Digestive System; Transforming Growth Factor–β.

Figure 1.

TGF-β signaling pathways. A simplified view of the core of the TGF-β and BMP pathways. X indicates an inhibitory interaction. The ligands are retained as inactive procomplexes, often associated with the ECM, before activation. The classes of various regulators are indicated at each level of the pathways in white boxes.

Figure 2.

GI tract with relevant mouse models for investigating TGF-β signaling in disease or cancer. (+), increased susceptibility to disease or cancer; (–), decreased susceptibility.

Figure 3.

Pancreas and liver with relevant mouse models for investigating TGF-β signaling in disease or cancer. (+), increased susceptibility to disease or cancer; (–), decreased susceptibility.