TGF-beta signaling and its targeted therapy in gastrointestinal cancers.

ABSTRACT

The transforming growth factor ß (TGFß) signaling pathway governs physiological homeostasis in the gastrointestinal system and its deregulation can lead to a diverse range of human pathologies including juvenile polyposis syndrome and tumor initiation, progression, and metastasis. In gastrointestinal malignancies, tumor cells evade the known tumor suppressive effects of TGFß signaling through frequent inactivation of the pathway. Paradoxically, tumor cells utilize TGFß-mediated regulation of epithelial-mesenchymal transition and immunomodulation to facilitate the invasive and migratory phenotype of gastrointestinal cancers and avoid immunosurveillance. The dichotomous role of TGFß as both a tumor suppressor and tumor promoter has highly challenged research efforts to specifically target TGFß signaling as a cancer therapy. The current preclinical approach is to inhibit TGFß-mediated generation of a favorable microenvironment for tumor growth, invasion, and metastasis. Here, we overview the alterations of TGFß signaling and its fundamental biological relevance in gastrointestinal tumorigenesis. We further discuss future perspectives for efficacious molecular targeted treatment of contextual TGFß tumor-promoting effects in gastrointestinal cancers.