| IDENTIFICATION OF GENES INFLUENCED
BY LOSS OF E-CADHERIN IN PROSTATE CANCER
Professor J Kilian Mellon, Dr Eugene Tulchinsky
|
The reason we can all stand on our feet and avoid collapsing on the floor is because normal cells have powerful mechanisms of intercellular adhesion. In abnormal tissue such as a tumour or a cancer, these adhesive mechanisms become abnormally weak and this partly explains why cancer cells develop the capability of spreading to other parts of the body.
One of the most important cellular molecules in this process is called E-cadherin and E-cadherin on the surface of a cell binds tightly to E-cadherin molecules on the surface of neighbouring cells. A feature of cancer cells is that they lose E-cadherin molecules from the cell surface.
Tumour cell dissemination is not quite as simple as loss of E-cadherin allowing a cancer cell to become detached and move elsewhere but is rather more complex. It has been shown in various laboratory experiments using a variety of cancer cells that when a cancer cell loses E-cadherin various signalling pathways in the cell are activated, ultimately having an effect on approximately 100 other genes in the cell.
Some of these genes are activated while others are suppressed as a result of loss of E-cadherin from the surface of the cell. These genes are capable of influencing the cell’s ability to become more motile and invade. This research is currently studying the consequences of loss of cell surface E-cadherin in prostate cancer cells
The first phase of this work has been to develop prostate cancer cells in which the level of E-cadherin can be reduced using a variety of methods. These include a method to inhibit the E-cadherin gene producing E-cadherin protein molecules, a method of introducing a non-functional mutant E-cadherin protein into the cell which binds and inactivates normal E-cadherin and a method using very recent technology called RNAi which blocks the intermediate steps between E-cadherin gene activation and protein production.
The second phase of the work will identify which genes are influenced by loss of E-cadherin using a recently developed technique called cDNA microarrays.
Finally, it is planned to study specimens of human prostate cancer particularly to look at areas of tumour which are positive or negative for E-cadherin for genes which have been identified by the earlier work as being E-cadherin-dependent.
Research summary, 27 January 2004
Project G2002/04.