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From OncoLog, March 2011, Vol. 56, No. 3

Assessing and Addressing the Biological Effects of Stress in Cancer Patients

By Joe Munch

Stress has long been linked to cancer progression. But the precise mechanisms by which stress exacts its pro-tumor effects are not fully understood.

At The University of Texas MD Anderson Cancer Center, researchers are working to better understand the role of stress in cancer patients to reduce its negative influence.

Chronic stress

“When people talk about stress, they are often actually talking about a stressor, meaning an event that is challenging, harmful, or that represents loss—an event that is overwhelming to the individual relative to the resources available to manage that situation,” said Lorenzo Cohen, Ph.D., a professor in the Department of Behavioral Science and the director of the Integrative Medicine Program at MD Anderson. “But the event itself is not stress; a person’s interpretation and then biological, psychological, and behavioral response to that event is stress.”

According to Anil Sood, M.D., a professor in the Department of Gynecologic Oncology and the Department of Cancer Biology at MD Anderson, having some stress is not necessarily a bad thing. “Periodic episodes of stress are actually quite adaptive and can improve cognition, improve the ability to function, and enhance the immune system,” he said.

When stress becomes chronic, however, it can have a negative overall effect on the body. Chronic stress—the kind of stress that can arise from being diagnosed with cancer or caring for a family member with a debilitating disease like Alzheimer’s—is defined less by the type of stressor or its duration than by the individual’s perception that the situation is perpetual and uncontrollable. “In chronic stress, there’s basically no end in sight,” Dr. Sood said.

The deleterious effects of chronic stress are many. “Regardless of the instigating event,” Dr. Cohen said, “chronic stress creates a relatively uniform and profound biological effect on every system in the body, literally down to having an impact on how chromosomes function.”

Stress and cancer

The research on stress and cancer is in its infancy. Stress has not been proven to initiate cancer; however, there is ample evidence suggesting that chronic stress can activate certain signaling pathways that can promote tumor growth, progression, and metastasis. But exactly which pathways are involved remains unknown. If the specific pathways can be identified—a feat complicated by the fact that cancer is not a single disease—they can be targeted with therapy to curb the effects of stress.

Most studies of stress in cancer patients have focused on the relationship between stress and the immune system. Instead of merely weakening the entire immune system, as was believed to be the case years ago, chronic stress actually dysregulates the immune system by suppressing the immunological processes that protect the body from viruses and malignancy (e.g., cellular immunity) and promoting the processes that make the body vulnerable to autoimmune disease and cancer progression (e.g., type II cytokine production).

In other words, Dr. Sood said, “In a chronic stress setting, the balance of the immune system is shifted more toward helping the tumor grow.”

Chronic stress elicits two major hormonal responses, each of which has distinct effects on the immune system that may facilitate cancer progression and metastasis. First, chronic stress overstimulates the hypothalamic-pituitary-adrenal axis, ultimately resulting in the prolonged release of glucocorticoids such as cortisol, which causes serious physiological changes in cardiovascular, metabolic, homeostatic, and immunological function. Second, the overstimulation of the hypothalamic-pituitary-adrenal axis spurs the ongoing release of the stress hormones epinephrine (adrenaline) and norepinephrine, which activate certain families of cell receptors, notably beta receptors. The downstream consequences of these receptors’ activation include the activation of proinflammatory cytokine pathways that, in addition to creating inflammation, promote angiogenesis and suppress the body’s immunological response to malignancy.

“There clearly seem to be effects of many of these stress hormones on the immune system. What these effects are and their magnitude and prevalence likely vary depending on the cancer type,” Dr. Sood said.

Identifying the exact sources of these effects would allow researchers to target them with therapy. Given what is known today, future potential pharmacological interventions may include antiinflammatory agents such as naproxen and ibuprofen and beta-adrenergic blocking agents, or beta blockers, which are typically used to treat heart-related conditions such as angina and hypertension. According to Dr. Sood, the initial evidence supporting beta blockers, which inhibit many of the negative effects of stress in part by blocking the action of norepinephrine, is particularly tantalizing. For example, one large study several years ago found that among a number of patients on different antihypertension medications, the patients on beta blockers had the lowest incidence of prostate cancer. A more recent study found that breast cancer patients taking beta blockers were at lower risk of cancer progression and cancer-related death than breast cancer patients not receiving the drugs.

“Identifying those individuals who would be the most likely to be affected by stress pathways could very well be an achievable goal,” Dr. Sood said. “For those patients, an individual intervention or cocktail of interventions could be optimal, but we are certainly not there at this point.”

Stress management

The negative biological effects of chronic stress may also be countered by stress management techniques. Very little research has been done in this area. Dr. Cohen is working to elucidate the impact that behavior-based forms of stress management have on the biology of cancer and on clinical outcomes.

At MD Anderson’s Integrative Medicine Center, patients are provided with resources to help manage their cancer-related stress, including conventional methods such as psychotherapy and cognitive behavioral therapy as well as traditional Eastern mind-body practices such as yoga, meditation, and tai chi. Research conducted at MD Anderson and elsewhere has shown that these types of mind-body practices affect stress hormones and other aspects of the immune system. “All these stress management techniques,” Dr. Cohen said, “are offered on the basic premise of trying to dampen the sympathetic nervous system response, giving the person a chance to calm his or her mind, which in turn will help get the body back to equilibrium.”

Such techniques, which can be implemented at any point of treatment, from early diagnosis through cancer survivorship, show promise in not only improving patients’ quality of life but also tempering their bodies’ biological responses to chronic stress. For example, Dr. Cohen and his colleagues found in one study that prostate cancer patients who were taught stress management skills had lower stress levels before undergoing radical prostatectomy and had better physical functioning 1 year after surgery than did prostate cancer patients who received supportive attention or standard care. They also found that the men in the stress management group had significantly higher immune function 48 hours after surgery than did the men in the supportive attention and standard care groups.

“We have a basic understanding that patients who are effectively able to manage stress in their lives are going to have better quality of life outcomes at minimum, and perhaps better clinical outcomes,” Dr. Cohen said. “One question that remains is: What form of stress management is most effective? For example, is something like yoga—a quintessential mind-body practice made up of meditation, special breathing exercises, and special movements all put together in a systematic, cohesive approach—actually better than gentle stretching exercises and some simple relaxation techniques?”

A $4.5 million grant from the U.S. National Cancer Institute may help Dr. Cohen and his colleagues answer such questions. The grant, the largest awarded for the study of yoga and cancer, will enable the researchers to determine the benefit of incorporating yoga into treatment plans for breast cancer patients. Documenting the potential psychological and biological rewards of this and other types of programs in a rigorous scientific fashion is essential to changing the standard of care.

“Stress management needs to become much more a part of the standard of care,” Dr. Cohen said. “It’s not that all patients will be required to undergo stress management, but it needs to be something that is offered up front and that health care professionals encourage patients to participate in. And it needs to be made available across the cancer care continuum, from early diagnosis to long-term survivorship.”

ADDITIONAL RESOURCES

Cohen L, Parker PA, Vence L, et al. Presurgical stress management improves postoperative immune function in men with prostate cancer undergoing radical prostatectomy [published online ahead of print January 21, 2011]. Psychosom Med. doi: 10.1097/PSY.0b013e31 820a1c26.

Moreno-Smith M, Lutgendorf SK, Sood AK. Impact of stress on cancer metastasis. Future Oncol 2010;6(12):1863–1881.

For more information, contact Dr. Lorenzo Cohen at 713-745-9202, Dr. Anil Sood at 713-745-5266, or the Integrative Medicine Center at 713-794-4700.

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