Growth Factor Raises Cancer Risk

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.”