Figure 1.

Key molecular events of EMT. Epithelial tumor cells receive EMT-inducing signals from the tumor microenvironment, such as growth factors, low pH, hypoxia, and ECM modifications. EMT-inducing factors trigger various intracellular signaling pathways and activate EMT-TFs, which then downregulate and upregulate epithelial and mesenchymal markers, respectively. EMT is further sustained by autocrine loops: for example, inhibition of E-cadherin leads to its dissociation from β-catenin, which translocates to the nucleus and transactivates EMT-associated genes. Later stages of EMT involve transformation of both intra- and extracellular compartments. The formation of actin stress fibers and vimentin intermediate filaments provides the mechanical force for migration. The cells that have undergone EMT have multidirectional effects on the ECM: they disrupt the basement membrane by degrading collagen IV with matrix metalloproteinases (MMPs) 2 and 9, but at the same time produce other ECM components such as collagen I and fibronectin, which further maintain EMT. Downward (↓) and upward (↑) arrows indicate downregulation and upregulation of expression, respectively.