Prostate cancer is the most commonly diagnosed cancer and the second leading cause of cancer-related death among men in the United States. African American men have a 60' greater incidence of prostate cancer and a twofold higher mortality rate than white men. The cause(s) for this discrepancy are currently unknown.

For prostate tumors to grow, they need an adequate supply of oxygen and nutrients to feed the tumor cells. As a prostate tumor grows, it needs to develop its own network of blood vessels to deliver the necessary nutrients to the tumor cells. The process of forming new blood vessels is called angiogenesis. Tumor angiogenesis occurs when tumor cells release small compounds that cause existing blood vessels to grow into the tumor. These compounds are called angiogenic factors. Conversely, there are also compounds that prevent angiogenesis; these are called angiostatic factors.

Chemokines are small molecules and some have potent angiogenic or angiostatic properties. Prostate tumor cells are known to produce large amounts of angiogenic chemokines, and our own studies suggest that they produce very little angiostatic chemokines. We believe that this imbalance in chemokine production is an important factor in the growth of prostate tumors. We will determine the importance of individual chemokines by measuring their production by a number of different prostate tumor cells. We will also determine how angiogenic and angiostatic chemokines regulate tumor angiogenesis and growth in a mouse model of prostate cancer.

The potential genetic or epigenetic factors responsible for the higher susceptibility to prostate cancer in African American men are currently unknown. One potential candidate is the Duffy antigen/receptor for chemokines (DARC). The DARC is a receptor that is required for red blood cell infection by malarial parasites. Individuals in West Africa, which is endemic for malaria infection, are negative for the DARC, as are approximately 70' of African Americans. The DARC also binds angiogenic chemokines and is thought to function as a sort of ¿mop¿ to clear these chemokines from areas of high production, such as sites of infection or, perhaps, tumors. We believe that the DARC does indeed function to remove angiogenic chemokines from the prostate tumor environment, and that those lacking the DARC on their red blood cells (i.e., 70' of African American men) have a greater angiogenic potential within newly formed prostate tumors. Our proposal will directly assess whether the DARC is an epigenetic factor for prostate cancer using mice lacking the DARC on their red blood cells that develop prostate cancer.

Our studies will employ a novel mouse model of prostate cancer. Mice have been genetically engineered to spontaneously develop prostate cancer. The prostate cancer in these mice closely resembles human prostate cancer. We will use these mice and breed them with mice that lack receptors for angiogenic or angiostatic chemokines, as well as with mice that lack the DARC. This model system is unique and will allow direct assessment of the roles of these factors in prostate tumor growth in a mammalian system.

The proposed studies will expand our current knowledge of the mechanisms of prostate tumor growth and will help identify multiple points of therapeutic intervention. In addition, these studies may potentially identify an epigenetic factor that predisposes African American men to developing, and succumbing to, prostate cancer.