The roles of TGFβ in the tumour microenvironment

Abstract

The influence of the microenvironment on tumour progression is becoming clearer. In this Review we address the role of an essential signalling pathway, that of transforming growth factor-β, in the regulation of components of the tumour microenvironment and how this contributes to tumour progression.

Figure 1. Epithelial TGFβ signalling during tumour progression

a | Normal transforming growth factor-β (TGFβ) signalling in TGFβ-responsive cells (blue cells) feeds through the type 2 TGFβ receptor (TGFBR2) to activate downstream signalling targets. Canonical signalling is activated through phosphorylation of TGFBR1 to induce nuclear localization and transcriptional activity of SMADs. Non-canonical signalling can occur independently of SMAD proteins and includes activation of RHOA, AKT and MAPK pathways. Early in tumorigenesis, TGFβ functions as a tumour suppressor, partly through the SMAD-dependent induction of cell cycle arrest. b | One hypothesis is that selective pressure leads to the expansion of the population of tumour cells that harbour inactivating mutations in the TGFβ pathway, thus allowing them to overcome the growth-inhibitory effects of active TGFβ signalling. As outlined by Levy et al., loss of TGFβ responsiveness (green cells) can occur through loss-of-function mutations, loss of expression or promoter methylation of genes (shown by the grey circles) that encode TGFβ receptors or SMADs. JNK, JUN N-terminal kinase; mTOR, mammalian target of rapamycin; PAR6, partitioning defective 6 homologue; ROCK1, RHO-associated protein kinase 1; RSMAD, receptor SMAD; SBE, SMAD-binding element.

Figure 2. TGFβ signalling in tumour cells determines microenvironmental modification

Transforming growth factor-β (TGFβ) signalling in tumour cells induces the expression of numerous mediators of extracellular change. Tumours in which cells show increased TGFβ activity are characterized by increased extracellular matrix (ECM) deposition; they show increased secretion of matrix proteins and maturation of these proteins through ECM-modifying enzymes such as lysyl oxidase homologue 4 (LOXL4). In addition, TGFβ signalling in tumour cells drives the induction of endothelial cell recruitment and proliferation, which promote increased angiogenesis. Conversely, TGFβ suppresses the expression of numerous cytokines and chemokines such as the CXC-chemokine ligand 1 (CXCL1) and CXCL5. Loss of TGFβ responsiveness relieves this suppression and results in enhanced immune cell infiltration. These microenvironmental changes promote epithelial cell and stromal cell phenotypical responses, which substantially affect tumour progression. The figure shows the phenotypical changes that specifically result from the epithelial-derived factors listed. ADAMTS9, a disintegrin and metalloproteinase with thrombospondin motifs 9; CTGF, connective tissue growth factor; EMT, epithelial-to-mesenchymal transition; G-CSF, granulocyte colony-stimulating factor; HGF, hepatocyte growth factor; IL-8, interleukin-8; MMP, matrix metalloproteinase; PDGFβ, platelet-derived growth factor-β; THBS1, thrombospondin 1; VEGFA, vascular endothelial growth factor A.