Does Stress Cause Cancer? Probably
Not, Research Finds
The question of whether there is a link
between stress and cancer has puzzled and intrigued researchers as well as
patients. Study after study has asked whether people who developed cancer
had more stress in the years before the diagnosis, and conversely, whether
people who experienced extreme stress were more likely to develop cancer.
Investigators have also explored possible
mechanisms, asking, for example, whether stress might suppress the immune
system cells that might be needed to squelch rogue cancer cells. And they
have tried to determine whether the immune system, the body's defense
system, protects people from cancer in the first place.
What has emerged is a tenuous connection
between stress, the immune system and cancer, with a surprising new
insight that is changing the direction of research: it now appears that
cancer cells make proteins that actually tell the immune system to let
them alone and even to help them grow.
for whether stress causes cancer, the question is still open.
"I have no idea, and nobody else does,
either," said Barbara Andersen, a psychology professor at Ohio State
University who studies stress reduction in cancer patients. "If somebody
suggested that they know, I would question them."
Polly Newcomb, the head of the cancer
prevention program at the Fred Hutchinson Cancer Research Center in
Seattle, decided to ask whether stress caused breast cancer, because women
seemed convinced that it did.
The issue came up in her epidemiologic
studies of what might be causing cancer. She used trained interviewers to
ask women with cancer and healthy women who served as controls about their
medical histories, their environments and the medicines they were taking.
Then the interviewers asked the women if
they had anything to add. Repeatedly, the women with cancer would turn to
their interviewers and say, "Why didn't you ask me about what really
caused my cancer?"
What really caused it, they would say, was
stress. It was plausible, Dr. Newcomb reasoned. After all, stress could
alter the functioning of the immune system, in turn altering
susceptibility to cancer.
So Dr. Newcomb incorporated standard
questions about stressful life events into her continuing study of nearly
1,000 women. Had family members or friends died? Had they gotten married
or divorced? Had they lost a job or had they retired? Had their financial
status changed? Were there stressful events not on the list that they
would like to add?
The women did not know why the questions,
incorporated as part of a longer interview, were being asked. And the
interviewers did not know which women had had cancer.
But the results were clear:
there was no association between
stressful events in the previous five years and a diagnosis of breast
cancer. Other studies had the same result.
Still, not everyone was convinced. Critics
told Dr. Newcomb and her colleague, Dr. Felicia Roberts, that they had
measured stressors, not stress. And Dr. Newcomb had to agree that they had
a point. She chose stressful life events as a surrogate for experienced
stress, but it is not easy to measure the actual physiological stress that
people experience and then follow them to see if they got cancer.
Barrie Cassileth, chief of the integrative
medicine service at Memorial Sloan-Kettering Cancer Center, suggested that
there was another way to ask the question.
"These are what we call natural experiments
in the real world," Dr. Cassileth said. "Look
at situations of extreme stress or distress - being in a concentration
camp, being a prisoner of war. How about a mother losing a child?
"People in all of those circumstances have been followed. And they have no
higher incidence of cancer."
Many large studies of cancer and stress
were done in Denmark, which has national records of illnesses. One looked
at the incidence of cancer in
11,380 parents whose children had cancer, surely a stressful event, Dr.
Cassileth said. The parents, though, had no more cancer than members of
the general population.
Another study looked at the
cancer rate among 21,062 parents
who had lost a child. There was no increase in cancer among the parents
for up to 18 years afterward. A third Danish study looked at cancer rates
among 19,856 parents who had a child with schizophrenia. Once again, there
was no increase in cancer.
also is unclear whether stress reduction can improve the prognosis of
people who already have cancer.
"If the question is, Have we established
it?, the answer is, Absolutely not," said Sheldon Cohen, a psychology
professor at Carnegie Mellon University who has studied the role of
support groups and stress reduction in cancer. "If the question is, Would
it work?, we don't know that, either."
The concern, Dr. Cassileth said, is that
cancer patients, under enormous stress, often worry that they are hurting
their own prognosis. And patients who look back over their lives and
remember that they went through stressful times before their diagnosis
often conclude they brought the cancer on themselves.
"People need answers," Dr. Cassileth said.
