EMT: from embryogenesis, through cancer progression, to the development of carcinosarcoma

Epithelial cells are tightly connected to one another by intercellular junctions which prevent much of their motility, and have distinct apical-basal cell polarity, with their basal pole facing the basement membrane; they form mono- or multilayered sheet-like structures, and establish the borders of tissues and organs. In contrast, mesenchymal cells fill the spaces delimitated by other tissues, do not form stable contacts with other cells, are embedded within the extracellular matrix with which their entire surface interacts, and have definite locomotory capabilities. Epithelial-mesenchymal transition (EMT) occurs when an epithelium loses its distinguishing characteristics, and acquires mesenchymal traits. It is recognised as an important and reversible mechanism of embryogenesis aimed at creating cells with the ability to move within the embryo, and implies the possibility of reforming new epithelia at distant sites through the reverse process, mesenchymal-epithelial transition (MET). Importantly, EMT-based phenotype changes are recapitulated in cancer progression and metastasis, thus indicating that EMT is a conserved mechanism in adult life and, furthermore, also suggesting that it may provide the possibility of expanding the differentiation potential of tumours. Indeed, in carcinomas, EMT may underlie the unexpected development of mesenchymal differentiation and give rise to tumours with mixed epithelial-mesenchymal phenotype, carcinosarcomas, malignant neoplasms known to be usually associated with high biological aggressiveness and poor response to therapy. Although these cancers have been known for a long time, the biological mechanisms underlying their histopathogenesis have not yet been definitively clarified, therefore requiring a conceptual placement in a modern framework. In this article an overview on EMT is provided, with brief presentations of single examples occurring in embryogenesis, the involvement of EMT in cancer progression is concisely illustrated and, finally, the proposition that carcinosarcoma develops through an EMT-based mechanism is discussed, refuting the two alternative mechanisms that have been proposed, the collision theory and the combination theory.