Epithelial–mesenchymal transition
[18][19][20] Slug triggers the steps of desmosomal disruption, cell spreading, and partial separation at cell–cell borders, which comprise the first and necessary phase of the EMT process.
[22] Snail and Slug are known to regulate the expression of p63 isoforms, another transcription factor that is required for proper development of epithelial structures.
[25] The phosphatidylinositol 3' kinase (PI3K)/AKT axis, Hedgehog signaling pathway, nuclear factor-kappaB and Activating Transcription Factor 2 have also been implicated to be involved in EMT.
[30] Activation of Wnt pathway in breast cancer cells induces the EMT regulator SNAIL and upregulates the mesenchymal marker, vimentin.
[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.
The trophoectoderm cells undergo EMT to facilitate the invasion of endometrium and appropriate placenta placement, thus enabling nutrient and gas exchange to the embryo.
Later in embryogenesis, during gastrulation, EMT allows the cells to ingress in a specific area of the embryo – the primitive streak in amniotes, and the ventral furrow in Drosophila.
Mesenchymal cells from the primitive streak participate also in the formation of many epithelial mesodermal organs, such as notochord as well as somites, through the reverse of EMT, i.e. mesenchymal–epithelial transition.
[34] EMT takes place during the construction of the vertebral column out of the extracellular matrix, which is to be synthesized by fibroblasts and osteoblasts that encircle the neural tube.
[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.
[14] Activation of EMT programs via inhibition of the androgen axis provides a mechanism by which tumor cells can adapt to promote disease recurrence and progression.
Brachyury, Axl, MEK, and Aurora kinase A are molecular drivers of these programs, and inhibitors are currently in clinical trials to determine therapeutic applications.
[46] Consequently, EMT enables cells to gain a migratory phenotype, as well as induce multiple immunosuppression, drug resistance, evasion of apoptosis mechanisms.
[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.
In urothelial carcinoma cell lines overexpression of HDAC5 inhibits long-term proliferation but can promote epithelial-to-mesenchymal transition (EMT).
When platelets are recruited to a site in the blood vessel they can release a variety of growth factors (PDGF,[53] VEGF,[54] Angiopoietin-1[55]) and cytokines including the EMT inducer TGF-β.
[64] This may be in part due to the redundancy of prothrombotic pathways which would require the use of multiple therapeutic approaches in order to prevent pro-metastatic events via EMT induction in cancer cells by activated platelets.
[64] Many studies have proposed that induction of EMT is the primary mechanism by which epithelial cancer cells acquire malignant phenotypes that promote metastasis.
[68] Silmitasertib (CX-4945) is a small molecule inhibitor of protein kinase CK2, which has been supported to be linked with TGF-β induced EMT, and is currently in clinical trials for cholangiocarcinoma (bile duct cancer), as well as in preclinical development for hematological and lymphoid malignancies.
[72] Galunisertib is currently being developed by Lilly Oncology and is in phase I/II clinical trials for hepatocellular carcinoma, unresectable pancreatic cancer, and malignant glioma.
[73] Small molecule inhibitors of EMT are suggested to not act as a replacement for traditional chemotherapeutic agents but are likely to display the greatest efficacy in treating cancers when used in conjunction with them.
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.
[76] The use of microRNA mimics to suppress EMT has expanded to other cancer cell lines and holds potential for clinical drug development.
[80] However, later, another set of experiments suggested that labelled β-cells de-differentiate to a mesenchymal-like phenotype in vitro, but fail to proliferate; thus initiating a debate in 2007.
