Epithelial–mesenchymal transition
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Epithelial-mesenchymal transition | |
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Details | |
Precursor | endoderm |
Identifiers | |
MeSH | D058750 |
Anatomical terminology |
The epithelial–mesenchymal transition (EMT) is a process by which
Introduction
Epithelial–mesenchymal transition was first recognized as a feature of embryogenesis by
Based on the biological context, EMT has been categorized into 3 types: developmental (Type I), fibrosis[6] and wound healing (Type II), and cancer (Type III).[7][8][9]
Inducers
Loss of
Several signaling pathways (
Wnt signaling pathway regulates EMT in gastrulation, cardiac valve formation and cancer.[30] Activation of Wnt pathway in breast cancer cells induces the EMT regulator SNAIL and upregulates the mesenchymal marker, vimentin. Also, active Wnt/beta-catenin pathway correlates with poor prognosis in breast cancer patients in the clinic. Similarly, TGF-β activates the expression of SNAIL and ZEB to regulate EMT in heart development, palatogenesis, and cancer. The breast cancer bone metastasis has activated TGF-β signaling, which contributes to the formation of these lesions.[31] However, on the other hand, p53, a well-known tumor suppressor, represses EMT by activating the expression of various microRNAs – miR-200 and miR-34 that inhibit the production of protein ZEB and SNAIL, and thus maintain the epithelial phenotype.[32]
In development and wound healing
After the initial stage of embryogenesis, the implantation of the embryo and the initiation of
In vertebrates,
During wound healing, keratinocytes at the border of the wound undergo EMT and undergo re-epithelialization or MET when the wound is closed. Snail2 expression at the migratory front influences this state, as its overexpression accelerates wound healing. Similarly, in each menstrual cycle, the ovarian surface epithelium undergoes EMT during post-ovulatory wound healing.[36]
In cancer progression and metastasis
Initiation of metastasis requires invasion, which is enabled by EMT.[37][38] Carcinoma cells in a primary tumor lose cell-cell adhesion mediated by E-cadherin repression and break through the basement membrane with increased invasive properties, and enter the bloodstream through intravasation. Later, when these circulating tumor cells (CTCs) exit the bloodstream to form micro-metastases, they undergo MET for clonal outgrowth at these metastatic sites. Thus, EMT and MET form the initiation and completion of the invasion-metastasis cascade.[39] At this new metastatic site, the tumor may undergo other processes to optimize growth. For example, EMT has been associated with PD-L1 expression, particularly in lung cancer. Increased levels of PD-L1 suppresses the immune system which allows the cancer to spread more easily. [40]
EMT confers resistance to oncogene-induced premature senescence. Twist1 and Twist2, as well as ZEB1 protects human cells and mouse embryonic fibroblasts from senescence. Similarly, TGF-β can promote tumor invasion and evasion of immune surveillance at advanced stages. When TGF-β acts on activated Ras-expressing mammary epithelial cells, EMT is favored and apoptosis is inhibited.[41] This effect can be reversed by inducers of epithelial differentiation, such as GATA-3.[42]
EMT has been shown to be induced by
EMT has been indicated to be involved in acquiring drug resistance. Gain of EMT markers was found to be associated with the resistance of ovarian carcinoma epithelial cell lines to paclitaxel. Similarly, SNAIL also confers resistance to paclitaxel, adriamycin and radiotherapy by inhibiting p53-mediated apoptosis.[45] Furthermore, inflammation, that has been associated with the progression of cancer and fibrosis, was recently shown to be related to cancer through inflammation-induced EMT.[46] Consequently, EMT enables cells to gain a migratory phenotype, as well as induce multiple immunosuppression, drug resistance, evasion of apoptosis mechanisms.
Some evidence suggests that cells that undergo EMT gain stem cell-like properties, thus giving rise to
However, recent studies have further shifted the primary effects of EMT away from invasion and metastasis, toward resistance to chemotherapeutic agents. Research on breast cancer and pancreatic cancer both demonstrated no difference in cells' metastatic potential upon acquisition of EMT.[49][50] These are in agreement with another study showing that the EMT transcription factor TWIST actually requires intact adherens junctions in order to mediate local invasion in breast cancer.[51] The effects of EMT and its relationship to invasion and metastasis may therefore be highly context specific.
