Preclinical Study Shows Chronic Stress Agitates Ovarian Cancer; Reducing Stress Slows Tumor Growth

The finding, published in the journal Nature Medicine, now available on-line, provides the first measurable link between psychological stress and the biological processes that make ovarian tumors grow and spread. Specifically, the researchers showed that stress hormones bind to receptors directly on tumor cells and, in turn, stimulate new blood vessel growth and other factors that lead to faster and more aggressive tumors.

"This study provides a new understanding of how chronic stress and stress factors drive tumor growth," says Anil Sood, M.D., associate professor of gynecologic oncology and cancer biology and director of ovarian cancer research.

In fact, when the researchers blocked the stress hormone receptors in their experimental system using a heart disease drug called propranolol, also known as a "beta blocker," they were able to stop the negative effects of stress on tumor growth. The researchers used the beta blocker because the same hormone receptors, called beta adrenergic receptors, are found in the heart and normally work to maintain blood flow.

"The concept of stress hormone receptors directly driving cancer growth is very new," says Sood, the study's senior author. "Not much had been known about how often these receptors are expressed in cancer, and more importantly, whether they had any functional significance. Our research opens a new area of investigation."

The research began when Sood and his colleague Susan Lutgendorf found an association between ovarian cancer patients who reported high levels of stress in their lives and an increase in a factor that stimulates blood vessel growth in tumors. By contrast, patients who had more social support in their lives had lower levels of this factor. Sood wondered if hormones associated with chronic stress might affect how cancers grow.

Sood's research team, led by investigators Premal Thaker, M.D., Liz Han, M.D., and Aparna Kamat, M.D., in the Department of Gynecologic Oncology, developed a mouse model of ovarian cancer to study the link. In their experiments, the researchers confined the mice in a small space for zero, two or six hours during the day.

The confinement caused the mice to produce the same stress hormones as humans produce when they are under stress. These beta adrenergic hormones are sometimes called the "fight-or-flight" hormones because they are released when people are fearful or threatened, and are also responsible for causing the heart to beat harder and faster.

Sood and his colleagues found that, surprisingly, cancer cells make receptors for these hormones on their surface and that when these receptors are activated they set in motion a chain of events that leads to formation of new blood vessels that feed tumors, a process called angiogenesis. New blood vessel formation is known to allow tumors to grow and spread more rapidly.

"We were quite surprised to find these beta adrenergic receptors on ovarian cancer cells," says Sood. "In fact, we found them in 17 of 19 ovarian cancer cell lines we tested."

After three weeks, the researchers measured the number and size of tumors in the mice. The number of tumors was 2.5 times greater in the mice that had been in the 2-hour stress group and 3.6 times greater in the 6-hour stress group compared to the mice with no stress. In addition, tumor growth was confined in the no-stress mice, but had spread to the liver or spleen in half of the stressed mice.

In additional experiments, the researchers gave the stressed mice propranolol, which blocked the effect of stress hormones. The medication completely neutralized the effect of stress on tumor growth," says Sood.

"Beta blockers have been shown to be protective against cardiac disease," he says. "No one has studied their effect on chronic stress as it relates to cancer in humans. There is a lot of interest now in this area of combining behavioral interventions to reduce stress, as well as using beta blockers in cancer patients."

In follow-up studies, Sood and his team are in the process of further refining the role of stress in cancer using animal models and examining the hormone receptor status of cancers besides ovarian cancer.

Other members of the research team included Chunhua Lu, M.D., Nicholas Jennings, Guillermo Armaiz-Pena, James Bankson, Ph.D., Murali Ravoori, Ph.D., William Merritt, M.D., Yvonne Lin, M.D., Selanere Mangala, Ph.D., Tae Jin Kim, M.D., Robert Coleman, M.D., Charles Landen, M.D., Yang Li, Edward Felix, Robert Newman, Ph.D. Mary Lloyd, David Gershenson, M.D., Vikas Kundra, M.D., Ph.D., Gabriel Lopez-Bernstein, M.D., of M. D. Anderson, and Steven Cole, Ph.D., Jesusa Arevalo, Rie Takahashi, of UCLA, and Susan Lutgendorf of the University of Iowa. The research was funded by grants from the National Institutes of Health, the M. D. Anderson Ovarian Cancer SPORE, a Program Project Development Grant from the Ovarian Cancer Research Fund, Inc., and a Donna Marie Cimitile-Fotheringham Award for Ovarian Cancer Research.