"Let me ask you this," begins Dr. Steven W. Cole, "with all we know about how stress aggravates cardiovascular disease, promotes viral infections, exacerbates metabolic diseases, halts reproduction, and regulates the normal function of virtually every cell in the body, why would cancer cells somehow be exempt?"

As associate professor of medicine at UCLA, Dr. Cole makes the point rhetorically to his students, pointing them to the growing literature showing that prime actors in the human stress response - catecholamines and glucocorticoids - can regulate some key aspects of cancer biology. NCI, through the Basic and Biobehavioral Research Branch (BBRB) in the Division of Cancer Control and Population Sciences, has supported much of this work.

"There's not much evidence that stress directly causes cancer," says Dr. Paige McDonald, acting chief of BBRB. "We know it is neither necessary nor sufficient to initiate the carcinogenic process." But, she notes, recent studies have shown that stress hormones can accelerate the growth of established tumors.

"Human cancer is quite complex," explains Dr. Anil Sood, professor of gynecologic oncology and cancer biology at the University of Texas M.D. Anderson Cancer Center. "Yet there are epidemiologic and experimental animal studies linking stress to tumor growth. In advanced solid tumors, such as ovarian cancer, we thought that the impact of stress on tumor biology had to go beyond stress effects on the immune system."

"Now we're looking much harder at the direct impact of neuroendocrine hormones on the tumor itself," says Dr. McDonald.

Recently, cancer biologists and psychologists have begun to work together to clarify how the brain interprets phenomena, releases hormones in response, and how those neuroendocrine factors may influence or regulate some of the key steps in tumor growth, including not only angiogenesis, but also cell proliferation, tumor invasion, and metastasis.

In an article published online July 23 in Nature Medicine, Dr. Sood and colleagues showed that - when exposed to catecholamines released by the sympathetic nervous system of mice put under stress - ovarian cancer cells that had been injected into the mice stimulated angiogenesis, increased in number, and began to metastasize.

Eventually Dr. Sood's group not only described the genes, molecules, and pathways involved, but identified a new molecular target for slowing tumor progression - beta-adrenergic receptors expressed on the tumor cell surface. "We routinely try to recapitulate human disease in our models," said Dr. Sood, "but we were surprised that nearly all of the ovarian cancer cell lines we tested had receptors for the stress-produced hormones."

Once they identified beta-adrenergic receptors as mediators of stress effects, the scientists tried to confirm what was happening by adding drugs that would either enhance or block those receptors. When they tried propranolol (Inderal), the effect of the stress-generated hormones was completely blocked. This nonspecific beta-blocker was originally marketed for high blood pressure. Dr. Sood's results suggest that such beta-blockers may one day assume a role in adjuvant chemotherapy for cancer.

With results like this, the entire field of stress biology begins to take new shape. "Previously, the assumption was that stress is a psychological influence," says Dr. Cole, "so its treatment should be at a psychological level, with elements such as psychotherapy, meditation, or guided imagery. This work suggests we might be able to protect cancer patients from the detrimental effects of stress using a pharmacologic approach."

Work like Dr. Sood's provides insight into the biochemical complexity of stress, and opens up the neuroendocrine system as a new context for developing strategies to combat the influence of stress hormones on cancer pathogenesis. NCI's Ovarian Cancer Specialized Program of Research Excellence (SPORE) at M.D. Anderson is supporting much of this work as well, illustrating its clinical relevance.

Further evidence comes from an NCI-supported study at the University of Iowa. Dr. Susan Lutgendorf interviewed women about to undergo surgery for ovarian cancer, and then obtained fresh tissue samples from the tumor. Women who lacked social support and had higher levels of distress were found to have tumors with higher levels of vascular endothelial growth factor, demonstrating for the first time "an association between a psychological factor and a cytokine involved in tumor angiogenesis among patients with malignant disease," she writes.

According to Dr. Cole, it makes sense that tumor cells would exploit stress biology because the healthy cells from which they develop often express receptors for catecholamines and glucocorticoids. A number of cancers are caused by viruses, and most cancer-related viruses have evolved DNA sequences that respond to either the corticoids or the catecholamines, he explains. "Stress biology is a niche into which many human pathogenic viruses have evolved," says Dr. Cole.

These scientists recently published an article on stress regulation of tumor biology in the March 2006 issue of Nature Reviews Cancer, "The influence of bio-behavioural factors on tumour biology: pathways and mechanisms." The experimental evidence supporting this perspective highlights the potential for novel therapeutic strategies that consider the role of stress on tumor growth and metastasis.

"Advances in cell biology and basic science have allowed us to see that cancer is not a homogenous disease," says Dr. McDonald, "and we think this work has implications for many other cancers beyond the ovarian model discussed here, perhaps to most of the cancers that involve epithelial changes."