New research published in the journal Brain, Behavior, and Immunity suggests that the use of commonly prescribed blood pressure medicines called beta-blockers might slow the development of malignant melanoma, a particularly aggressive form of skin cancer.

Researchers at the Ohio State University have been looking for links between stress hormones and diseases like cancer. Eric V. Yang, a research scientist at the Institute for Behavioral Medicine Research (IBMR), exposed samples of three melanoma cell lines to the compound norepinephrine, a naturally occurring catecholamine that functions as a stress hormone. In times of increased stress, levels of norepinephrine increase in the bloodstream.

Yang and colleague Ronald Glaser were looking for changes in the levels of three proteins released by the cells. One of the proteins – vascular endothelial growth factor (VEGF) – plays a key role in stimulating angiogenesis, or the growth of new blood vessels needed to feed a growing tumor. The other two proteins, Interleukin-6 and Interleukin-8, are both involved in fostering tumor growth.

All three of the cell lines were grown from tissues taken from secondary tumors that had metastasized from a primary site, and signify aggressive forms of cancer. But one of them – C8161 – represented the most aggressive and advanced form of melanoma.

"We noticed that all three of these proteins increased in response to the norepinephrine," Yang explained, adding that in the C8161 cells, "we got a 2,000 percent increase in IL-6. In untreated samples from this cell line, you normally can't detect any IL-6 at all. What this tells us is that stress might have a worse effect on melanoma that is in a very aggressive or advanced stage, and that one marker for that might be increased levels of IL-6," he said.

The researchers ruled out cell proliferation – an increase in the number of cells present – as a reason for the increase in all three proteins. That meant that the only other answer was that the cells were increasing their expression of the genes responsible for producing these compounds. Their experiments showed that the norepinephrine molecule binds to receptors on the surface of cancer cells, and once this linkage occurs it stimulates the release of the proteins that support angiogenesis and tumor growth.

Yang and Glaser first confirmed that the receptors were present on cells in all three cell lines and then tested what would happen when the receptors were blocked by common blood pressure medicine – the so-called "beta-blockers." When the beta-blockers did bind to the receptors, the production of the three proteins was reduced significantly, suggesting that in patients with melanoma, using these types of medications might be used to slow the progression of the disease.

While the study was restricted to tumor cell lines grown in the laboratory, the findings are still exciting. The researchers found strong evidence that the same receptors are expressed on the surface of tumor cells from biopsies that were taken from melanoma patients, which supports the clinical importance of the results.

Two earlier studies on different tumor cell lines – one prepared from a multiple myeloma and the other from a nasopharyngeal carcinoma – also showed that exposure to norepinephrine increased the levels of proteins responsible for accelerating tumor growth.

The research is showing not only that different forms of cancer react differently to stress hormones but also that those reactions can vary within a specific form of the disease, with the possibility of a more aggressive form of the disease reacting more strongly to the stressors.

For melanoma patients, that can be very important since these tumors are able to metastasize, or spread, when they are much smaller than most other solid cancers. The American Cancer Society estimates that nearly 48,000 cases of melanoma are diagnosed each year and nearly 8,000 people are killed each year by the disease.

By Roderick Smith, M.S.

References: Yang EV, Kim Seung-jae, Donovan EL, Chen M, Gross AC, Marketon JIW, Barsky SH, Glaser R. Norepinephrine upregulates VEGF, IL-8, and IL-6 expression in human melanoma tumor cell lines: implications for stress-related enhancement of tumor progression. Brain, Behavior, and immunity 2009; 23:267-275