Figure 1.

Model for reversible EMT over time. Epithelial cells undergo genetic transformation to become carcinoma in situ. Microenvironmental and genetic factors can promote the malignant conversion of these cells to activate the EMT program. During these early stages of tumor development, tumor cells that have undergone EMT can invade the local matrix (step I) and intravasate into the vasculature (step II). These epithelial–mesenchymal-transitioned cells are then transported in the circulation and survive via various prosurvival mechanisms (step III). At the distant tissue site, maintenance of the EMT program is required to help tumor cells extravasate into the parenchyma (step IV) to establish micrometastases. This initial seeding of tumor cells at distant sites can occur rapidly, after which cells may remain “dormant” for a long period of time. Subsequent colonization in distant organs requires the reversion of EMT and/or activation of the MET program to establish secondary tumors (step V).