In
Platelets in cancer EMT
To improve the chances for the development of a cancer metastasis, a cancer cell must avoid detection and targeting by the immune system once it enters the bloodstream. Activated platelets have the ability to bind glycoproteins and glycolipids (P-selectin ligands such as PSGL-1) on the surface of cancer cells to form a physical barrier that protects the cancer cell from natural killer cell-mediated lysis in the bloodstream.[65] Furthermore, activated platelets promote the adhesion of cancer cells to activated endothelial cells lining blood vessels using adhesion molecules present on platelets.[66][64] P-selectin ligands on the surface of cancer cells remain to be elucidated and may serve as potential biomarkers for disease progression in cancer.[64]
Therapeutics targeting cancer EMT
Many studies have proposed that induction of EMT is the primary mechanism by which epithelial cancer cells acquire malignant phenotypes that promote metastasis.[67] Drug development targeting the activation of EMT in cancer cells has thus become an aim of pharmaceutical companies.[68]
Small molecule inhibitors
Small molecules that are able to inhibit TGF-β induced EMT are under development.
Antagomirs and microRNA mimics have gained interest as a potential source of therapeutics to target EMT induced metastasis in cancer as well as treating many other diseases.[74] Antagomirs were first developed to target miR-122, a microRNA that was abundant and specific to the liver, and this discovery has led to the development of other antagomirs that can pair with specific microRNAs present in the tumor microenvironment or in the cancer cells.[75][73] A microRNA mimic to miR-655 was found to suppress EMT through the targeting of EMT inducing transcription factor ZEB1 and TGF-β receptor 2 in a pancreatic cancer cell line. Overexpression of the miR-655 mimic in the Panc1 cancer cell line upregulated the expression of E-cadherin and suppressed the migration and invasion of mesenchymal-like cancer cells.[76] The use of microRNA mimics to suppress EMT has expanded to other cancer cell lines and holds potential for clinical drug development.[74] However, microRNA mimics and antagomirs suffer from a lack of stability in vivo and lack an accurate delivery system to target these molecules to the tumor cells or tissue for treatment.[77] Improvements to antagomir and microRNA mimic stability through chemical modifications such as locked nucleic acid (LNA) oligonucleotides or peptide nucleic acids (PNA) can prevent the fast clearing of these small molecules by RNases.[77][74] Delivery of antagomirs and microRNA mimics into cells by enclosing these molecules in liposome-nanoparticles has generated interest however liposome structures suffer from their own drawbacks that will need to be overcome for their effective use as a drug delivery mechanism.[77] These drawbacks of liposome-nanoparticles include nonspecific uptake by cells and induction of immune responses.[78] The role that microRNAs play in cancer development and metastasis is under much scientific investigation and it is yet to be demonstrated whether microRNA mimics or antagomirs may serve as standard clinical treatments to suppress EMT or oncogenic microRNAs in cancers.[74]
Generation of endocrine progenitor cells from pancreatic islets
Similar to generation of Cancer Stem Cells, EMT was demonstrated to generate endocrine progenitor cells from human
Since these studies in human islets lacked lineage-tracing analysis, these findings from irreversibly tagged beta cells in mice were extrapolated to human islets. Thus, using a dual lentiviral and genetic lineage tracing system to label β-cells, it was convincingly demonstrated that adult human islet β-cells undergo EMT and proliferate in vitro.[84][85] Also, these findings were confirmed in human fetal pancreatic insulin-producing cells, and the mesenchymal cells derived from pancreatic islets can undergo the reverse of EMT – MET – to generate islet-like cell aggregates.[86] Thus, the concept of generating progenitors from insulin-producing cells by EMT or generation of Cancer Stem Cells during EMT in cancer may have potential for replacement therapy in diabetes, and call for drugs targeting inhibition of EMT in cancer.[86]
Partial EMT or a hybrid E/M phenotype
Not all cells undergo a complete EMT, i.e. losing their cell-cell adhesion and gaining solitary migration characteristics. Instead, most cells undergo partial EMT, a state in which they retain some epithelial traits such as cell-cell adhesion or apico-basal polarity, and gain migratory traits, thus cells in this hybrid epithelial/mesenchymal (E/M) phenotype are endowed with special properties such as collective cell migration.[51][87][88][30][89][90][91][92] Single-cell tracking contributes to enabling the visualization of morphological transitions during EMT, the discernment of cell migration phenotypes, and the correlation of the heritability of these traits among sister cells.[93] Two mathematical models have been proposed, attempting to explain the emergence of this hybrid E/M phenotype,[89][91] and its highly likely that different cell lines adopt different hybrid state(s), as shown by experiments in MCF10A, HMLE and H1975 cell lines.[90][94] Although a hybrid E/M state has been referred to as 'metastable' or transient, recent experiments in H1975 cells suggest that this state can be stably maintained by cells.[95]
See also
- Collective cell migration
- Collective–amoeboid transition
- Mesenchymal-epithelial transition
- c-Met inhibitors
- Vasculogenic Mimicry
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