Reassessing Epithelial to Mesenchymal Transition as a Prerequisite for Carcinoma Invasion and Metastasis

Abstract

For most carcinomas, progression toward malignancy is accompanied by loss of epithelial differentiation and a shift towards a mesenchymal phenotype. This process, referred to as epithelial to mesenchymal transition (EMT), exacerbates motility and invasiveness of many cell types and is often considered a prerequisite for tumor infiltration and metastasis. However, there are numerous examples of advanced carcinomas that adopt some mesenchymal features, yet retain characteristics of well-differentiated epithelial cells. We provide a review of these reports and describe mechanisms to explain the morphologic and molecular heterogeneity and plasticity of malignant carcinoma cells, including incomplete EMT, reversion to an epithelial phenotype, and collective migration. We suggest that these mechanisms can manifest in a series of independent and reversible steps and that EMT represents just one mechanism in the global metastatic carcinoma development process. (Cancer Res 2006; 66(17): 8319-26)

Classification of epithelial–mesenchymal transition phenotypes in esophageal squamous cell carcinoma is strongly associated with patient prognosis

“…3,4 Our work demonstrated that the loss of E-cadherin itself, without a mesenchymal phenotype, may not be associated with invasive behavior, whereas tumors with a mesenchymal phenotype, regardless of E-cadherin expression, showed aggressive behavior in esophageal squamous cell carcinoma. Recently, Uchikado et al 21 reported that the patients with esophageal squamous cell carcinoma who were positive for Slug expression had deeper tumor invasion and worse prognosis in the E-cadherin preserved group.…”

“…In addition, because of the dynamic and reversible nature of epithelial-mesenchymal transition, numerous advanced carcinomas that adopt some mesenchymal features retain the characteristics of well-differentiated epithelial cells. 3,4 In vivo, epithelial-mesenchymal transition phenotypes include the extremes, ranging from an epithelial phenotype to a complete mesenchymal phenotype with a variety of intermediate sub-phenotype combinations between these extremes. Examples of intermediate sub-phenotypes include the 'hybrid type' that is a mixed epithelial and mesenchymal phenotype and the 'null type' that can be defined as the loss of the epithelial phenotype without acquisition of mesenchymal phenotype.…”

Epithelial–mesenchymal transition in malignant mesothelioma

“…One of the most important arguments against the existence of epithelial-mesenchymal transition in human solid tumors is that it has not been identified in most cases. 40,41 This could be due to the clonal heterogeneity of epithelial-mesenchymal transition in primary tumors, that is, cells that have undergone …”

Oncogenic transformation of normal breast epithelial cells co-cultured with cancer cells

“…During EMT, epithelial cells lose the characteristics of epithelial cells (cell junctions, apical-basal polarity and contact inhibition) and gain a mesenchymal phenotype including enhanced invasiveness, increased cell-to-extracellular matrix contact and resistance to apoptosis [23]. In addition, epithelial cells reduce the expression of epithelial markers (epithelial keratins, E-cadherin and β-catenin) and upregulate mesenchymal markers (vimentin and fibronectin) [24,25].…”