TGF-beta signaling and its targeted therapy in gastrointestinal cancers

The transforming growth factor β (TGFβ) 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 TGFβ signaling through frequent inactivation of the pathway. Paradoxically, tumor cells utilize TGFβ-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 TGFβ as both a tumor suppressor and tumor promoter has highly challenged research efforts to specifically target TGFβ signaling as a cancer therapy. The current preclinical approach is to inhibit TGFβ-mediated generation of a favorable microenvironment for tumor growth, invasion, and metastasis. Here, we overview the alterations of TGFβ signaling and its fundamental biological relevance in gastrointestinal tumorigenesis. We further discuss future perspectives for efficacious molecular targeted treatment of contextual TGFβ tumor-promoting effects in gastrointestinal cancers.