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The role of integrins in TGF? activation in the tumour stroma #MMPMID27515461
Khan Z; Marshall JF
Cell Tissue Res 2016[]; 365 (3): 657-73 PMID27515461show ga
TGF?1 is the most pleiotropic of all known cytokines and thus, to avoid uncontrolled TGF?-activated processes, its activity is tightly regulated. Studies in fibrosis have led to the discovery that ?v integrins are the major regulators of the local activation of latent TGF? in our tissues. Since all cells can express one or more types of ?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?. In normal tissues, TGF?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? growth suppression, TGF? 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? drives epithelial-to-mesenchymal transition (EMT) increasing the potential for metastasis. Since ?v integrins activate TGF?, they almost certainly drive TGF?-dependent cancer progression. In this review, we discuss the data that are helping to develop this hypothesis and describe the evidence that ?v integrins regulate the TGF? promotion of cancer.Graphical AbstractMechanisms of integrin-mediated transforming growth factor beta (TGF?) activation and its effect on stromal processes. 1 Matrix-bound latent LAP-TGF?1 binds ?v integrins expressed by epithelial cells or fibroblasts (LAP latency-associated peptide). TGF?1 becomes exposed. 2 Active TGF?1 binds the TGF? receptor in an autocrine or paracrine fashion. 3 TGF?1 signalling increases integrin expression, LAP-TGF?1 secretion and trans-differentiation of fibroblasts into contractile cells that secrete collagens and collagen cross-linking proteins. By contracting the matrix, latent TGF?1 is stretched making the activation of latent TGF?1 easier and creating a continuous cycle of TGF?1 signalling. TGF?1 promotes cancer progression by promoting angiogenesis, immune suppression and epithelial-to-mesenchymal transition (EMT)
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Cell+Tissue+Res 2016 ; 365 (3): 657-73
