The Biological and Biomechanical Role of Transglutaminase-2 in the Tumour Microenvironment

SIMPLE SUMMARY: Transglutaminase-2 (TG2) is an enzyme primarily involved in protein cross-linking, which has been shown to play a role in the development and progression of numerous cancers. Increasing evidence indicates that TG2 is capable of modulating the tumour microenvironment (TME), resulting in changes which influence tumour initiation, growth, and metastasis. This review aims to highlight TG2’s role in the biological and biomechanical changes observed in the TME and the potential for therapeutic targeting of these changes in order to improve patient outcomes. ABSTRACT: Transglutaminase-2 (TG2) is the most highly and ubiquitously expressed member of the transglutaminase enzyme family and is primarily involved in protein cross-linking. TG2 has been implicated in the development and progression of numerous cancers, with a direct role in multiple cellular processes and pathways linked to apoptosis, chemoresistance, epithelial-mesenchymal transition, and stem cell phenotype. The tumour microenvironment (TME) is critical in the formation, progression, and eventual metastasis of cancer, and increasing evidence points to a role for TG2 in matrix remodelling, modulation of biomechanical properties, cell adhesion, motility, and invasion. There is growing interest in targeting the TME therapeutically in response to advances in the understanding of its critical role in disease progression, and a number of approaches targeting biophysical properties and biomechanical signalling are beginning to show clinical promise. In this review we aim to highlight the wide array of processes in which TG2 influences the TME, focussing on its potential role in the dynamic tissue remodelling and biomechanical events increasingly linked to invasive and aggressive behaviour. Drug development efforts have yielded a range of TG2 inhibitors, and ongoing clinical trials may inform strategies for targeting the biomolecular and biomechanical function of TG2 in the TME.