Epithelial-mesenchymal transition: a cancer researcher's conceptual friend and foe

Abstract

Epithelial-mesenchymal transition (EMT) describes a series of rapid changes in cellular phenotype. During EMT, epithelial cells down-modulate cell-cell adhesion structures, alter their polarity, reorganize their cytoskeleton, and become isolated, motile, and resistant to anoikis. The term EMT is often applied to distinct biological events as if it were a single conserved process, but in fact EMT-related processes can vary in intensity from a transient loss of cell polarity to the total cellular reprogramming, as found by transcriptional analysis. Based on clinical observations, it is more appropriate in most cases to describe the emergence of an EMT-like phenotype during tumor progression. Although EMT implies complete trans-differentiation, EMT-like emphasizes the intermediary phenotype associated with tumor cell renewal and adaptation to specific microenvironments. Here, we categorize the various EMT-like phenotypes found in human carcinomas that, depending on the tumor type, may or not represent analogous stages in tumor progression. We based these categories on the global tumor phenotype. The tumor microenvironment, which is associated with stromal reactions, hypoxia, paucity of nutrients, impaired differentiation, and activation of various EMT-associated pathways, modulates overall tumor phenotype and leads to tumor heterogeneity.

Figure 1

EMT, EMT-like phenotype, and tumor progression in breast carcinoma. An EMT-like phenotype can be interpreted in several ways. A: It can result from the transformation of normally differentiated epithelial cells followed by an EMT process, generating tumor cells with poorly differentiated features. Conversely, an EMT-like phenotype can result from a lack of differentiation by stem/progenitor cells, resulting in cells expressing a partially differentiated phenotype: P1 (most tumor cells characterized by loss of cell polarity but retaining cohesive cell-cell contacts and keratin expression), P2 (loss of cell-cell adhesion in most tumor cells, still expressing keratins), or P3 (loss of keratin and substantial expression of vimentin). B: These early progenitors express a metastable phenotype but do not reach an epithelial differentiated state. In both situations, the tumor microenvironment controls cell phenotype through several tumor-specific pathways, which are currently under investigation.

Figure 2

Tumor-specific changes converge in inducing EMT phenotype. Most pathways controlling EMT-like behavior in cancer cells can be linked to specific environmental changes that occur during tumor growth and progression. Tumor cells adapt to an impoverished and hypoxic environment by activating alternative pathways to adjust to hypoxia and by adopting hypermetabolism. Tumor cells typically express a partially differentiated phenotype, suggesting impairment in differentiation pathways. Finally, another specific feature of the tumor microenvironment is the stromal reaction. Stromal and inflammatory cells play a major role in secreting activating factors and controlling tumor cell motility.