Abstract
Transitions between epithelial and mesenchymal phenotypes – the epithelial to mesenchymal transition (EMT) and its reverse the mesenchymal to epithelial transition (MET) – are hallmarks of cancer metastasis. While transitioning between the epithelial and mesenchymal phenotypes, cells can also attain a hybrid epithelial/mesenchymal (E/M) (i.e., partial or intermediate EMT) phenotype. Cells in this phenotype have mixed epithelial (e.g., adhesion) and mesenchymal (e.g., migration) properties, thereby allowing them to move collectively as clusters. If these clusters reach the bloodstream intact, they can give rise to clusters of circulating tumor cells (CTCs), as have often been seen experimentally. Here, we review the operating principles of the core regulatory network for EMT/MET that acts as a “three-way” switch giving rise to three distinct phenotypes – E, M and hybrid E/M – and present a theoretical framework that can elucidate the role of many other players in regulating epithelial plasticity. Furthermore, we highlight recent studies on partial EMT and its association with drug resistance and tumor-initiating potential; and discuss how cell–cell communication between cells in a partial EMT phenotype can enable the formation of clusters of CTCs. These clusters can be more apoptosis-resistant and have more tumor-initiating potential than singly moving CTCs with a wholly mesenchymal (complete EMT) phenotype. Also, more such clusters can be formed under inflammatory conditions that are often generated by various therapies. Finally, we discuss the multiple advantages that the partial EMT or hybrid E/M phenotype have as compared to a complete EMT phenotype and argue that these collectively migrating cells are the primary “bad actors” of metastasis.
Highlights
Despite remarkable progress in charting the hallmarks of cancer, understanding the cell-fate decisions during tumor initiation, progression, dormancy, and relapse is a major challenge in modern oncology [1]
epithelial to mesenchymal transition (EMT) marks the first step of “invasionmetastasis cascade” where epithelial cells of the primary tumor lose their cell–cell adhesion and apico-basal polarity, and gain the ability to migrate individually and invade basement membrane and blood vessels. These cells stay in the bloodstream as circulating tumor cells (CTCs), until they exit at some distant organs to seed micrometastases
Cells expressing endogenous levels of OVOL can maintain their partial EMT phenotype, knockdown of OVOL leads to complete EMT and overexpression of OVOL induces the reversal of EMT – a mesenchymal epithelial transition (MET) [48, 49]. These experimental findings can be unified via our theoretical framework by coupling OVOL to the core EMT network, where we show that OVOL can both act as a “critical molecular brake on EMT” preventing the cells “that have gained partial plasticity” to undergo a complete EMT, and a driver of MET when overexpressed [48, 53] (Figure 5B)
Summary
While transitioning between the epithelial and mesenchymal phenotypes, cells can attain a hybrid epithelial/mesenchymal (E/M) (i.e., partial or intermediate EMT) phenotype. Cells in this phenotype have mixed epithelial (e.g., adhesion) and mesenchymal (e.g., migration) properties, thereby allowing them to move collectively as clusters. If these clusters reach the bloodstream intact, they can give rise to clusters of circulating tumor cells (CTCs), as have often been seen experimentally.
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