EMT Process

Epithelial tissues make up one of the four basic tissue types of the body, along with connective tissue, muscle and nervous tissue. Epithelial cells are characterised by a tendency to form into sheets of polarised cells held together by strong intercellular junctions. As a consequence of this epithelial cells are not able to move freely and show little migration compared to other cell types. In contrast, mesenchymal-like cells (e.g. fibroblasts) lack strong intercellular junctions and can move as individual cells. They can be highly motile and able to migrate through the extracellular matrix.

The Epithelial-Mesenchymal Transition (EMT) is a natural cellular program in which individual epithelial cells lose the gene expression patterns and behaviours characteristic of epithelial cells and instead begin to look, behave and express genes typical of mesenchymal cells. In so doing they lose adhesion and apical-basal polarity and gain the ability to migrate and invade the extracellular matrix. EMT is not irreversible. A mirror process called Mesenchymal-Epithelial Transition (MET) results in loss of mesenchymal characteristics and re-establishment of cell-cell adhesion and apical-basal polarity.

EMT is especially important during embryonic development. It plays a fundamental role in gastrulation, where an embryo consisting of a single epithelial cell layer develops into one with the three classical germ layers, ectoderm, mesoderm and endoderm. Slightly later in vertebrate development, EMT gives rise to the neural crest cells. These cells migrate throughout the embryo and give rise to many different structures including ganglia of the peripheral nervous system, bone and cartilage of the face and head, pigment cells and glial cells. Further rounds of MET and EMT are essential for the formation of internal organs from both the mesoderm and endoderm.

EMT and Disease

In contrast to its importance during embryonic development, the EMT program is seldom activated in healthy adults. It is however induced in response to inflammation following injury or disease: EMT plays a role in wound healing and tissue repair, and occurs during organ degenerative disease (e.g. renal fibrosis).

EMT and Cancer Metastasis

EMT is also increasingly understood to play a key role in cancer metastasis. Carcinomas are epithelial cancers, and in order for metastasis to occur individual cells much escape the primary tumour and undergo a series of migrations. These include migration from the primary tumour into the local circulatory or lymphatic system, and extravasation from the vasculature and establishment at the site of metastasis. There is now good and growing evidence that interactions between tumour cells and their microenvironment can lead to induction of EMT in some of the tumour cells. The resulting increased cell migration and invasion potential of these cells then enhances the likelihood of a metastasis becoming established.

EMT and Cancer Stem Cells

As well as this role in increasing metastatic potential, EMT has recently been linked with Cancer Stem Cells (CSCs). These cells have been postulated to represent a subset of tumour cells with stem cell characteristics – the ability to give rise to all the cell types found in a particular cancer, and thus the ability to form a new tumour. Although they may represent only a tiny fraction of the cells in a tumour, CSCs are thought to be particularly resistant to existing anti-cancer drugs. Even though drug treatment may kill the vast majority of cells in the tumour, a single surviving CSC can lead to a relapse of the disease. Recent evidence suggests an overlap between EMT and CSC phenotypes, suggesting that EMT may also play a role in recurrence of cancer after chemotherapy and the development of drug-resistant tumours.

Robust biomarkers for EMT will thus be useful in identifying patients at particular risk of developing metastatic or drug-resistant cancer, while novel drugs that target cells that have undergone EMT will reduce metastasis and relapse following conventional therapy.

For further information we recommend an excellent series of reviews published in the Journal of Clinical Investigation, Volume 119, Issue 6, 2009.