Stress can Spur Cancer Growth; Heart Drug May Halt that Process

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Preclinical Study Shows Chronic Stress Agitates Ovarian Cancer;

Reducing Stress Slows Tumor Growth

M. D. News Release 07/23/06

When mice with ovarian cancer are stressed, their tumors grow and

spread more quickly, but that effect can be blocked using a

medication commonly prescribed for heart disease, according to a

preclinical study by researchers at The University of Texas M. D.

Cancer Center.

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 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.,

Jennings, Guillermo Armaiz-Pena, Bankson, Ph.D.,

Murali Ravoori, Ph.D., Merritt, M.D., Lin, M.D.,

Selanere Mangala, Ph.D., Tae Jin Kim, M.D., , M.D.,

Landen, M.D., Yang Li, Felix, Newman, Ph.D.

Lloyd, Gershenson, M.D., Vikas Kundra, M.D., Ph.D.,

-Bernstein, M.D., of M. D. , and Cole,

Ph.D., Jesusa Arevalo, Rie Takahashi, of UCLA, and Lutgendorf

of the University of Iowa. The research was funded by grants from the

National Institutes of Health, the M. D. 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.