Epithelial-mesenchymal transition, stemness, and carcinosarcoma generation

During epithelial-mesenchymal transition (EMT), epithelial cells dissociate from their neighbors and become able to move away from the parent epithelium while acquiring mesenchymal traits. EMT was originally described as a major event indispensable for embryonic morphogenesis; however, it has become increasingly accepted that this phenomenon can be recapitulated in various physiological and pathological contexts of adult life, including cancer invasion and metastasis. Epithelia undergoing EMT disrupt cell–cell adhesion, lose polarity, and remodel the cytoskeleton to become motile. However, this biological program is not limited to the acquisition of the migration capacity necessary to invade and metastasize, since EMT in malignancies is accompanied by complementary, noncanonical aspects, including the emergence of stemness, enhanced tumorigenicity, increased plasticity, acquisition of a greater capacity to adapt to varying microenvironments, and resistance to apoptosis and therapy. Enhanced stemness is of particular interest as it confers an expanded differentiation potential to tumors. In carcinomas, this could unexpectedly underlie the development of mesenchymal differentiation, thus giving rise to tumors with a dual component: carcinomatous and sarcomatous. Cancers with such a mixed phenotype have been known for a long time, are mostly called carcinosarcomas or sarcomatoid carcinomas, and are usually associated with advanced progression, biological aggressiveness, and poor response to therapy. Although it was previously hypothesized that in these tumors, carcinoma could transform into sarcoma, the biological mechanisms underlying this impressive phenomenon have not been elucidated, thus requiring conceptual placement in a modern biological framework. In this review, the basis of EMT and the associated emergence of stemness are briefly summarized, and the histopathogenesis of carcinosarcomas is addressed with specific reference to EMT-based mechanisms of development.