Biological Factors May Drive Prostate Tumor Aggressiveness
Researchers analyzing prostate tumors have identified differences in gene expression (the degree to which individual genes are turned on or off) between African-American and European-American men that show the existence of distinct tumor microenvironments (the area that includes the tumor and the surrounding non-cancerous tissue) in these two patient groups. These findings by researchers at the National Cancer Institute (NCI), part of the National Institute of Health, appeared online February 1, 2008, in Cancer Research.
Many of the genes that are differentially expressed between the tumors of African-American and European American men are related to the immune system. The results of this study suggest that biological differences may, in part, underlie the disparity in prostate cancer survival rates observed between African-Americans and European-Americans.
Prostate cancer is the second leading cause of cancer-related death among all men in the United States. However, incidence and mortality rates for this disease vary substantially among geographic areas and ethnic groups. Most notably, African-American men in the U.S. have the highest risk of developing prostate cancer, and, due to the development of more aggressive disease, they have more than twice the mortality rate observed for other racial and ethnic groups.
"Although preliminary, our findings are novel and could have implications for cancer therapy," said Stefan Ambs, Ph.D., of NCI's Center for Cancer Research Laboratory of Human Carcinogenesis and head of the Breast and Prostate Unit. "Our data suggest that African-Americans and European-Americans might respond differently to immunotherapies currently under study for prostate cancer. Understanding the biological differences that play a role in the development and progression of cancer among racial and ethnic groups may aid in the development of therapies tailored to these differences."
Lead author Tiffany Wallace, Ph.D., and colleagues analyzed differences in gene expression in prostate tumors from 33 African-American and 36 European-American men. Their analysis revealed higher expression of numerous genes that influence immune responses and the spread of cancer (metastasis) in the tumors of African-American men compared with European-American men. Among the genes with elevated expression in prostate tumors from African-American men were genes that encode different types of chemokines and their receptors. Chemokines are proteins released by cells to regulate both immune system function and cell migration. Two of these genes, CXCR4 and CCR7, have been linked to cancer metastasis and encode proteins that are commonly produced during inflammation and infection.
In addition, expression of a number of genes that are induced by a cytokine called interferon was found to be elevated in the African-American prostate tumor tissues. Interferon is produced by cells in response to various pathogens, including viruses. This observation suggests the possibility that viral infections could be associated with the development of prostate tumors in African-Americans.
As part of the study, the team also analyzed the expression of genes in non-cancerous prostate tissue from African-American and European-American men. They found that differences in the expression of genes related to immune system function were more prominent in the tumor microenvironment than in non-cancerous prostate tissue.
"In future studies, we hope to investigate why gene expression profiles in prostate tumors from African-American men contain changes associated with immune responses. Perhaps mechanisms that block the tumor-destroying ability of immune cells are more prevalent in African-Americans or certain viruses are more common in African-Americans," noted Ambs.
Having uncovered genes that were expressed at different levels in tumors from these two ethnic populations, the researchers asked if the converse were true: Can differences uncovered in the profiles be used in a blind test to identify the ethnic origin of a prostate tumor sample? The researchers identified two potential candidate genes for successfully differentiating between tumors from African-American and European-American men. The genes, PSPHL and CRYBB2, were more highly expressed in the prostate tumors of African-Americans compared with European-Americans. While little is known about the functions of the two genes, PSPHL is located in a chromosomal region related to advanced tumor stage in prostate cancer. Further research is needed to determine whether PSPHL contributes to prostate cancer.
The results from this paper suggest that prostate tumors from African-American patients may differ in their immune biology from those of European-American patients. "The immune-related differences in the gene profiles could also be pointing to predisposing factors for tumor progression and metastasis," said Ambs.