New research from the University of California, Los Angeles has found a previously unknown molecular mechanism involving cholesterol that may promote tumor growth in the intestines.
One of the methods that the researchers used to increase the availability of cholesterol to intestinal cells in the mice was to feed them a high-cholesterol diet.
"We were excited to find," says senior author Peter Tontonoz, a professor of pathology and laboratory medicine, "that cholesterol influences the growth of stem cells in the intestines, which in turn accelerates the rate of tumor formation by more than 100-fold."
He and his colleagues believe that their findings could pave the way to new treatments for gastrointestinal diseases, such as colon cancer.
Cholesterol is present in all cells
Cholesterol is a fat-like, waxy organic compound that is present in all of the body's cells and serves many needs. It is used to make vitamin D, hormones, compounds that aid digestion, and to form cell walls.
Our bodies can make all the cholesterol that our cells need, but they can also get it from animal sources in the diet, such as meat, milk, cheese, and eggs.
Cholesterol travels through the body in the bloodstream in packages called lipoproteins, of which there are two main types: low-density lipoprotein (LDL) and high-density lipoprotein (HDL). These proteins are commonly referred to as "bad" and "good" cholesterol, respectively.
Research shows that there is a strong link between high blood cholesterol and heart disease, and suggests that foods high in saturated fat, such as cheese, fatty beef, and pork, raise LDL.
The debate about cholesterol and cancer
The biology of cholesterol is complex, and there is currently a debate going on in the cancercommunity about its role in cancer development and whether targeting it with drugs has any therapeutic value.
Although cancer cells tend to have higher levels of cholesterol than healthy cells, it is not clear whether this is significant or not to the development of cancer. The new study sheds light on this thorny question.
Some studies have suggested that there is a link between certain cancers and higher blood levels of cholesterol and that the use of cholesterol-lowering statins might lower this risk. However, others have found no such links.
The American Institute for Cancer Research (AICR) accept that while blood cholesterol may be linked to heart disease, they maintain that research "has not shown a link between dietary cholesterol and cancer risk."
They do, however, point out that a "diet high in cholesterol often includes high amounts of foods that could affect cancer risk," and by means of example, cite high consumption of red and processed meats.
"There is room in a cancer-protective diet for high cholesterol foods, including eggs, shrimp and other seafood, low-fat dairy products, and moderate amounts of lean red meat," the AICR advise.
The authors of the new study are of the view that while it is debatable whether use of statins lowers the risk of intestinal cancer or not, it is now "widely accepted" that a high-cholesterol diet raises the risk, although "the underlying mechanisms are still not clear."
'Previously unrecognized link'
Prof. Tontonoz and colleagues discovered a cell mechanism involving an enzyme called Lpcat3 that "unexpectedly" influences the speed at which intestinal stem cells divide and multiply by controlling the production of cholesterol inside cells.
They found out how cholesterol influences the mechanism by increasing levels of cholesterol in the intestinal cells of live mice.
They did this in two ways: they increased cholesterol in one group of mice by feeding them on a high-cholesterol diet, and, in another group, by altering a gene to make the animals' cells make more cholesterol. The gene that they altered controls phospholipids, the main type of fat that goes into making cell walls.
Both ways of raising cholesterol levels — dietary and genetic — in the mice caused their intestinal stem cells to divide and multiply much faster.
This led to rapid expansion of the tissue lining their intestines and increased the growth rate of colon tumors.
The researchers conclude that their findings highlight a "previously unrecognized link between phospholipid remodeling and cholesterol biosynthesis" inside cells that regulates the stability of intestinal stem cell production and the generation of tumors.
They note that intestinal stem cells have been shown to be "cells of origin for intestinal tumors" and suggest that their findings are "consistent with this notion."
"While the connection between dietary cholesterol and colon cancer is well established, no one has previously explained the mechanism behind it."
Prof. Peter Tontonoz