EPITHELIAL-MESENCHYMAL TRANSITIONS IN CANCER PROGRESSION

Epithelial cells are the most important cell type in the development o f human malignancies. More than 90% of all malignant tumors are carcin omas, and thus of epithelial origin. Aberrant growth and the ability t o invade the underlying tissues are intrinsic properties of the fatall y altered cells. Multiple genetic alterations that can influence growt h and genetic stability of the carcinoma cells have been characterised during tumor progression. Loss of epithelial morphology and the acqui sition of mesenchymal characteristics are typical for carcinoma cells late in tumor progression and correlate with metastatic potential. In vitro, epithelial-mesenchymal transitions can be induced by interferen ce with the integrity of the adherens junction, by signalling via tyro sine kinases, and by oncogene expression. In carcinoma cells, loss or downregulation of E-cadherin expression are frequently observed in car cinomas, and correlate with the malignancy of the tumor. In general, t his change in expression is regulated at the transcriptional level. Ho wever, tumor types or cell lines exist which show mesenchymal characte ristics but nevertheless express E-cadherin protein or mRNA. A more-de tailed analysis demonstrated that other mechanisms that interfere with E-cadherin-mediated cell adhesion can be operative. Mutations in the E-cadherin gene and loss or mutation of the second, intact copy as wel l as mutation in the catenin genes, which encode proteins that interac t with the cytoplasmic portion of E-cadherin, can be observed. In addi tion, transient or unregulated phosphorylation by receptor tyrosine ki nases or oncogenic tyrosine kinases, respectively, can interfere with the epithelial morphology and induce a mesenchymal conversion. Since t yrosine phosphorylation of beta-catenin correlates with the epithelial -mesenchymal transition that is observed, E-cadherin-mediated cell adh esion might be modulated by such a mechanism. Interestingly, the same molecules implicated in the control of malignant properties turn out t o play fundamental roles in the control of normal epithelial growth, d ifferentiation and morphogenesis.