The role of integrins in TGFβ activation in the tumour stroma

TGF beta 1 is the most pleiotropic of all known cytokines and thus, to avoid uncontrolled TGF beta-activated processes, its activity is tightly regulated. Studies in fibrosis have led to the discovery that alpha v integrins are the major regulators of the local activation of latent TGF beta in our tissues. Since all cells can express one or more types of alpha v integrins, this raises the possibility that, in the complex milieu of a developing cancer, multiple cell types including both cancer cells and stromal cells activate TGF beta. In normal tissues, TGF beta 1 is a tumour suppressor through its ability to suppress epithelial cell division, whereas in cancer, in which tumour cells develop genetic escape mechanisms to become resistant to TGF beta growth suppression, TGF beta signalling creates a tumour-permissive environment by activating fibroblast-to-myofibroblast transition, by promoting angiogenesis, by suppressing immune cell populations and by promoting the secretion of both matrix proteins and proteases. In addition, TGF beta drives epithelial-to-mesenchymal transition (EMT) increasing the potential for metastasis. Since alpha v integrins activate TGF beta, they almost certainly drive TGF beta-dependent cancer progression. In this review, we discuss the data that are helping to develop this hypothesis and describe the evidence that alpha v integrins regulate the TGF beta promotion of cancer.