The gene mutation prevents expression of the Duffy antigen/receptor for chemokines (DARC) on red blood cells. The DARC originally was described by scientists as a red blood cell receptor required for infection by the malarial parasite. More recent evidence, however, suggests that the DARC may also play a role in preventing or slowing the formation of new blood vessels produced by tumors in order to gain nutrients needed to grow.
Dr. Alex B. Lentsch says this is an important first step towards identifying a causative factor for the higher prevalence of prostate cancer in African-American men as well as their two-fold higher mortality than white men. His study suggests that prostate cancer in men with a mutated DARC gene would develop more quickly to the level of detection and grow more aggressively.
These pre-clinical studies will need to be validated in prostate cancer patients, he adds. But once that is done, a simple blood test measuring the presence or absence of the DARC on red blood cells could be used to identify prostate cancer patients at higher risk for aggressive growth of the tumor. It is also possible that anti-chemokine therapies could be tested and applied to these patients.
Tumor angiogenesis occurs when tumor cells release small compounds or angiogenic factors that cause existing blood vessels to grow into the tumor. One class of angiogenic factors released by prostate tumors are chemokines, small proteins that promote angiogenesis by binding to receptors on the cells lining blood vessels adjacent to the tumor and by "attracting" them toward the tumor. This, in cooperation with the effects of other angiogenic factors, initiates new blood vessel growth towards, and ultimately into, the tumor. The DARC receptor is believed to bind to and remove angiogenic chemokines from a site of overproduction, such as inflammation or a tumor, thus limiting its ability to develop new blood vessel growth and feed itself for growth.
Breeding mice genetically engineered to develop prostate cancer to mice lacking the gene for the DARC, Drs. Lentsch and Hui Shen were able to compare growth and size of prostate cancer tumors in mice with and without the DARC.
The mice developed tumors at approximately the same time, which is not surprising, say the researchers, since chemokines have not been linked to the formation of cancer, just to its spread through angiogenesis. Once the mice's tumors formed and began to grow, however, the story was very different. In mice bred to have the mutation, and thus unable to express the chemokine-clearing DARC receptor, tumors grew much faster and were nearly four times the size of tumors, developed at the same time, in mice without the mutation. In addition, levels of angiogenic chemokines were much higher in tumors of mice without the gene for DARC.
Funding for this work was provided by the United States Army Medical and Material Command.