Cancer Trigger Mechanism of Cholesterol Identified
For the first time, researchers have identified a biochemical mechanism by which high cholesterol levels can help trigger colorectal and pancreatic cancers, two of the five most deadly tumors among U.S. cancer victims.
Epidemiological studies had previously linked diets high in meat and other fatty foods, as well as high cholesterol levels, to colorectal cancer, but researchers had virtually no idea what role cholesterol played in tumor formation.
Now, a UC Berkeley group has found that a chemical crucial to the formation of cholesterol is necessary for the functioning of a gene that triggers tumor formation in the pancreas, colon and rectum. Their research, reported in today’s issue of the journal Science, suggests that diet and the use of drugs that interfere with cholesterol metabolism might be used to prevent and perhaps even treat certain forms of cancer.
Their research also provides a strong rationale for current efforts to prevent colorectal cancer by eating foods low in fat and high in fiber that reduce cholesterol levels. Oncologist Robert Mayer of the Harvard Medical School called the study “an elegant observation . . . that may provide the first step in linking epidemiological evidence to cancer mechanisms.”
Colorectal cancer is second only to lung cancer as a cause of death. Of the 151,000 Americans who contract colorectal cancer each year, 62,000 die. Pancreatic cancer is fifth in number of deaths, and has an extremely high mortality rate, accounting for 25,000 deaths among 27,000 cases annually.
Colorectal cancer occurs much more commonly in industrialized countries that have a diet rich in meats and other fatty materials than it does in developing countries whose inhabitants have only a subsistence diet.
Two 1985 studies, one from Sweden and one from West Germany, also associated a high incidence of colorectal cancer with high levels of cholesterol in the bloodstream. One study showed, for example, that individuals with cholesterol levels in the highest 20% were more than twice as likely to develop tumors as those in the lowest 20%.
Researchers have had a difficult time explaining the biochemical mechanisms involved in these findings. Currently, the most widely accepted theory is that high levels of fat in the colon increase the percentage of organisms there that might produce carcinogens. This theory, Mayer noted, has been particularly difficult to prove.
Smoking Link
Pancreatic cancer, in contrast, has not been strongly associated with diet. The only well-known risk factor for it is smoking.
But the two types of cancer share one trait: at least 50% of pancreatic tumors and 90% of colorectal tumors are thought to be triggered, at least in part, by the ras oncogene. Oncogenes are genes normally found in cells that, when activated under certain conditions, trigger unrestrained proliferation of cells--in other words, a tumor.
Although researchers do not yet know how the ras oncogene operates, they do know one crucial fact: The protein produced from it, called the RAS protein, must be bound to the cell’s membrane before it can signal the cell to begin dividing and developing into a tumor.
Geneticists Jasper Rine and William Schafer of UC Berkeley discovered that, in yeast, the RAS protein is bound to the membrane by a molecule that is converted into cholesterol. If the molecule, called farnesyl pyrophosphate, is not present in the yeast, the RAS protein cannot bind to the yeast cell membrane and stimulate cellular proliferation.
Because the yeast ras oncogene is very similar to its human counterpart, the Berkeley scientists began collaborating with chemist Sung-Hou Kim and his colleagues at the Lawrence Berkeley Laboratory to study the human gene.
In their key experiment, they injected the human RAS protein into frog eggs and found that it stimulated the eggs to divide. But when they simultaneously injected a drug called lovastatin, which is used to reduce cholesterol levels in humans by blocking its synthesis, they found that the RAS protein had no effect on the eggs.
Simply put, Kim said, “Drugs that block cholesterol synthesis block RAS protein activity” and thus should block cancer cells from proliferating.
Much more speculative is the possibility that cholesterol-blocking drugs or foods could kill existing tumors. But Kim suggests that because every cell in a tumor has to have the RAS protein anchored to the membrane, interfering with cholesterol synthesis could halt, or even reverse, this process and shrink the tumor.
“Our finding opens new avenues for investigating these cancers and potentially for treating them with cholesterol-reducing drugs, which are safer than current therapies,” which have many potent side-effects, Rine said. Kim noted that the group plans to begin studying this in mice in the near future.
Normal levels of cholesterol are necessary to the cell, which uses it in building membranes. Apparently only the excess cholesterol is used for anchoring the RAS protein, contributing to the formation of tumors.
Thus, Kim pointed out, one could conceivably allow the farnesyl pyrophosphate level to be high enough for the cell’s healthy needs but low enough to rob the RAS proteins of their necessary anchor.
