Epithelial Plasticity: A Common Theme in Embryonic and Cancer Cells

Background During embryonic development, cells often travel long distances to form tissues and organs. To be able to migrate, embryonic cells undergo a process known as epithelial-to-mesenchymal transition (EMT). Once migratory embryonic cells reach their destination, they undergo the reverse process, mesenchymal-to-epithelial transition (MET), to later differentiate into multiple cell types. This reveals a high degree of cell plasticity, referring to the ability of cells to reversibly change phenotype, a common feature of embryonic cells. Research indicates that the EMT program is reactivated in cancer cells in the delamination from a primary tumor, the first step toward the colonization of distant organs to form secondary tumors (metastasis). The dissemination of cancer cells and the subsequent formation of metastasis are responsible for the vast majority of cancer-associated deaths. As in EMT, recent advances show that cancer cells rely on the reactivation of developmental programs through MET for the localization and proliferation of disseminating cells. The embryo provides clues to understanding the complex cell biology of EMT and MET in cancer and moving toward improved therapeutic strategies. Epithelial plasticity in three-dimensional (3D) cultures. Epithelial cells [Madin-Darby canine kidney (MDCK) cells] form ducts when grown on 3D matrices resembling the in vivo microenvironment (left). When grown under identical conditions, MDCK cells expressing Prrx1 (an EMT inducer) form networks of mesenchymal cells (right). Note the dramatic phenotypic change that is accompanied by the acquisition of motility and invasive properties. Blue, nuclei revealed by 4′,6-diamidino-2-phenylindole staining; red, actin filaments as seen after phalloidin binding; green, E-cadherin (epithelial marker) (left) and vimentin (mesenchymal marker) (right). Advances Due to the importance of the EMT and MET programs in normal development for the generation of tissues and organs, as well as their role in cancer, stringent regulatory mechanisms are needed. Multiple extracellular signals converge in the activation of transcription factors that can trigger the full EMT program. In addition, epigenetic and splicing programs, as well as microRNA regulatory networks, control epithelial plasticity toward EMT or MET. As differentiated normal and cancer cells can reenter an undifferentiated stemlike state, another level of cell plasticity has become apparent, helping to elucidate complex cell behaviors and interactions. Outlook Technical advances in noninvasive in vivo imaging of embryos will help define cell behavior and plasticity in normal development, fundamental to the understanding of congenital malformations. This knowledge will undoubtedly facilitate the study of tumor progression in animal models of cancer. Cancer cells can also be directly interrogated about their plastic states in molecular terms after the purification and analysis of circulating or disseminated single cells from animal models and also from patients, aiding in the design of improved therapies. With respect to antimetastatic therapies, inhibiting EMT may be counterproductive in tumors that disseminate early, as rather than preventing metastasis, it could favor the formation of secondary tumors from already disseminated cells. Strategies aimed at targeting cancer stem cells are very promising, but it is important to consider that new cancer stem cells can be produced from differentiated nonstem bulk tumor cells. From Here to There To form different tissues and organs, embryonic cells must migrate to new locations. Specific transcription factors, epigenetic and splicing programs, and microRNA regulatory networks regulate this process, which is known as the epithelial-to-mesenchymal transition (EMT). During EMT, considerable cellular plasticity is observed, and once activated at their new location, cells must again change into their new differentiated form. This “reverse” event is called the mesenchymal-to-epithelial transition (MET). Nieto (p. 10.1126/science.1234850) reviews EMT and MET as observed during normal development and in the generation of cancer when cells leave the primary tumor and travel to other parts of the body forming metastases and secondary tumors. During embryonic development, many cells are born far from their final destination and must travel long distances. To become motile and invasive, embryonic epithelial cells undergo a process of mesenchymal conversion known as epithelial-to-mesenchymal transition (EMT). Likewise, EMT can be seen in cancer cells as they leave the primary tumor and disseminate to other parts of the body to colonize distant organs and form metastases. In addition, through the reverse process (mesenchymal-to-epithelial transition), both normal and carcinoma cells revert to the epithelial phenotype to, respectively, differentiate into organs or form secondary tumors. The parallels in phenotypic plasticity in normal morphogenesis and cancer highlight the importance of studying the embryo to understand tumor progression and to aid in the design of improved therapeutic strategies.