November 1, 2006. Hormones produced during periods of stress may increase the growth rate of cancer. A new study shows that an increase in norepinephrine, a stress hormone, can stimulate tumor cells to produce two compounds. These compounds can break down the tissue around tumor cells and allow the cells to more easily move into the bloodstream. From there, they can travel to another location in the body to form additional tumors, a process called metastasis.
The research suggests that norepinephrine can also stimulate tumor cells to release another compound that can aid in the growth of new blood vessels that feed cancer cells, hastening the growth and spread of the disease. The work was reported in the latest issue of the journal Cancer Research.
"This opens up an entirely new way of looking at stress and cancer that's different from current interpretations," explained Ronald Glaser, a professor of molecular virology, immunology and medical genetics, and director of the Institute for Behavioral Medicine Research at Ohio State University.
"This suggests a new approach to possibly fight some cancers  the prescribing of beta-blocker-type drugs that would block these receptors and perhaps slow the progression of the disease," Glaser said.
"Using this approach may not cure this cancer but perhaps we could slow down its growth, making the tumor more sensitive to anti-cancer therapy, and therefore extending the patientÂs lifespan and improve their quality of life."
Glaser and Eric Yang, a research scientist in the same institute, focused on the role of three compounds. Two of them, both matrix metalloproteinases -- MMP-2 and MMP-9 -- play a role in breaking down the scaffolding that cells attach to in order to maintain their shape. The third compound, vascular endothelial growth factor (VEGF), is important in the growth of new blood vessels into tumor cells.
Earlier work by Susan Lutgendorf at the University of Iowa found that ovarian cancer patients with greater social support had lower levels of vascular endothelial growth factor (VEGF) in their blood, whereas higher VEGF was found in patients with greater distress.
In the laboratory, researcher Anil Sood at the University of Texas has shown that the two stress hormones - norepinephrine and epinephrine - can stimulate ovarian tumor cells to produce the three pro-metastatic compounds. The key to that discovery was that the two stress hormones would bind to places on the surface of ovarian cancer cells, called adrenergic receptors, and stimulate the release of MMP-2, MMP-9 and VEGF which might then foster cancer growth.
The Ohio State team wanted to see if process demonstrated in the ovarian cancer research done in Texas occurred with other cancer cells. They turned to cell lines Glaser had developed decades ago to study a rare, severe type of nose and throat cancer (NPC) that occurs most frequently among people of Chinese descent. They treated GlaserÂs cell line with norepinephrine and, as predicted, the cells all produced MMP-2, MMP-9 and VEGF. This showed that the receptors for this hormone were present on cells in GlaserÂs cell line. But that might have been just a laboratory aberration in the tissue cultures.
"We needed to see how relevant this finding was to what happened with actual tumors," he said. Glaser asked colleagues for samples of actual NPC tumors to look for the presence of similar receptors. They studied tumor samples which included different types of NPC tumors. All had the sought-after receptors.
"From this we can say that there is likelihood that all NPC tumors will have these receptors as well," he said.
"MMP-2 and MMP-9 contribute to the aggressiveness of these tumors," Yang said. "It isnÂt clear exactly how they are operating but they may work with VEGF to facilitate blood vessel growth in new tumors so that they can grow."
The target adrenergic receptors for these hormones are well-known to clinicians dealing with high-blood-pressure patients. Typically, such patients are given a class of drugs known as beta-blockers which lead to a lowering of blood pressure levels.
Glaser and Yang wanted to see how these same drugs affected these tumor cells. They added propanol, a beta-blocker, to the tumor cells and then exposed them to both norepinepherine and epinephrine. With the drug present, the levels of MMP-2, MMP-9 and VEGF didn't increase.
Support for this research came from the National Cancer Institute, the National Heart, Lung and Blood Institute, the Gilbert and Kathryn Mitchell Endowment and the OSU Comprehensive Cancer Center.
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Sources and links:
Norepinephrine Up-regulates the Expression of Vascular Endothelial Growth Factor, Matrix Metalloproteinase (MMP)-2, and MMP-9 in Nasopharyngeal Carcinoma Tumor Cells [Abstract]
Cancer Res. 2006 66: 10357-10364. Eric V. Yang, Anil K. Sood, Min Chen, Yang Li, Tim D. Eubank, Clay B. Marsh, Scott Jewell, Nicholas A. Flavahan, Carl Morrison, Peir-En Yeh, Stanley Lemeshow, and Ronald Glaser.
Ronald Glaser Ph.D. homepage, Ohio State: Ronald Glaser is Professor of Molecular Virology, Immunology and Medical Genetics at The Ohio State University College of Medicine , and Director of the Institute for Behavioral Medicine Research.
Stress-related mediators stimulate vascular endothelial growth factor secretion by two ovarian cancer cell lines. [Abstract] Clin Cancer Res. 2003 Oct 1;9(12):4514-21. Lutgendorf SK, et al. Department of Psychology, University of Iowa, Iowa City, Iowa 52242, USA.
Susan Lutgendorf homepage U of Iowa
Stress and Ovarian Cancer. Anile Sood. The Health Report, ABC Net Australia, July 2006
Stress HormoneÂMediated Invasion of Ovarian Cancer Cells. Clinical Cancer Research Vol. 12, 369-375, January 2006. Anil Sood et a. The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
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