Figure 2 |.

Many roads lead to EMT: the molecular basis for the mechanisms of EMT and EMT-like states. Inductive stimuli in the tumor microenvironment, including hypoxia and growth factors (e.g. TGF-β, FGF and IGF-1), trigger downstream signaling. These pathways, via MAPK, Smad, GSK3β, and NFκB, result in increased activity of transcriptional repressors in the ZEB, Twist, and Snail families, which repress E-cadherin and other epithelial cell adhesion proteins and induce other mesenchymal proteins. Epigenetic mechanisms involving EZH2 can promote EMT-like states, whereas miRNAs (such as miR-101 or those in the miR-200 family) might act to maintain epithelial status. Importantly, this picture presents numerous mutually reinforcing mechanisms that might promote the EMT-like state. Abbreviations: CDH1, cadherin-1 (E-cadherin); ERβ, estrogen receptor β; FGF, fibroblast growth factor; GSK3β, glycogen synthase kinase 3β; HIF-1α, hypoxia inducible factor 1α; IGF, insulin-like growth factor; ITGβ4; integrin β4; LAM332, laminin-332; MAPK, mitogen-activated protein kinase; miRNA, micro RNA; NFκB, nuclear factor κB; PKD1, protein kinase D1; RKIP, Raf kinase inhibitor protein; sFRP, secreted frizzled-related protein; TGF-β, transforming growth factor β; VEGF-A, vascular endothelial growth factor A; WIF, Wnt inhibitory factor.