Epithelial-Mesenchymal Transition (EMT) is a fundamental biological process where epithelial cells undergo a transformation. These cells, characterized by strong cell-to-cell adhesion and distinct polarity, lose these features and become more migratory and invasive, effectively changing into mesenchymal cells. This dynamic shift is reversible through Mesenchymal-Epithelial Transition (MET), where cells can transition back to an epithelial state.
Cellular Transformation During EMT
During EMT, cells undergo noticeable changes in their physical characteristics. Epithelial cells typically form tight layers, connected by specialized structures like adherens junctions, tight junctions, and desmosomes, and display apical-basal polarity. A key change is the loss of E-cadherin, an adhesion protein that helps bind epithelial cells. This disruption allows cells to detach from their neighbors.
As cells transition, they acquire mesenchymal features, including an elongated, spindle-like shape. They also begin to express mesenchymal markers such as vimentin and N-cadherin, replacing their epithelial counterparts. This shift in protein expression and cellular organization enables increased cell motility and the ability to invade surrounding tissues. Transformed cells also gain the capacity to secrete components of the extracellular matrix, further supporting their new, more mobile phenotype.
Molecular Orchestration of EMT
The changes observed during EMT are precisely controlled by a complex network of molecular players and signaling pathways. A set of transcription factors acts as master regulators, directly influencing the expression of genes that dictate cell identity. These include Snail, Slug, ZEB1/2, and Twist, which work to suppress genes characteristic of epithelial cells, such as E-cadherin, while activating genes associated with mesenchymal traits like vimentin and N-cadherin.
Various signaling pathways initiate and regulate the activity of these transcription factors. The Transforming Growth Factor-beta (TGF-β) pathway is one of the most studied inducers of EMT, activating intracellular signals that lead to the expression of these key transcription factors. Other pathways, including Wnt, Notch, Hedgehog, and Receptor Tyrosine Kinase (RTK) pathways, also contribute to EMT by converging to activate or modify the function of Snail, Slug, ZEB1/2, and Twist.
EMT in Healthy Biological Processes
EMT plays roles in normal physiological processes, particularly during organism development and tissue repair. In embryonic development, EMT is essential for shaping the body plan and forming various tissues and organs. During gastrulation, cells in the epiblast, an initial epithelial layer, undergo EMT to migrate and form the mesoderm and endoderm, which are precursors for many tissues and organs.
Neural crest cells delaminate from the neural tube through an EMT-like process. These cells travel to various parts of the embryo, differentiating into diverse cell types, including neurons, glial cells, and cartilage. In adult organisms, EMT contributes to tissue repair and wound healing, allowing epithelial cells at the wound edge to become more mobile and migrate to close the damaged area. This process often involves a partial EMT, where cells temporarily adopt mesenchymal features to facilitate movement, then revert once the wound is closed.
EMT in Disease Progression
Dysregulation of EMT can contribute to the progression of diseases, notably cancer and organ fibrosis. In cancer, EMT enables tumor cells to become aggressive and spread throughout the body, a process known as metastasis. Cancer cells undergo EMT, which allows them to detach from the primary tumor and invade surrounding tissues.
These transformed cancer cells can then enter the bloodstream or lymphatic system, travel to distant sites, and establish new tumors. EMT also contributes to organ fibrosis, a condition characterized by excessive scar tissue formation that can lead to organ dysfunction and failure. In kidney fibrosis, tubular epithelial cells can undergo EMT, transitioning into myofibroblasts that produce large amounts of extracellular matrix proteins, leading to scarring. Similarly, in lung fibrosis, alveolar epithelial cells can undergo EMT, contributing to the development of fibroblastic foci.