Professor Mellon explains his research

Why do cancers spread?

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 unusually 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.  Molecules of Ecadherin on the surface of one cell binds tightly to similar 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 cannot simply be explained as loss of E-cadherin allowing a cancer cell to become detached and move elsewhere.  It has been shown in various laboratory experiments using a variety of cancer cells that when a cancer cell loses Ecadherin 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.

We have been studying the consequences of loss of cell surface Ecadherin in prostate cancer cells thanks to a generous grant from Prostate Research Campaign UK.  The first phase of our work has been to develop prostate cancer cells in which we can reduce the level of E-cadherin.  We have done this by inhibiting the E-cadherin gene from producing E-cadherin protein molecules, by introducing a nonfunctional mutant E-cadherin protein into the cell which binds and inactivates normal E-cadherin and by using a new technology - 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.  Finally, we plan to study specimens of human prostate cancer and will look at areas of tumour which are positive or negative for Ecadherin for genes which have been identified by our earlier work as being E-cadherin-dependent.