Researcher Investigates a Vitamin’s Potential Dual Effect on Cancer

Division of Cancer Biology

Folate, a B vitamin, is essential for the normal functioning of the body. A shortage of folate in the diet can cause many problems, most notably birth defects such as spina bifida in children born to mothers with low levels of folate during early pregnancy.

In the 1990s, to reduce the number of children born with birth defects many countries, including the United States, mandated that flour and other grain products – such as pasta and cereal – be fortified with folate. In addition to consuming fortified foods, many people receive substantial amounts of the dietary compound through the use of vitamin supplements.

Since a low intake of folate in the diet can also increase the risk of cancer, particularly colorectal cancer, on first glance it seems that maximizing the intake of folate could only be a good thing. But Joel Mason, M.D., professor in the Friedman School of Nutrition Science and Policy at Tufts University, who has devoted his career to studying the effects of dietary folate and cancer, urges caution about this positive assessment.

“It’s pretty much well accepted as a scientific fact now that habitual under-consumption of folate leads to an increased risk of cancer,” Dr. Mason noted. “But interestingly, one of the things we noticed in several of our animal models is that there seemed to be a bi-modal effect of folate: if we gave inadequate amounts of folate to our animals it would increase tumor formation. On the other hand, when we gave them large quantities of folate – levels of dietary folate that were way beyond the basal requirements – we would sometimes see a promotion of cancer.”

This unexpected finding is not as paradoxical as it seems, Dr. Mason said. Folate serves as an essential growth factor for dividing cells because the vitamin participates in the biochemical reaction that produces the nucleotide thymidine, one of the four building blocks of DNA, he explained. A lack of thymidine interferes with healthy DNA synthesis and appropriate cell division, Dr. Mason continued, but a flood of thymidine, as could be provided by excess folate, could potentially help fuel rapidly dividing cancer cells.

In 2007, Dr. Mason and his colleagues published a paper* hypothesizing that colorectal cancer incidence in the United States and Canada experienced a spike about a year after the introduction of mandatory folate fortification, reversing a 20-year trend of decline. “While this epidemiologic data is by no means proof of causality, it’s rather interesting and provocative,” said Dr. Mason.

After participating in a meeting convened by the European Food Safety Authority, which found the evidence inadequate to determine whether or not excess folate could increase the risk of cancer, Dr. Mason decided to further study the issue in a new animal model of colorectal cancer. “These types of studies can’t ethically be done in humans, so [after the European meeting] there was an acknowledgment that to really determine whether this hypothetical risk is genuine in the human population it was going to require some modeling in animals,” he recounted.

A colleague at Tufts, Kenneth Hung, M.D., had recently developed a new mouse model of colon cancer, called the GEM-1 mouse, which proved to be ideal for studying the effects of folate on colon cancer growth. The model has several advantages over older, more widely used models, explained Dr. Mason. One advantage is that the GEM-1 mouse develops tumors in the actual colon, also known as the large intestine. Most other mouse models of colon cancer develop tumors in the small intestine, which has a different biology from the colon, he noted.

A second advantage is that the GEM-1 mouse develops all its tumors in the distal (lower) half of the colon, which can be reached using a micro-colonoscope created by Dr. Hung. This allows tumor growth to be measured on an ongoing basis in live animals. Finally, the mutation driving colon cancer formation in the GEM-1 mouse is only found in the cells lining the distal colon, as would be found in colon cancer in people, Dr. Mason added. Most other models contain a germline mutation — meaning it would be found in every cell of the body — which does not replicate most cases of colon cancer.

With NCI support for his ongoing experiments**, Dr. Mason is feeding mice either a diet with a regular level of folate or a diet with nine times the amount of folate required for basic body functioning, an amount easily achieved in people eating a number of fortified foods and taking vitamin supplements, he explained. With the micro-colonoscope, “we can actually watch the growth of tumors over time, and see if they have accelerated growth in those mice taking extraordinarily large amounts of folate.”

As part of the experiments, some of the mice will receive the naturally occurring form of folate, and some will receive folic acid — the artificial, shelf-stable form of the vitamin used in fortification (natural folate breaks down quickly, making it unsuitable for fortification and use in supplements). This will hopefully shed some light on another unresolved question — whether folic acid rather than natural folate is the substance that can accelerate cancer growth, Dr. Mason said.

Folic acid quickly saturates the body’s system that coverts it to the natural form of the vitamin. As little as half the amount found in a typical multivitamin overwhelms the system, leading to folic acid spilling into the circulation, explained Dr. Mason.

“If you insert naturally occurring forms of folate into [metabolism], it has to go through several regulatory steps that help control how much folate is getting utilized for DNA synthesis,” Dr. Mason continued. “When you give folic acid, it gets inserted into folate metabolism in a way that can directly be used for the synthesis of DNA.”

As part of the experiments, the researchers will be comparing the thymidine content within the lining of the colon between mice given natural and artificial folate, to see if the artificial form may be providing more material for dividing cells.