Epigenetic Regulation of Epithelial to Mesenchymal Transition in the Cancer Metastatic Cascade: Implications for Cancer Therapy

Abstract

Metastasis is the end stage of cancer progression and the direct cause of most cancer-related deaths. The spreading of cancer cells from the primary site to distant organs is a multistep process known as the metastatic cascade, including local invasion, intravasation, survival in the circulation, extravasation, and colonization. Each of these steps is driven by the acquisition of genetic and/or epigenetic alterations within cancer cells, leading to subsequent transformation of metastatic cells. Epithelial–mesenchymal transition (EMT), a cellular process mediating the conversion of cell from epithelial to mesenchymal phenotype, and its reverse transformation, termed mesenchymal–epithelial transition (MET), together endow metastatic cells with traits needed to generate overt metastases in different scenarios. The dynamic shift between these two phenotypes and their transitional state, termed partial EMT, emphasizes the plasticity of EMT. Recent advances attributed this plasticity to epigenetic regulation, which has implications for the therapeutic targeting of cancer metastasis. In this review, we will discuss the association between epigenetic events and the multifaceted nature of EMT, which may provide insights into the steps of the cancer metastatic cascade.

Integration of Epigenetic Mechanisms into Non-Genotoxic Carcinogenicity Hazard Assessment: Focus on DNA Methylation and Histone Modifications

“…The dysplastic stage (change in morphology, abnormal mitosis, disorganised cell proliferation with loss of cell polarity, cellular and/or structural atypia) may represent the decisive carcinogenic progression step. Progression across these histological stages requires molecular adaptations, pathway signaling, and epigenetic mechanisms conducive to cytoskeleton modifications, changes in cellto-cell adhesion, and interactions between the cells and the extracellular matrix [556,557]. These mechanisms involve various structures (e.g., intercellular desmosome, gap, tight, and adherens junctions; extracellular matrix hemidesmosomes and focal contact), interacting protein families (e.g., integrins, actins, connexins, claudins, occludin, catenins, cadherins, fibronectin), and signaling pathways (TGFβ-SMAD3, WNT-β CATENIN, and NOTCH) inducing the expression of transcription factors (e.g., ZEB1, ZEB2, SNAIL, SLUG, TWIST) to downregulate or upregulate the expression of epithelial (e.g., E-CADHERIN, CLAUDINS, OCCLUDIN), and mesenchymal markers (e.g., N-CADHERIN, VIMENTIN, FIBRONECTIN).…”

“…These mechanisms involve various structures (e.g., intercellular desmosome, gap, tight, and adherens junctions; extracellular matrix hemidesmosomes and focal contact), interacting protein families (e.g., integrins, actins, connexins, claudins, occludin, catenins, cadherins, fibronectin), and signaling pathways (TGFβ-SMAD3, WNT-β CATENIN, and NOTCH) inducing the expression of transcription factors (e.g., ZEB1, ZEB2, SNAIL, SLUG, TWIST) to downregulate or upregulate the expression of epithelial (e.g., E-CADHERIN, CLAUDINS, OCCLUDIN), and mesenchymal markers (e.g., N-CADHERIN, VIMENTIN, FIBRONECTIN). There is an increasing number of studies on different cancers highlighting epigenetic modifications and changes in gene expression that have already occurred by the stage of dysplasia [558][559][560][561][562], and later during EMT [557]. Therefore, monitoring epigenetic deregulation may assist in better predicting the potential adversity of cellular transformation processes.…”

Expression and Clinical Utility of Transcription Factors Involved in Epithelial–Mesenchymal Transition during Thyroid Cancer Progression

“…Epithelial–mesenchymal transition (EMT) indicates a physiological path by means of which a well-polarized epithelial cell gradually loses its cell–cell contacts and acquires the morphological and functional capabilities of a mesenchymal cell [ 1 , 2 ]. Three different types of EMT have been described: type I takes place during the embryogenesis and morphogenesis of organs, type II occurs during tissue regeneration, as well as the fibrotic process, and type III is responsible for cancer metastasis [ 2 , 3 , 4 ]. It is worth noting that the conversion from an epithelial to a mesenchymal cell embraces a variety of cellular modifications, not all of which are realized during the EMT.…”

“…It is worth noting that the conversion from an epithelial to a mesenchymal cell embraces a variety of cellular modifications, not all of which are realized during the EMT. Actually, regarding type III EMT, there is evidence indicating that tumor cells infrequently undertake a complete EMT, whereby they acquire some mesenchymal characteristics while conserving epithelial features [ 2 , 3 , 4 , 5 , 6 ]. The ability of a cancer cell to acquire a mixed epithelial–mesenchymal phenotype, together with its capability to move along the epithelial–mesenchymal spectrum, is now recognized as the epithelial–mesenchymal plasticity (EMP) [ 7 ].…”

“…These include: (i) cellular and humoral components of inflammation, which have been shown to be potent inducers of EMT in tumor cells [ 9 , 10 ]; (ii) hypoxia and the induction of hypoxia-inducible factors (HIFs) [ 11 , 12 ]; and extracellular matrix components, such as laminins, fibronectin, and collagens [ 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. In addition, Wnt by binding to its frizzled receptor, along with a number of growth factors, including the epidermal growth factor (EGF), the fibroblast growth factor (FGF), the insulin growth factor (IGF), the platelet-derived growth factor (PDGF), and the transforming growth factor β (TGFβ), by binding with their cognate tyrosine kinase receptors, have been shown to modulate the EMT process [ 3 , 4 ]. All the above-mentioned factors have been shown to upregulate the expression of the so-called EMT transcription factors (EMT-TFs) of the Zeb, Snail (also known as Slug), and Twist families [ 3 ].…”