Figure 4: TGFβ prometastatic effects. Tumor cells synthesize and secrete a significant amount of TGFβ, which affects both the cancer cell and the stroma. As a result, TGFβ promotes tumor progression and metastasis by acting directly on the cancer cells themselves and by affecting the stroma and surrounding environment. (a) In cancer cells, TGFβ promotes the epithelial to mesenchymal transition (EMT) by decreasing cell adhesion and by blocking expression of epithelial proteins (E-Cadherin, ZO-1, etc.) while increasing the expression of mesenchymal proteins (N-Cadherin, vimentin, fibronectin, tenascin-C). TGFβ also promotes cell migration and invasion through multiple signalling pathways (increased p21 expression, microRNA regulation, increased synthesis and secretion of metalloproteinase expression, activation of RhoGTPases, decreased TIMP3 expression, and regulation of the plasminogen activator system (PAS)). TGFβ also promotes tumor metastasis by potentiating chemoattraction of the cancer cells to distant organs (bone, lymph node, lung, liver, and brain) and by increasing expression of cytokines (CXCR4, IL-11 and PTHrP) that will promote osteoclast differentiation and the development of osteolytic lesions. (b) TGFβ affects the stroma and the surrounding environment to varying degrees. TGFβ induces angiogenesis and stimulates the vascularisation surrounding the tumor by increasing VEGF and CTGF expression in epithelial cells and fibroblasts. Furthermore, TGFβ also inhibits expression of angiopoetin-1 in fibroblasts, thus increasing permeability of blood vessels associated to the tumor. By inducing hematopoietic cell death, TGFβ induces local and systemic immunosuppression, preventing the immune cells from infiltrating the tumor and allowing the tumor to escape host immunosurveillance. TGFβ also promotes myofibroblast differentiation, further promoting tumor growth.