Stress can promote breast cancer cell colonization of bones, Vanderbilt Center for Bone Biology investigators have discovered. The preclinical studies, reported on July 17 in PLoS Biology, demonstrate that activation of the sympathetic nervous system, which is active in response to stress, primes the bone environment for breast cancer cell metastasis.

In addition, the researchers were able to prevent breast cancer metastasis in bones by propranolol, a cardiovascular medicine that inhibits sympathetic nervous system signals.

Sympathetic nervous system stimulates bone remodelling
Florent Elefteriou, PhD, director of the Vanderbilt Center for Bone Biology and associate professor of medicine, pharmacology and cancer biology, and his colleagues knew from their previous studies that the sympathetic nervous system stimulated bone remodelling, and that it used some of the same signalling molecules that have been implicated in breast cancer metastasis to bone.

Stress and depression
They came to the hypothesis that sympathetic activation might remodel the bone environment and make it more favourable for cancer cells to metastasize. Evidence from the clinic supported this notion. Breast cancer patients who suffered from stress or depression following their primary treatment had shorter survival times. Both stress and depression activate the sympathetic nervous system.

Benefits of treatment
Efforts to reduce stress and depression in patients with cancer may have unappreciated benefits in terms of metastasis prevention. To explore the possible link, the researchers studied cancer cell metastasis in mice. They followed fluorescently tagged human breast cancer cells that were injected into the mouse heart to model the stage of metastasis when breast cancer cells leave the primary site and move through the circulation.

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Sympathetic nervous system activation
The researchers found that treating the mice with a drug that mimics sympathetic nervous system activation caused more cancer lesions in bone. Using physical restraint to stress the mice and activate the sympathetic nervous system also caused more metastases in bones. Treating the restrained mice with propranolol (Propranolol Hydrochloride; Inderal? LA, Whyeth/Pfizer), which belongs to a family of blood pressure medicines beta-blockers, reduced the number of bone lesions.

Signaling molecule RANKL
The investigators demonstrated that sympathetic nervous system activation increases bone levels of a signaling molecule RANKL, which is known to promote the formation of osteoclasts, bone cells that break down bone tissue. RANKL has also been implicated in cell migration, and Elefteriou and colleagues were able to show that breast cancer cell migration to the bone depends on RANKL.

Preventing breast cancer cell metastasis to bone
The findings suggest that beta-blockers or drugs that interfere with RANKL signalling, such as denosumab (Xgeva?, Amgen), may be useful in preventing breast cancer cell metastasis to bone. Propranolol and other beta-blockers are inexpensive, well characterized, and safe in most patients. They may be a good choice for long-term treatment if future studies in patients with breast cancer confirm their ability to block cancer cell metastasis to bone.

About the study
Graduate student Preston Campbell is the first author of the PLoS Biology paper. The research was supported by grants from the USA National Cancer Institute (CA040035), the National Center for Advancing Translational Sciences (RR024975), and the National Institute of General Medical Sciences (GM007628) of the National Institutes of Health.

References:
Campbell JP, Karolak MR, Ma Y, Perrien DS, Masood-Campbell SK, Penner NL, et al. Stimulation of host bone marrow stromal cells by sympathetic nerves promotes breast cancer bone metastasis in mice.PLoS Biol. 2012 Jul;10(7):e1001363. Epub 2012 Jul 17. [Download PDF]

For more information:
– Inderal Long-Acting Capsules U.S. Physician Prescribing Information(PDF)
Denosumab/Xgeva? U.S.Physician Prescribing Information (PDF)

Other Studies:
Yoneda T. Anti-RANKL antibody for the management of bone metastasis
Gan To Kagaku Ryoho. 2011 Sep;38(9):1439-45. [Article in Japanese]

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