Bridging the molecular divide: alcohol-induced downregulation of PAX9 and tumour development.

The pathogenesis of oro-oesophaeal squamous cell carcinoma is causally linked to the consumption of alcohol. Beyond the carcinogenic effects of ethanol and its metabolites via DNA damage, the precise mechanisms by which alcohol drives tumourigenesis remain to be fully elucidated. A novel contributor now revealed is aberrant differentiation and proliferation mediated by suppression of PAX9, a key regulator of normal squamous maturation in oro-oesophageal tissues. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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

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.