The EMT universe: space between cancer cell dissemination and metastasis initiation

Tumor metastasis, the cause of more than 90% of cancer cell mortality, is a multistep process by which tumor cells disseminate from their primary site via local invasion and intravasation into blood or lymphatic vessels and reach secondary distant sites, where they survive and reinitiate tumor growth. Activation of a developmental program called the epithelial-to-mesenchymal transition (EMT) has been shown to be a very efficient strategy adopted by epithelial cancer cells to promote local invasion and dissemination at distant organs. Remarkably, the activation of EMT programs in epithelial cells correlates with the appearance of stemness. This finding suggests that the EMT process also drives the initial cancer cell colonization at distant sites. However, recent studies support the concept that its reverse program, a mesenchymal-to-epithelial transition, is required for efficient metastatic colonization and that EMT is not necessarily associated with stemness. This review analyzes the conflicting experimental evidence linking epithelial plasticity to stemness in the light of an "EMT gradient model," according to which the outcome of EMT program activation in epithelial cells would be bimodal: coupled to stemness during initial activation, but when forced to reach an advanced mesenchymal status, it would become incompatible with stem cell abilities.