For many, a diagnosis of cancer is a
complete shock. They thought that they were healthy; they were exercising
and eating right. "They are at a loss to understand why that happened to
them," she said.
And, she added, all people can find stress
in their lives if they look for it.
"I tell them they did not cause their
cancer. Absolutely not," Dr. Cassileth said.
The question for Dr. Drew Pardoll, director
of the cancer immunology program at Johns Hopkins' Kimmel Comprehensive
Cancer Center, was not whether stress causes cancer. It was how cancers
can even exist.
The white blood cells of the immune system
are always bumping into cancer cells. They should attack cancers as
foreign bodies and destroy them. Why don't they? Is it that the immune
system is too weak? Or is it something else?
As it turns out, Dr. Pardoll and others
found, it was something else, and not at all what most scientists
old idea, Dr. Pardoll said, was that cancers arise every day but the
immune system destroys them. Anything that weakens the immune system -
stress, for example - could hinder this surveillance. The result would be
a cancer that grows large enough to resist the body's effort to heal
itself. "Nobody believes that anymore," Dr. Pardoll said.
Dr. Fred Applebaum, director of the
clinical research division at the Fred Hutchinson Center, said that he and
most other cancer experts believed the theory. But then they looked at
mice that were genetically engineered to have no functioning immune
"They really don't show a huge increase in
the incidence of cancer," Dr. Applebaum said.
For example, researchers looked at people
whose immune systems were
suppressed because they were taking drugs to prevent rejection of a
transplanted organ or because they had AIDS.
are small increases in certain types of cancers," Dr. Applebaum said, but
those tend to be cancers that are associated with infections - like
stomach cancer, associated with ulcer-causing Helicobacter pylori; liver
cancer, associated with hepatitis B and hepatitis C infections; Kaposi's
sarcoma, associated with herpesvirus 8 infections; lymphoma, associated
with Epstein-Barr virus; and cervical cancer, associated with human
common types of cancer, the ones
that cause the huge burden of suffering in humans, really aren't increased,"
What happens to the immune system in cancer
patients? It should be protecting them. Every tissue of the body is larded
with white blood cells, and cancers are no exception. In fact, Dr. Pardoll
said, in some tumors, including melanomas and kidney cancers, white blood
cells make up 50 percent of the cancer's weight.
cancer cells are clearly foreign tissue. Their surfaces are studded with
proteins that look very different from the proteins on normal cells. The T
cells of the immune system, which should start the attack, are perfectly
capable of recognizing the foreignness of the cancer cells. But for some
reason, they do not.
Why not? The answer, Dr. Pardoll, Dr.
Allison and others have found, is that proteins on the surface of cancer
cells turn off the immune system's attack. At the same time, the tumor is
excreting molecules that recruit immune system cells to help it
metastasize, spreading through tissues and organs. (see
"We knew very little about what regulated
these immune responses to tumors until very recently," Dr. Pardoll said.
"We now are in a position to totally rewrite the book."
immediate consequence of this line of thinking is a new idea for
treatment: scientists could seal off the cancer cells' proteins that block
the immune system and enable white blood cells to kill the tumor. Or they
could make the immune system more aggressive. To do that, they can block a
molecule on the surface of T cells, CTLA-4, that tends to dampen the
The first strategy is only starting to be
investigated because the discoveries are so new. But the second strategy
is well under way.
In mice, said James Allison, chairman of
the immunology program at Sloan-Kettering, some cancers went away after
just a single injection of an antibody to CTLA-4. Other cancers required a
vaccine, as well, to bolster the newly unleashed immune attack. But then,
Dr. Allison found, even the most intractable tumors in mice were
Dr. Allison licensed the technique to
Bristol-Myers Squibb, which is working with Medarex to see if the method
will work in humans. But while the work showed that the immune system can
destroy cancers, at least in mice, it leaves unanswered the question that
plagues many patients: Did a
weakened immune system, possibly weakened by stress, cause cancer in the
Cancer immunologists are skeptical. "There
is absolutely no evidence for that association," Dr. Pardoll said.
Dr. Allison agreed. "I can't rule it out,"
he said, "but I would be very skeptical."