Lowering serum cholesterol appears to suppress tumor angiogenesis and the growth of prostate tumors in mice, according to a new study appearing in the March 2009 issue of The American Journal of Pathology.

High cholesterol not only leads to atherosclerosis and heart disease, but may also contribute to cancer growth and progression. Prostate cancer is the most common non-skin cancer in the United States, affecting approximately 1 in 6 men. Prostate tumors accumulate high levels of cholesterol, and tumor incidence correlates with consumption of a high fat/high cholesterol diet "Western" diet. In addition, prostate tumor progression has been linked to serum cholesterol levels.

To examine the role of high cholesterol in prostate cancer, Dr. Keith Solomon and colleagues from Harvard Medical School, Children’s Hospital Boston, and Rutgers University used mice implanted with human prostate cancer xenografts. The mice were then divided into one of four groups: those fed high fat/high cholesterol "Western" diets with or without ezetimibe (Zetia™), a drug that blocks absorption of cholesterol from the intestine, and those fed low fat/no cholesterol diets with or without ezetimibe.

High cholesterol levels were significantly associated with greater tumor growth and increased angiogenesis. Notably, serum cholesterol was inversely correlated with levels of thrombospondin-1 (TSP-1), a potent endogenous inhibitor of angiogenesis—TSP-1 was suppressed in mice with high cholesterol and increased in those on low fat diets or that received ezetimibe. Other markers of angiogenesis were also affected by ezetimibe therapy. Mice treated with the drug had significant decreases in microvessel density, a marker of angiogenesis, and increased vessel pericyte coverage (suggesting a more stable vascular structure). Another finding was that high cholesterol levels were associated with greater numbers of fibroblasts in tumors; stromal fibroblasts have been shown to increase tumor angiogenesis through increased levels of stromal cell-derived factor-1.

The team found that over several weeks, nerve signal speed and sensitivity to temperature were restored to normal in diabetic mice injected with the bone marrow cells. A fraction of the bone marrow cells appear to become endothelial cells although many of them retain characteristics that make them look like white blood cells. However, they secrete molecules that stimulate the growth of both endothelial cells and Schwann cells, which protect and insulate peripheral nerves, the authors found.

"Lowering cholesterol levels whether through diet, exercise, or the use of safe cholesterol-lowering drugs is known to provide a substantial benefit to patients—in the future it may be possible to add reduced risk of serious prostate cancer to that list of benefits" said Dr. Solomon. "We are in the process of working with clinicians to translate these findings into potential human studies. If we can demonstrate the effects noted in our pre-clinical studies in human patients we may be save lives and improve the quality of life," added Dr. Michael Freeman, senior author of the study.

By Roderick Smith, M.S.

References: Solomon KR, Pelton K, Boucher K, et al. Ezetimibe Is an Inhibitor of Tumor Angiogenesis. Am J Pathol 2009;174:1017-1026.