The role of integrins in TGFβ activation in the tumour stroma

Abstract

TGFβ1 is the most pleiotropic of all known cytokines and thus, to avoid uncontrolled TGFβ-activated processes, its activity is tightly regulated. Studies in fibrosis have led to the discovery that αv integrins are the major regulators of the local activation of latent TGFβ in our tissues. Since all cells can express one or more types of αv 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 TGFβ. In normal tissues, TGFβ1 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 TGFβ growth suppression, TGFβ 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, TGFβ drives epithelial-to-mesenchymal transition (EMT) increasing the potential for metastasis. Since αv integrins activate TGFβ, they almost certainly drive TGFβ-dependent cancer progression. In this review, we discuss the data that are helping to develop this hypothesis and describe the evidence that αv integrins regulate the TGFβ promotion of cancer. Graphical Abstract Mechanisms of integrin-mediated transforming growth factor beta (TGFβ) activation and its effect on stromal processes. 1 Matrix-bound latent LAP-TGFβ1 binds αv integrins expressed by epithelial cells or fibroblasts (LAP latency-associated peptide). TGFβ1 becomes exposed. 2 Active TGFβ1 binds the TGFβ receptor in an autocrine or paracrine fashion. 3 TGFβ1 signalling increases integrin expression, LAP-TGFβ1 secretion and trans-differentiation of fibroblasts into contractile cells that secrete collagens and collagen cross-linking proteins. By contracting the matrix, latent TGFβ1 is stretched making the activation of latent TGFβ1 easier and creating a continuous cycle of TGFβ1 signalling. TGFβ1 promotes cancer progression by promoting angiogenesis, immune suppression and epithelial-to-mesenchymal transition (EMT).

Keywords: Integrin; TGFβ; Tumour microenvironment; Tumour stroma; αvβ1, αvβ3, αvβ5, αvβ6, αvβ8.

Graphical Abstract

Mechanisms of integrin-mediated transforming growth factor beta (TGFβ) activation and its effect on stromal processes. 1 Matrix-bound latent LAP-TGFβ1 binds αv integrins expressed by epithelial cells or fibroblasts (LAP latency-associated peptide). TGFβ1 becomes exposed. 2 Active TGFβ1 binds the TGFβ receptor in an autocrine or paracrine fashion. 3 TGFβ1 signalling increases integrin expression, LAP-TGFβ1 secretion and trans-differentiation of fibroblasts into contractile cells that secrete collagens and collagen cross-linking proteins. By contracting the matrix, latent TGFβ1 is stretched making the activation of latent TGFβ1 easier and creating a continuous cycle of TGFβ1 signalling. TGFβ1 promotes cancer progression by promoting angiogenesis, immune suppression and epithelial-to-mesenchymal transition (EMT)

Fig. 1

Cycle of contribution of transforming growth factor β1 (TGFβ1)-activated fibroblasts to extracellular matrix (ECM) composition and stiffness and further TGFβ1 activation (LTBP latent TGFβ-binding proteins, ITGB6 integrin subunit gene 6, LOX lysyl oxidase, POSTN periostin)

Fig. 2

Contribution of integrin-mediated TGFβ1 activation of pro-tumour mechanisms via regulation of cells of the immune system, promotion of epithelial-mesenchymal transition and angiogenesis. Immune system 1) Active TGFβ stimulates naive T-cell-to-Treg differentiation (top). Tregs exhibit αvβ8-mediated TGFβ1 activation, amplifying the differentiation of other naive T-cells. Tregs suppress anti-tumour T-cell responses. Tumour cell integrins mediate TGFβ1 activation (bottom). Active TGFβ1 stimulates macrophage and neutrophil pro-tumour responses. Epithelial-to-mesenchymal transition TGFβ1 stimulation of epithelial cells represses epithelial gene signatures, e.g., cell-cell adhesion molecule E-cadherin (top). This promotes a more mesenchymal invasive cell phenotype (bottom). Angiogenesis TGFβ1 stimulation of tumour cells increases VEGF expression, which binds to its receptor on local endothelial cells. Integrin αvβ3 promotes activation and recycling of VEGFR (left). The αvβ8-mediated activation of TGFβ1 facilitates TGFβ activation of local endothelial cells, which can promote or inhibit angiogenesis via separate TGFβ receptors (right)