The Epithelial–Mesenchymal Transition in Cancer: Comparison
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Please note this is a comparison between Version 2 by Lindsay Dong and Version 1 by Monica Fedele.

The transition between epithelial and mesenchymal phenotype is emerging as a key determinant of tumor cell invasion and metastasis. It is a plastic process in which epithelial cells first acquire the ability to invade the extracellular matrix and migrate into the bloodstream via transdifferentiation into mesenchymal cells, a phenomenon known as epithelial–mesenchymal transition (EMT), and then reacquire the epithelial phenotype, the reverse process called mesenchymal–epithelial transition (MET), to colonize a new organ. During all metastatic stages, metabolic changes, which give cancer cells the ability to adapt to increased energy demand and to withstand a hostile new environment, are also important determinants of successful cancer progression.

  • pithelial–mesenchymal transition (EMT)
  • cancer
  • tumor progression

1. Introduction

The concept that epithelial cells can transform into mesenchyme has been known since the early 1980s [1]. Later, it was called epithelial–mesenchymal transition (EMT) to delineate its transient nature. In fact, the reverse process, called mesenchymal–epithelial transition (MET), is also possible, due to the high plasticity of the epithelial tissue that can transdifferentiate to a mesenchymal phenotype, partially or completely, and then return to the epithelial. During EMT, epithelial cells lose their junctions and baso-apical polarity, while they acquire a back-to-front polarity and the ability to migrate and invade surrounding tissues. Changes also occur in the cell shape due to cytoskeleton reorganization and new signaling programs with the acquisition of a spindle phenotype [2][3]. Different biological contexts contribute to the induction of such transformations. Depending on these, we can distinguish three types of EMT: type 1, which occurs during embryogenesis; type 2, which occurs during wound healing and fibrosis; type 3, which occurs in cancer and represents the first step toward its progression to the metastatic stage, due to the acquired ability to erode the extracellular matrix, migrate, and extravasate into the bloodstream [4]. An emerging concept is that a hybrid epithelial-mesenchymal state harbors a higher plasticity for metastasis [5][6].
EMT is associated with complex metabolic reprogramming, which supports the energy requirements of increased proliferation and/or motility, as well as the growth in a new hostile environment in the case of type 3 EMT. In fact, in all the phases of the metastatic process, the supply of nutrients can be limited, and cancer cells undergo various degrees of stress to which they adapt by modifying their metabolism, including the metabolism of glucose, lipids, amino acids (AA), and nucleotides. In fact, most cancer cells are more dependent on glycolysis than on mitochondrial oxidative phosphorylation (OXPHOS) for their energy production, even in the presence of oxygen, a phenomenon known as the Warburg effect [7]. This altered glucose metabolism, which enhances biosynthetic fluxes and antioxidant defense during rapid proliferation of cancer cells, is regulated by transcription factors (TFs) such as the hypoxia inducible factor 1 alpha (HIF-1α) that activates either glycolytic enzymes or glucose and lactate transporters while inhibiting OXPHOS [8][9]. Moreover, cancer cells enhance glutamine metabolism, pentose phosphate pathway, and the synthesis of fatty acids (FAs) and cholesterol. EMT-TFs can induce such metabolic changes. In addition, it has been shown that mutations in metabolic genes, can activate EMT, supporting the idea that EMT and metabolism are closely interrelated and that both are necessary for the complete progression of the tumor to the metastatic stage [10].

2. The Epithelial–Mesenchymal Transition in Cancer

2.1. Cellular and Molecular Changes

Epithelial cells are characterized by apical-basal polarity and the presence of tight junctions, adherent junctions, and desmosomes that allow the formation of layers that are positioned on the basement membrane through hemidesmosomes and constitute the epithelia, i.e., a permeable barrier that covers tissues and organs. Activation of EMT in cancer, as in other physio-pathological situations, entails loss of cell polarity, disruption of cell–cell junctions, and degradation of basement membrane resulting in cells that acquire mesenchymal characteristics with front–rear polarity, a reorganized cytoskeleton characterized by actin stress fibers, increased cell protrusions and motility, and, in addition, the ability to degrade extracellular matrix (ECM) enabling cells to invade [3][11]. These morphological alterations are the result of changes in gene expression. Typical changes that characterize the EMT and lead to the loss of the epithelial barrier function are the downregulation of E-cadherin together with other proteins that cause the destabilization and dissolution of the different type of epithelial junctions. These changes are accompanied by the expression of proteins promoting mesenchymal adhesion such as N-cadherin, vimentin, fibronectin, integrin α5β1, and proteases such as MMP2 and MMP9 that alter cell adhesion, cytoskeleton, cell polarity, and the ECM.

