The findings, published in the April 1 issue of the Journal of Clinical Investigation (available online March 17), are in keeping with population studies that have linked prostate cancer with high cholesterol levels and Western diets high in cholesterol. The researchers also present evidence that cholesterol-lowering "statin" drugs, now widely used in cardiovascular disease, may inhibit cancer growth.
A team led by Michael Freeman, PhD, Program Director of the Urological Diseases Research Center at Children's, injected human prostate cancer cells into mice and observed tumor growth. When the animals' blood cholesterol was raised by diet, cholesterol accumulated in the outer membranes of the tumor cells, specifically in structures called lipid rafts. Cholesterol elevation in the rafts activated a chemical "cell-survival" pathway known as Akt, thought to be a central pathway in prostate cancer. Activation of Akt enabled the tumor cells to resist chemical cues to commit suicide through the process known as apoptosis, thereby allowing the cancer to proliferate.
Increased cholesterol levels didn't trigger new cancers in the mice, but six weeks after tumor cells were injected, the incidence of tumors was more than doubled in the mice on high-cholesterol diets, and the tumors were markedly larger in size.
"What we're looking at is progression, not initiation of a tumor," says Freeman.
In addition, test-tube studies showed that when the cholesterol-lowering drug simvastatin was used to reduce cholesterol in cell membranes, the Akt pathway was inhibited, apoptosis increased, and tumors stopped proliferating. Replenishing cell membranes with cholesterol reversed this inhibitory effect.
"Our study opens up a new paradigm in thinking about how cancer might be controlled pharmacologically by manipulating cholesterol," says Freeman. "Our data support the notion that cholesterol-lowering drugs -- which are widely used and fairly safe -- might be effective in prevention of prostate cancer, or as an adjunctive therapy."
Although there is some epidemiologic evidence linking high cholesterol levels with certain types of cancer, there has been little research at the cellular level to try to explain why this is so. More recently, epidemiologic studies have begun reporting that people taking cholesterol-lowering drugs have a significantly reduced incidence of prostate and other cancers.
Lipid rafts are structures in the outer cell membrane which Keith Solomon, PhD, a co-investigator on the study and a lipid-raft expert, likens to ice floating on water -- they are dynamic and continually aggregate and disaggregate. They have naturally high concentrations of cholesterol and are believed to be important in cell signaling. Solomon and Freeman believe that cholesterol in the lipid rafts may help sequester proteins involved in cancer pathways in close proximity with each other, facilitating biochemical reactions that promote cancer growth.
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