Epithelial-Mesenchymal Transition (EMT)
As previously mentioned, the epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells undergo transitional changes into a mobile mesenchymal cell . Depending on normal epithelial cell motility in an organism, this process lends to movement of cells known as migration if part of normal cell physiology or metastasis if aberrant. Underlying the mechanism of EMT are changes in expression of proteins that function in adhesion and cytoskeleton remodeling which enables cell movement.
Discovery of EMT
In 1960, Elizabeth Hays discovered EMT . At Harvard, Hays observed the migration of cells by observing the primitive streak of chick embryos. At the time, this migration was first believed to result from the transformation of cells. In fact, EMT once stood for “epithelial-mesenchymal transformation” . But Hay’s work revealed that the change in cells was reversible by discovering that migratory cells could become anchored and epithelial-like in a process she called "mesenchymal-epithelial transition (MET)" . As a result, her work furthered EMT and cancer by redefining the distinction between the terms “transformation” as seen in neoplasms and “transition” in migratory cells on the basis of whether it was possible to reversibly interconvert a state of a cell .
Three Types of EMT
At present, there are three types of EMT, which are grouped on the basis of their function . As you will see in this ebook, we will focus on Type III EMT.
Type I: Development – These EMT events function in embryogenesis, the process whereby a single fertilized egg can form into a multicellular embryo [4,3]. These EMT events enable cells to move to the right location to create the various germ layers and organs of the body. A well-known example of Type I EMT is gastrulation. This is the process where by movement of cells from a bilaminar embryo sets up the body plan of an embryo with three germ layers: ectoderm, mesoderm, and endoderm . These three tissues give rise to all of the different organs and tissues of the body. For example, the ectoderm gives rise to the skin and nervous system, the mesoderm to the musculature, bone and connective tissue, and the endoderm to the intestinal and respiratory epithelia.
Type II: Wound Healing – These EMT events function in tissue regeneration involved in wound healing . For example, as a hardworking student, it's quite likely you might have gotten a paper cut while flipping through your textbook. At the site of the paper cut, epithelial cells undergo EMT in order to move to the wound and regenerate new tissue to fill the gap. Stromal cells help mediate epithelial cell EMT in wound healing by secreting metalloproteinases, which promote the release of growth factors sequestered in the extracellular matrix . These growth factors promote EMT. However, this EMT is only transient. MET (the reverse process) will quickly settle in to re-anchor migratory epithelial cells to suture your cut .
Type III: Cancer – These EMT events function to allow benign cancers to metastasize . Changes in tumor cell genomes affecting cell adhesion and cytoskeleton reorganization enable a benign cancer cell to gain properties to move through the blood stream and invade surrounding tissue . Generally, metastasis is characterized in late stages of cancer disease. This is based on the standard Tumour, Lymph Node, Metastasis (TNM) Staging that is commonly used to characterize the severity of a cancer and determine patient outcomes . For the rest of this ebook, we will be diving further into Type III EMT.
Model for Type III EMT
Interestingly, a strong body of evidence has emerged suggesting a model that Type III EMT in metastatic cancers results from reactivation of genes silenced in normal somatic cells, but which were previously activated during embryogenesis and wound repair . Transcription factors such as TWIST, SNAIL, SLUG, and ZEb1 have been found to activate EMT in epithelial cells . This suggests a cancer cell does not need to acquire genetic mutations in order to become metastatic, but that reactivation of genes normally found and latent in the genome of a somatic cell is sufficient to induce metastasis .
Mechanism of EMT and the role of the microenvironment
The widely accepted heirarchal model conflicts with widespread metastasis of some cancers since only a small fraction of tumors comprise the CSCs and the probability of a metastatic CSC is low. This has caused some researchers to look for ways CSCs are able to metastasize and the discovery of EMT revertants that regain CSC-like properties before metastasizing. It is thought that the recruitment of specific stromal cells by the tumor causes the formation of a reactive microenvironment that releases factors enabling tumor cells to regain CSC phenotype and establish another tumor. This is suggested by evidence of an altered phenotype of tumor cells residing in this enviroenment and by the fact that observable metastasis does not match probability calculations that a CSC may become metastatic (6)
miRNA and EMT
Recently it has been discovered that miRNA plays an important role in the regulation of EMT. Of prominent interest is the miR-200 family of miRNA, which is a multi-member grouping whose actions are intimately linked with the regulation of EMT (8); an example is miR-200b, which targets the mRNA of BMI1 to reverse EMT and inhibit metastasis (8). Furthermore, miR-200b binds to the 3’ UTR of Zeb1, a protein that represses E-Cadherin, to downregulate its expression and aid in the maintenance of E-cadherin levels appropriate for an epithelial phenotype. Interestingly it seems that miRNA act in a further signal network, where miR21 has an E-box promoter element that can be bound by Zeb1 (9). Therefore, miRNA acts with a cascade effect on EMT; as miR200 is downregulated increased levels of Zeb1 not only repress E-cadherin to aid in EMT induction (8), but further the cascade to miR21 activation (9) and further accelerate the process. miRNA is quickly establishing itself as a major regulator in many cellular processes, where aberrant expression has been shown to induce EMT and metastasis progression.
1. Denoix, P. F. (1946). Enquête permanente dans les centres anticancéreux. Bull Inst Nat Hyg., 1, 70–75.
2. Elizabeth Hay. (2004). Journal of Cell Science, 117(20), 4617–4618. doi:10.1242/jcs.01391
3. Gilbert, S. F. (2014). Developmental biology.
4. Kalluri, R., & Weinberg, R. A. (2009). The basics of epithelial-mesenchymal transition. Journal of Clinical Investigation, 119(6), 1420–1428. doi:10.1172/JCI39104
5. Weinberg, R. A. (2013). Biology of cancer. [S.l.]: Garland Science.
6. C.L. chaffer, R.A. Weinberg. (2011). A perspective on Cancer Cell metastasis. Science 25 March 2011: Vol. 331 no. 6024 pp. 1559-1564
7. Tam, W. L., & Weinberg, R. A. (2013). The epigenetics of epithelial-mesenchymal plasticity in cancer. Nature Medicine,19(11), 1438. doi:10.1038/nm.3336
8. Bouyssou, JMC et al. (2014). Regulation of microRNAs in cancer metastasis. Biochimica et Biophysica Acta. 1845: 255-265
9. Srivastava SP et al. (2013). MicroRNAs in Kidney Fibrosis and Diabetic Nephropahty: Roles on EMT and EndMT. Hindawi Publishing Corporation. 2013: 1-11