2.2. EMT Transcription Factors

Changes of gene expression occurring during EMT are orchestrated by master regulators, i.e., TFs that, in addition to regulate each other, coordinate a cascade of events leading to the repression of epithelial genes and the induction of mesenchymal genes [3]. These EMT-TFs include SNAIL (SNAIL1 and SNAIL2/SLUG), TWIST (TWIST1 and TWIST2), and zinc-finger E-box-binding (ZEB). SNAIL1 represses epithelial gene expression by binding to the E-box DNA sequences, cis-elements present in several promoter proximal regions of epithelial specific genes. For example, it binds to the E-box located in the regulatory regions of the E-cadherin gene and recruits the polycomb repressive complex 2 (PRC2) that operates post-translational modifications on histones resulting in repression of E-cadherin expression [12][13][14]. In addition, SNAIL1 activates the expression of genes that contribute to the mesenchymal phenotype [3]. Similar to SNAIL1, the basic helix-loop-helix (bHLH) transcription factor TWIST downregulates the expression of epithelial specific genes and activates the expression of mesenchymal genes; it represses E-cadherin and induces N-cadherin with mechanisms different from SNAIL1 through the recruitment of the SET8 methyltransferase [15]. ZEB1 and ZEB2 can also bind E-boxes repressing or activating transcription [3], but the co-factors recruited by ZEB are different from those used by SNAIL and TWIST. They include the CTBP repressor or the chromatin SWI/SNF remodeling complex member BRG1 [16], while transcriptional activation is often mediated by the co-activators p300/CBP-associated factors PCAF and p300 [17]. In conclusion, SNAIL, TWIST, and ZEB, by binding to the E-boxes present in several regulatory regions of epithelial and mesenchymal genes, can coordinately regulate the expression of genes that define the epithelial or mesenchymal phenotype.
Among the TFs involved in EMT, we should also mention the architectural TFs that belong to the high mobility group A (HMGA) family. In fact, increasing evidence, including some from our laboratories, have shown a pivotal role of HMGA in inducing stem-like state and metastatic progression through the activation of EMT-TFs and enhancement of the transcription of EMT-related genes [18][19][20][21][22][23]. In basal-like breast cancer (BLBC), for example, HMGA1 promotes migration and invasion in vitro as well as metastases formation in vivo, by regulating genes linked to the Wnt/β-catenin, Notch, and Pin1/mutant p53 signaling pathways [18]. Similarly, in colorectal cancer, HMGA1 promotes EMT and metastases by positively regulating Wnt/β-catenin signaling [23][24]. HMGA2, instead, is induced by the TGFβ signaling pathway during EMT, regulating the transcription of the EMT-TFs SNAIL, SLUG, and TWIST in the NMuMG cellular model [20].

