Epithelial-mesenchymal transition, or EMT, refers to the transformation of epithelial cells into mesenchymal cells. This transformation possesses great importance in embryonic development. However, this process also plays a key role in the development of metastases in carcinomas.
What is epithelial-mesenchymal transition?
Epithelial-mesenchymal transition is a conversion of already differentiated epithelial cells into undifferentiated mesenchymal stem cells. This process is of particular importance during embryonic development. In the course of this transformation, the epithelial cells break free from their attachment and can migrate in the body. In the process, they pass through the basement membrane. The basement membrane separates the epithelia, the glial cells and the endothelium from the connective tissue-like intercellular space. As undifferentiated multipotent stem cells, the migrated cells thus reach all areas of the developing organism and can be differentiated again into any cell type. The epithelial cells form the so-called epithelium, which is a collective name for the glandular and covering tissue. The mesenchyme includes the gelatinous and embryonic connective tissues from which bones, cartilage, smooth muscle, cardiac muscle, kidneys, adrenal cortex, hematopoietic system with blood and lymphatic vessels, and reticular, tight, and loose connective tissues develop.
Function and task
Epithelial-mesenchymal transition is an important process during embryogenesis. During this period, increased growth takes place in which all cells of the body participate. Already differentiated epithelial cells are also involved in these growth processes. For this, however, they must be converted back into multipotent stem cells. The most intensive growth takes place in the first eight weeks of pregnancy. The actual process of embryogenesis begins approximately on the sixth day of pregnancy after the so-called germinal stage (cell development) and lasts until the end of the eighth week of pregnancy. In this phase, the epithelial-mesenchymal transition gains great importance, since all organs are created now. Many epithelial cells lose their differentiation and attachment again here. They migrate through the basement membrane and distribute throughout the body. There they behave again like normal multipotent stem cells and undergo renewed differentiation into different cell types. Of course, they can also differentiate back into epithelial cells. To do this, cell contact must first be reduced and the polarity of the epithelial cells must be reversed. Cell contact is understood as the cohesion of cells by so-called adhesion molecules. One important adhesion molecule is E-cadherin. E-cadherin is a transmembrane glycoprotein that is dependent on calcium ions. It connects epithelial cells together and provides cell polarity and signal transduction. During embryogenesis, the activity of E-cadherin is reduced. This leads to the loosening of the cell association. At the same time, the polarity of the cells also disappears. Epithelial cells have both a so-called apical (outer) side and a basal side facing the underlying tissue. The outer side is located on the surface of skin and mucous membranes, while the basal side is associated with connective tissue located under a basal lamina. Both sides have different functional and structural differences, providing for organ morphology. However, embryogenesis requires rapid changes and flexibility of cells to adapt quickly to growth processes. After the end of embryogenesis, epithelial-mesenchymal transition loses its importance for the organism.
Diseases and disorders
Epithelial-mesenchymal transition (EMT) benefits the organism only during the very short period of embryogenesis. After the tumultuous growth phase, the cells are differentiated. The need for a large number of multipotent stem cells then no longer exists. Therefore, this process is inactivated. If there is nevertheless an activation of the epithelial-mesenchymal transition after the end of embryogenesis, this usually occurs in connection with malignant tumor diseases. Thus, EMT is responsible for the development of metastases in the context of cancer. The process is similar to embryogenesis.Overall, it is a multi-layered process based on genetic regulatory mechanisms that are not yet fully understood. For example, many responsible genes are only active during embryonic development. Afterwards, they are silenced. One possible cause for the renewed activation of these genes could be the upregulation of the transcription factor Sox4. Corresponding research results were presented at the University of Basel. Sox4 in turn activates a number of other genes involved in epithelial-mesenchymal transition. The inactivity of the corresponding genes is thought to be due to their unreadability due to being encased in certain proteins (histones). However, the Sox4 gene ensures the formation of an enzyme called Ezh2. This is a methyltransferase that induces the methylation of the corresponding histones. In this process, the other genes involved become readable again and thus activate the epithelial-mesenchymal transition. The change in the genetic material takes place within a cancerous tumor and thus provides the cause for the complete de-differentiation of the cancer cells. Without epithelial-mesenchymal transition, the cancer would only grow at the site of its origin and not spread. However, metastasis makes a tumor particularly malignant and aggressive. Therefore, work is underway to develop drugs that inhibit the formation of the methyltransferase Ezh2. Appropriate drugs have already been developed, although they are still being tested. On the one hand, the inhibition of metastasis formation would mitigate the aggressiveness of cancer growth, and on the other hand, it would open up the chance of curatively treating previously hopeless cases.
