April 22, 1999
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Growth Factor Raises Cancer Risk

By William J. Cromie
Gazette Staff

Edward Giovannucci (left), Jing Ma, and their colleagues have linked high levels of a natural growth factor to colorectal, breast, and prostate cancer. Phoro by Kris Snibbe.

High levels of a well-known growth factor significantly increase the risks of colorectal, breast, and prostate cancer, medical researchers have found.

At the same time, they determined that a protein that binds to the growth factor seems to neutralize it and reduce the risk of these malignancies, which are three of the four biggest cancer killers in the United States.

"If further studies confirm these findings, blood levels of the growth factor and its binding protein might be used to identify people at the highest risk for these cancers and, therefore, who might benefit most from lifestyle changes and other means of prevention," says Jing Ma, an instructor in medicine at Harvard Medical School. Also, future work on the binding protein could lead to new drugs for treating colorectal, breast, and prostate tumors in their earliest stages.

The growth factor, known as insulin-like growth factor-1, or IGF- 1, is necessary for proper growth in children, but studies of men and women more than 40 years old raise the possibility that it contributes to the growth of tumors. These studies were conducted at Channing Laboratory in Boston, a joint facility of Harvard Medical School and Brigham and Women's Hospital in Boston, and at the Harvard School of Public Health.

Last week, the researchers announced that, in a six-year study of 32,826 nurses, those with the highest levels of IGF-1 had a two-and- a-half times greater risk of colorectal cancer. High levels of IGF binding protein-3 (IGFBP-3) produced the opposite effect.

The week before, another group from the same laboratory reported in the Journal of the National Cancer Institute that a study of 14,916 male physicians concluded that men run the same risk. In the case of those with the highest IGF-1 and lowest IGFBP-3, the relative risk of colorectal cancer rose fourfold, after accounting for differences in weight, height, alcohol intake, and other known risk factors.

"The fact that these two large studies give the same results for both men and women increases our confidence in the findings," notes Edward Giovannucci, an assistant professor of medicine who led the nurses' study. Giovannucci is also assistant professor in the Department of Nutrition at the Harvard School of Public Health.

Last year, data from the investigation of male physicians also showed that men with the highest levels of IGF-1 had more than four times the risk of prostate cancer than those with the lowest levels.

Another Channing Laboratory team concluded that premenopausal women with high IGF-1 levels have more than double the relative risk of breast cancer. Younger women are at greatest risk. This team was led by Susan Hankinson, an assistant professor of epidemiology at the School of Public Health and an assistant professor of medicine at the Medical School.

In all these studies, blood samples were collected from 32,826 nurses and 14,916 physicians between 1982 and 1990. None of these people had cancer at the time. They were then followed by questionnaires for 6 to 14 years. Those who developed cancer were then matched by age and smoking frequency with those who stayed cancer-free, and their blood levels of IGF-1 and IGFBP-3 were compared.

Slowing Aging

These results raise concern about attempts to slow aging in older people by giving them growth hormone to increase their IGF-1. Since levels of both substances decrease with age, some observers suggest that injections of the hormone may counter several effects of getting old.

In one study, 12 men, 61 to 81 years old, were given growth hormone three times a week. After six months, their blood showed levels of growth hormone similar to those in men 10 to 20 years younger. They achieved increases in muscle mass and skin thickness and decreases in body fat compared to a matched group who didn't take the hormone.

A subsequent study of 27 women, 62 to 82 years old, who took the hormone showed a decrease in fat and some protection against bone loss.

These results caused a torrent of media reports suggesting that science had found away to stall, even reverse, some degenerative changes of aging.

"We would advise healthy people not to take the hormone," Ma says. "Our studies raise concern that giving it over long periods will increase the risk of prostate and colorectal cancers." Other researchers have found a lack of gain in muscle strength and physical performance despite the increase in muscle mass and decrease in fat.

"We've not shown directly that the hormone is harmful," Giovannucci adds. "Potentially, there could be some benefit from giving it to people with a growth-hormone deficiency. But people should understand that there's a risk involved, and proceed cautiously."

Too Much Growth

"There's good biological rationale for the associations we found," Giovannucci says. When IGF-1 is added to dishes of cells growing in the laboratory, the cells flourish like flowers blooming in spring. In children, the hormone stimulates bone growth and development of organs such as the heart, liver, and kidneys. But in older people, rapidly proliferating cells increase the opportunity for genetic mutations that may lead to cancer. And once cancer cells begin to form, IGF-1 will promote their growth as well as that of normal cells.

Ma mentions evidence of a connection between colorectal cancer and acromegaly, a condition that causes enlargement of facial features, hands, and feet due to excess secretion of growth hormone. "The rate of colorectal cancer among acromegalics is abnormally high, because their IGF-1 levels can be up to 10-fold higher that those of normal people," she notes.

"The levels of IGF-1 implicated in increased risks for cancer among middle-aged and older nurses and physicians in our studies are not as high as those in acromegalics or abnormally tall people," Giovannucci explains. "Rather they are at the high end of what we would consider a normal range."

IGF-1 is a major determinant of height, and taller people are at higher risk for colorectal, breast, and prostate cancer, according to Ma. "It is possible that people who grow tall, because of higher levels of IGF-1 in childhood and adolescence, have a high risk of cancer in adulthood," Giovannucci points out. "However, someone who retains high levels of the hormone from childhood through middle age might be at even higher risk."

Levels of IGF-1 drop when people eat less. Animal studies show that decreases in food intake lessen tumor growth and increase life span, Ma and Giovannucci agree. "However, it's too early to make specific recommendations about restricting calories on the basis of our results," Ma cautions.

It's also too early to determine if a test based on blood levels of IGF-1 and IGFBP-3 will predict who will get colorectal, prostate, or breast cancer. The findings of the Harvard researchers must be confirmed by additional large studies.

Meanwhile, drug companies and other research teams are exploring the feasibility of designing new cancer drugs based on the activity of IGF-1 and IGFBP-3.

Giovannucci, Ma, and their colleagues are now investigating the role of diet, physical activity, alcohol consumption, and other possible determinants of high IGF-1 and low IGFBP-3 levels. "It might be possible to adjust these levels and lower cancer risks with lifestyle changes that are not too drastic," Ma speculates.

"We're also looking at genes that might control levels of the growth factor and its binding protein," notes Giovannucci. "People found to possess a genetic predisposition to IGF-1- related cancers could be closely monitored and, perhaps, pretreated with lifestyle changes and new drugs."


Copyright 1999 President and Fellows of Harvard College