2.3. Pathways Regulating EMT

How is the EMT process triggered? The growth of the primary tumor modifies the ECM and creates a tumor microenvironment (TME) in which there are stromal cells, such as cancer-associated fibroblasts (CAFs), and inflammatory cells (T-lymphocytes, macrophages, and myeloid-derived suppressor cells) that secrete a vast array of chemokines, cytokines, and growth factors that strongly influence cancer cells. Specific signals present in this milieu activate pathways that induce EMT in cancer cells by the activation of EMT-TFs. A central role is played by TGFβ, Wnt, Notch, and growth factor receptors. The TGFβ family (three TGFβ isoforms, two activins, and many bone morphogenetic proteins) has a prominent role in EMT; the binding to the TGFβ family receptors leads to receptor phosphorylation and activation of the SMAD complexes that translocate to the nucleus and bind TFs regulating the expression of a set of genes including those coding for EMT-TFs. The Wnt signaling pathway has a crucial role in the embryonic development of all animal species, in the regeneration of tissues in adult organisms, and in cancer [25]. The canonical Wnt pathway is activated upon binding of Wnt ligands to the Frizzled family of membrane receptors, leading to the release and stabilization of β-catenin from the GSK3β–AXIN–APC complex. β-catenin, then, moves to the nucleus and becomes part of a transcriptional complex embedding TCF (T cell factor) and LEF (lymphoid enhancer-binding factor) to promote a gene expression program, which includes the activation of EMT-TFs [26]. The Notch pathway is activated upon binding of the Delta-like or Jagged family of ligands to the four different isoforms of the Notch receptor (Notch1-4). This binding triggers a series of proteolytic cleavage events that culminate in the release of the active, intracellular fragment of the Notch receptor (Notch-ICD), that, with a direct route from the membrane to the nucleus, functions as a transcriptional co-activator in association with different binding partners and TFs [27]. Several growth factors, such as epidermal growth factor (EGF), fibroblast growth factor (FGF), insulin growth factor (IGF), hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF) act through their cognate tyrosine receptor kinases. The binding triggers receptor dimerization followed by the stimulation of the kinase activity that phosphorylate the receptor and leads to the activation of the PI3K/AKT, ERK/MAPK, p38 MAPK, and JNK pathways, promoting cell growth and proliferation, as well as cell migration and motility via induction of EMT [11][28]. Inflammation and hypoxia conditions that are present in the TME can activate EMT as well. Several cytokines trigger the phosphorylation and activation of Janus kinases (JAKs) and signal transducer and activator of transcription proteins (STATs) that, following dimerization, foster the transcription of genes encoding EMT-TFs. Hypoxia can promote EMT through HIF1α, which activates the expression of the EMT-TFs TWIST and SNAIL1 [3][29][30]. Evidence coming from in vitro cell cultures and in vivo models suggest the presence of signaling cooperation and the convergence of these pathways on common targets during EMT. Functional crosstalk among the different pathways have been reported and include, for example, the cooperation between the TGFβ pathway with FGF-activated growth factor receptors [31], and the crosstalk of TGFβ with Wnt and Notch signaling achieved through SMAD complexes [3][11].

2.4. EMT, Chemoresistance, and Cancer Stem Cells

The EMT program is a highly dynamic process. Cancer cells that enter in the EMT process usually progress only partially toward the mesenchymal state. This means that cancer cells do not necessarily complete the process toward a fully mesenchymal state and that not all the cells within a tumor will progress to the same “partial” state, i.e., there are cancer cells within the same tumor that reside at the same time in a different state of this transition process, and this contributes to intra-tumor heterogeneity [32]. Epithelial cells that have acquired enough mesenchymal characteristics and initiate to disseminate will begin to produce factors, for example, TGFβ, creating an autocrine signaling loop that reinforces the mesenchymal state of the cells, even if, moving away from the primary tumor cells, they are no longer exposed to the EMT-inducing signals present in the TME [33]. During the metastatic process, cells that have acquired mesenchymal traits leave the primary tumor site, invade the bloodstream, and arrive at the metastatic site where they re-epithelize. Therefore, it appears that in this reverse process of MET their partial mesenchymal state endow them with a phenotypic plasticity necessary for successful metastasis formation [32][34]. It is noteworthy that the experimental activation of EMT confers many characteristics of cancer stem cells (CSCs) to carcinoma cells [35][36]. CSCs represent a small subgroup of cells in the tumor bulk with stem-like features, acknowledged to be responsible of tumor onset, maintenance, and relapse after therapy. Considering their ability to seed new tumors, it is possible that the EMT program activation is necessary not only for the physical dissemination of carcinoma cells to distant tissues, but also for entrance into the CSC state that enables the disseminated cells to serve as founders of metastatic colonies [35]. The identification of the EMT program as a source of cells with CSCs characteristics in combination with the notion that CSCs are more resistant to conventional chemotherapy and radiotherapy suggest the involvement of the EMT process in therapeutic resistance. Increasing evidence supports this association, including a strong correlation between an EMT-associated gene expression signature and treatment resistance [37][38][39]. Due to their key role, CSCs constitute an election target for innovative anticancer therapies. Studies on the connections between EMT, CSCs, and therapeutic resistance are needed to develop new strategies for cancer treatment.

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