Impact of epithelial-mesenchymal transition on the regulation of cell motility and colon cancer progression.

摘要

The epithelial-mesenchymal transition (EMT) has been employed to examine the mechanisms of and identify markers intrinsic to colon carcinoma progression. The EMT, which is essential for development, involves the down-regulation of intercellular adhesion, loss of apical-basal polarity, and the acquisition of migratory and invasive behavior.; Utilizing an in vitro organoid model of inducible EMT, it was discovered that p120ctn, a cadherin-interacting protein that can enhance cell motility, is displaced from the cell periphery and delocalizes to the cytoplasm following loss of E-cadherin. Analysis of tissue microarrays (TMA's) containing 557 primary colorectal tumors confirmed that this altered localization is recapitulated in vivo and significantly correlates with disease progression as assessed by reduced patient survival, increased tumor stage, and enhanced metastasis. This EMT involves suppression of RhoA GTPase activity, an event that is mediated by p120ctn. It also involves expression and activation of RhoC, a closely related protein associated with metastasic carcinoma. The expression of RhoC was validated in colorectal tumors, and it correlated significantly with reduced patient survival. The reciprocal regulation of these two Rho GTPases serves to enhance post-EMT cell migration.; The EMT also influences the ability of cells to interact with extracellular matrix. We observed that alphavbeta6 integrin, a receptor for fibronectin and tenascin that is expressed in the developing colon but not later, is expressed in an EMT-dependent manner and is prognostic for poor outcome when analyzed on TMA's. This integrin is necessary for colon carcinoma cells to migrate on fibronectin, and it stimulates the activation of latent TGF-beta, which could enhance the EMT itself. One key finding is the identification of Ets-1 as a regulator of RhoC and beta6 integrin expression, underscoring a potential role for this transcription factor in EMT and cancer progression. Together, this dissertation demonstrates the utility of the EMT as a model for studying colon cancer progression as related to cell migration and, importantly, for the identification of markers of aggressive carcinomas. The results obtained also reveal that the 'EMT' of colon carcinoma may involve aspects of both mesenchymal transition (E-cadherin loss) and epithelial dedifferentiation (beta6 integrin expression).