E-cadherin is highly expressed in epithelial cells. Many think that E-cadherin i
ID: 179680 • Letter: E
Question
E-cadherin is highly expressed in epithelial cells. Many think that E-cadherin is a metastasis suppressor (that it inhibits the ability of cancer cells to spread to another location/tissue).
What is the simplest possible explanation as to why E-cadherin prevents tumor cell metastasis? You should be able to answer this one just based upon class and/or a textbook and some clean thinking.
Imagine you are collaborating with an oncologist and that you have access to a collection of cells from patients with cancer of graded severity. Some of the tumor samples are benign ranging all the way to highly metastatic. If the overall hypothesis is correct, that E-cadherin suppresses metastasis, then provide a ridiculously simple experiment to test this hypothesis and what you expect to see. I do not need the experimental details. Tell what basic approach you would use and what you expect to see.
Explanation / Answer
E-cadherin is a calcium-regulated adhesion molecule expressed in most of the normal epithelial tissues. Located on chromosome 16q22.1 it is associated with gland formation, stratification, and epithelial polarization.
Classical cadherins like e-cadherin are type 1 membrane glycoproteins, which function as active membrane-spanning macromolecular complexes. Their extracellular regions are the sites for adhesive recognition, which bind to the ectodomains of cadherins of neighboring cells. On the reverse side of the plasma membrane, the cadherin cytoplasmic tails interact with a series of intermediary proteins that link the receptor to primary intracellular processes. These associated proteins include -catenin, (binds directly to the distal region of the cytoplasmic tail) -catenin (indirectly coupled to the cadherin complex by association with -catenin) and p120-catenin (binds to the membrane-proximal region of the cadherin cytoplasmic tail). The cadherins establish and maintain cell-to-cell cohesion, thereby linking isolated cells into cohesive populations; cell–cell recognition during sorting and tissue reorganization; cell-upon-cell locomotion and epithelial polarity.
Thus E-cadherin, behave as adhesion-activated signaling receptors, stimulating intracellular signal-transduction pathways ultimately affecting processes as diverse as the cytoskeleton and cell proliferation. The cell-cell adhesion and cell junctions are mediated through homophilic binding, without which the cells get dissociated from the primary tumors, invade surrounding tissues and migrate to distant locations. The ability of E-cadherin expressing tumor cells to metastasize is due to a downregulation of the adhesive activity state of E-cadherin at the surface rather than its amount.
Since majority of solid tumors are carcinomas that arise from epithelial tissues, the key target is the prototypical epithelial cadherin, E-cadherin. Selective loss of E-cadherin, is proved to cause dedifferentiation and invasiveness in human carcinomas. A reciprocal relationship has been established between E-cadherin expression levels and invasiveness in different cell lines. A gene mutation and loss of heterozygosity of wild-type alleles can lead to loss of E-cadherin protein expression. These data indicate that E-cadherin is a classic tumor suppressor gene.
A simple experiment to test the hypothesis involves increasing the adhesive activity of E-cadherin by activating with monoclonal antibodies and studying its effect on the extent of tumor metastasis in mammary cell lines. The expected result is that the process significantly reduces metastasis.
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