AN OVERVIEW OF EPITHELIOMESENCHYMAL TRANSFORMATION

Epithelium is the tissue phenotype of early embryos and primitive adul ts of the chordate phylum. A second tissue type, however, is produced by epithelial-mesenchymal transformation (EMT) in higher chordates, su ch as vertebrata. Mesenchymal cells have the ability, which true epith elia do not, to invade and migrate through the extracellular matrix (E CM) to create dramatic cell transpositions. The first-formed or primar y mesenchymal cells in amniote vertebrates migrate from the primitive streak to differentiate into the mesodermal and endodermal epithelia. Definitive mesenchyme with connective tissue and muscle potentials ari ses from the epithelial mesoderm at about the same time as the neural crest mesenchyme forms from the ectoderm. Later on in embryogenesis. E MT is used to remodel unwanted epithelia, such as that of the palate m edial edges. We discuss the mechanisms by which epithelial cells trans form into mesenchyme and vice versa. On the one hand, cells activate p utative mesenchymal master genes, turn off epithelial genes, and acqui re motility machinery that allows them to interact in 3 dimensions (3D ) with ECM via actin cortex while sliding their endoplasm into their n ew front ends. On the other hand, primary mesenchymal cells can reacti vate epithelial regulatory genes, such as E-cadherin, turn off the mot ility machinery for invading ECM, and reexpress apical-basal polarity. We review the genes, such as FSP1, src, ras, and fos, that are activa ted in cells transforming to mesenchyme and the genes their neighbors activate to induce EMT, such as those for TGF beta, NT-3, and sonic he dgehog. Suspension in 3D collagen gels can induce adult epithelium to undergo EMT; alpha 5 beta 1 integrin is activated on surfaces in conta ct with collagen, including apical surfaces that do not normally expre ss integrins. In vivo, it is possible that pathological manipulations of a cell's environment likewise induce EMT. Of the examples we give, the creation of invasive metastatic carcinoma cells by EMT is the most fearful. Interestingly, transfection of either metastatic cells or no rmal embryonic fibroblasts with the E-cadherin gene converts them to t he epithelial phenotype. It may be possible in the future to manipulat e the tissue phenotype of diseased cells to the advantage of the anima l.