CXCR4 and DPPIV in colorectal cancer

Cancer of the colon becomes most threatening when it acquires the ability to spread from the large bowel into local lymph nodes and to other sites like the liver. The capacity of the cancer cells to invade the outer layers of the intestinal wall and become disseminated to other sites (metastasis) depends in large part on certain proteins that are present on the surface of the cancer cells. Two of these proteins are CXCR4 and DPPIV, and these work together to regulate cellular behavior. Although they benefit the cell in normal conditions, like many cellular components they are 'conscripted' into a less favorable use when the cell becomes cancerous. An increase in the amount of CXCR4 then helps to direct the cancer cell to the metastatic site, while declining levels of DPPIV allow the accumulation of the molecule (SDF-1alpha, or CXCL12) that activates CXCR4 to promote metastasis. In our previous research we have shown how the tumor tissue itself acts to favor this metastatic pathway. In the present work we will be using different techniques to find out how this mechanism operates at the different stages of cancer, and whether any of three different classes of existing drugs - drugs that block certain receptors on the cell surface, drugs that target a protein in the cell nucleus, anticancer drugs themselves at low doses - can interfere with this process. If we are successful we will have identified a pathway by which proteins on the cancer cell can actively cooperate to allow metastasis, and may find a way of intervening in this process using existing, approved drugs to the benefit of patients with metastastic colon cancer.