||Miércoles 30 de Noviembre de 2005, Ip nº 137
|Is There a Link Between Stress and Cancer?
Por GINA KOLATA
Christina Koenig found out she had breast cancer on a Friday afternoon. She was just 39 years old.
On Monday, she thought she knew why the cancer had struck.
"I went in and talked to a team of medical professionals who ultimately performed a lumpectomy, and I said, 'How long has this been there?' They said, 'Five to ten years.' And immediately, my mind jumped to: 'Well, I did go through a divorce. I did have stress.' "
Ms. Koenig, who lives in Chicago, was divorced four years before her cancer was diagnosed. Was it just a coincidence, she wondered?
Now, four years later, she still wonders. So do many other women who get breast cancer. Ms. Koenig now works for Y-ME National Breast Cancer Organization, which gets 40,000 calls a year on its hot line. Over and over, she says, women ask, Did stress cause their cancer by weakening their immune system and allowing a tumor to grow?
"It's a widespread belief," Ms. Koenig said.
And it is not restricted to women with breast cancer.
Jim Kiefert of Olympia, Wash., is absolutely convinced that stress led to his prostate cancer. It was diagnosed in 1989, when he was 50. Mr. Kiefert was a school superintendent, and he was in the midst of difficult negotiations with teachers over their contracts. "I was stressed out," he says. "I know stress caused my cancer."
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.
As 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.
It 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 expected.
The 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 systems.
"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.
"There 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 papillomavirus.
"The common types of cancer, the ones that cause the huge burden of suffering in humans, really aren't increased," he said.
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.
And 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.
"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."
One 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 immune response.
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 destroyed.
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 first place?
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."
Christina Koenig said that her group, Y-ME, is careful in its response to women who think stress caused their breast cancer. While Ms. Koenig said she thought it might have contributed in her case, she knows what scientists say and she does not want to overstate the evidence.
When women ask, she said, Y-ME hot line peer counselors tell them, "We don't have scientific evidence" and focus on recruiting emotional support to help them now, when they are dealing with treatment and survival.
As for Mr. Kiefert, he is now chairman of the board of Us Too, an advocacy and support group for cancer patients, and he does not hesitate to tell men what he believes: that stress caused his cancer, that stress fuels the growth of the prostate cancer cells that are still in his body, and that stress may well have caused their cancer, too.
That is not what many men want to hear, he said.
"Men almost never like to admit that they are under stress," Mr. Kiefert said. "Our male ego says it is a sign of weakness. We have a tendency to keep it inside, we try to tough it out." Not him, he adds. He still has prostate cancer, and he has changed his life.
"I avoid stress," Mr. Kiefert says. "I know what happens when I'm under stress."
|| 29/11/2005. The New York Times.