Trefoil Factor Family (TFF) Peptides in Gastrointestinal Disease: Mucosal Protection, Oncogenesis, Global Prevalence, and Non-Invasive Salivary Biomarker Discovery — A General Review

Abstract

Trefoil Factor Family (TFF) peptides, including TFF1, TFF2, and TFF3, are small, structurally stable, and protease-resistant secretory proteins that play essential roles in gastrointestinal mucosal protection, epithelial repair, and tissue restitution. Increasing evidence suggests that abnormal expression of these peptides, particularly TFF3, is strongly associated with the development and progression of gastrointestinal malignancies. Overexpression of TFF3 has been reported in approximately 52–82% of gastrointestinal cancers, including colorectal, gastric, pancreatic, and hepatocellular carcinomas, and is frequently correlated with advanced tumor stage, metastasis, and poor patient survival. Gastrointestinal cancers collectively represent a major global health burden, accounting for nearly 26% of worldwide cancer incidence, with more than 5 million new cases annually, and approximately 35% of cancer-related deaths. These statistics highlight the urgent need for reliable and early diagnostic biomarkers. Recent advances in biomarker research have identified saliva as a promising non-invasive diagnostic biofluid, in which TFF3 levels have been shown to increase significantly in cancer patients, reaching up to 9.5-fold higher concentrations compared with healthy individuals in advanced disease stages. This review compiles current scientific evidence regarding the biological functions of TFF peptides, their role in gastrointestinal tumorigenesis, global epidemiological trends, and the diagnostic potential of salivary TFF3 as a biomarker. The findings provide a strong scientific basis for further clinical and translational research exploring salivary TFF3 as a practical tool for early detection and monitoring of gastrointestinal cancers.