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Understanding EMT and MET in Cancer: Drivers of Tumor Progression and Metastasis

Cancer metastasis, or the spread of cancer cells from the primary tumor to distant sites, is a leading cause of cancer-related deaths. A significant part of this process is regulated by two crucial cellular transitions: epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET). EMT and MET enable cancer cells to become more invasive and adaptable, allowing them to navigate and colonize distant organs. Understanding these transitions is vital for developing therapies aimed at limiting metastatic spread.

What is EMT?

EMT is a biological process in which epithelial cells, which are typically organized, polarized, and adhere tightly to each other, lose these characteristics and acquire a mesenchymal phenotype. This shift enables cells to detach, become motile, and migrate.

The following features characterize EMT:

Loss of Cell Polarity and Adhesion: Epithelial cells naturally have polarity (distinct apical and basal surfaces) and form strong adhesive contacts via cell junctions, like E-cadherin. During EMT, cells downregulate E-cadherin, reducing adhesion and allowing cells to detach.
Acquisition of Mesenchymal Traits: Cells gain mesenchymal markers like N-cadherin and vimentin, which are associated with a more elongated, spindle-shaped morphology and an increased capacity for movement.
Increase in Migratory and Invasive Properties: These mesenchymal cells can degrade extracellular matrix components and invade surrounding tissues. This mobility allows cancer cells to enter the bloodstream, ultimately facilitating metastasis.

Mechanisms Driving EMT:

Transcriptional Factors (TFs): Key transcription factors like Snail, Slug, Twist, and Zeb1/Zeb2 are upregulated in EMT. They repress epithelial markers like E-cadherin and activate mesenchymal markers.
Signaling Pathways: Growth factors and signaling pathways (e.g., TGF-β, Wnt/β-catenin, and Notch) are crucial in triggering EMT. In the tumor microenvironment, TGF-β signaling, in particular, promotes EMT and can also create an immunosuppressive environment.
Epigenetic Modifications: Histone modification and microRNAs (miR-200 family) contribute to EMT by suppressing genes associated with epithelial characteristics and stabilizing the mesenchymal state.

What is MET?

MET is essentially the reverse process of EMT, where cells with a mesenchymal phenotype revert to an epithelial phenotype. In cancer, MET is hypothesized to play a role in the colonization of metastatic sites. After circulating tumor cells (CTCs) reach a new site, MET allows them to establish organized and proliferative colonies by re-acquiring epithelial characteristics like cell adhesion and polarity. This transition is essential for forming secondary tumors and contributes to the outgrowth of metastatic lesions.

Mechanisms of MET:

Suppression of EMT Transcription Factors: Downregulation of EMT-inducing transcription factors (Snail, Slug, etc.) and restoration of epithelial markers (such as E-cadherin) are key steps in MET.
Extrinsic Signals: The local microenvironment at the metastatic site, including factors secreted by stromal and immune cells, often supports MET to promote colonization. For example, the bone microenvironment provides signals that can induce MET in prostate cancer cells.

EMT, MET, and Cancer Stem Cells

EMT and MET are also closely associated with the plasticity of cancer stem cells (CSCs). EMT can induce a stem-like state in cancer cells, endowing them with properties such as self-renewal and resistance to therapies. This plasticity allows cancer cells to switch between different phenotypic states, adapting to environmental pressures. Importantly, this adaptability is a major obstacle in cancer treatment, as it enables tumors to resist chemotherapy and immune responses.

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