Abstract
Metastasis of tumor cells from primary sites of malignancy to neighboring stromal tissue or distant localities entails in several instances, but not in every case, the epithelial-mesenchymal transition (EMT). EMT weakens the strong adhesion forces between differentiated epithelial cells so that carcinoma cells can achieve solitary or collective motility, which makes the EMT an intuitive mechanism for the initiation of tumor metastasis. EMT initiates after primary oncogenic events lead to secondary secretion of cytokines. The interaction between tumor-secreted cytokines and oncogenic stimuli facilitates EMT progression. A classic case of this mechanism is the cooperation between oncogenic Ras and the transforming growth factor β (TGFβ). The power of TGFβ to mediate EMT during metastasis depends on versatile signaling crosstalk and on the regulation of successive waves of expression of many other cytokines and the progressive remodeling of the extracellular matrix that facilitates motility through basement membranes. Since metastasis involves many organs in the body, whereas EMT affects carcinoma cell differentiation locally, it has frequently been debated whether EMT truly contributes to metastasis. Despite controversies, studies of circulating tumor cells, studies of acquired chemoresistance by metastatic cells, and several (but not all) metastatic animal models, support a link between EMT and metastasis, with TGFβ, often being a common denominator in this link. This article aims at discussing mechanistic cases where TGFβ signaling and EMT facilitate tumor cell dissemination.
Highlights
Epithelial cells differentiate from stem cells in various tissues and retain the ability to change their differentiation into different lineages, including a transition towards the mesenchymal lineage, best known as the epithelial-mesenchymal transition (EMT; Figure 1) [1,2]
mesenchymal-epithelial transition (MET) is logically thought as a mere reversion of the EMT, the established concept of partial EMT together with the molecular complexity that governs the step-wise transitions in differentiation propose an complex mechanism of MET progression such as the one that initiates the EMT, which is worth elucidating in full detail
More important from the point of view of cancer research remains the clarification and detailed elucidation of the circumstances under which the EMT contributes to the early stages of metastatic dissemination of malignant cells
Summary
Epithelial cells differentiate from stem cells in various tissues and retain the ability to change their differentiation into different lineages, including a transition towards the mesenchymal lineage, best known as the epithelial-mesenchymal transition (EMT; Figure 1) [1,2]. An important aspect in the understanding of EMT has been the transitory nature of this process, which has been termed plasticity, and naturally implies the ability of mesenchymal cells to undergo an inverse process, the mesenchymal-epithelial transition (MET; Figure 1) [1,2,3]. The families of EMT-TFs include the proteins known as Snail, Snail2/Slug, zinc finger E-box binding homeobox 1 and 2 (ZEB1 and ZEB2), and members of the Twist family [1,6] These transcription factors have distinct and characteristic DNA-binding or transactivation domains, e.g., zinc-fingers for Snail, Snail, both zinc finger and homeodomain for ZEB1/2 and a basic helix loop helix for Twist, acting as DNA-binding domains, yet they seem to regulate a similar set of genes and clearly contribute to the same overall phenotypic process, the EMT
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