Reducing Stress Retards Breast Cancer Metastasis to the Bone

Molecular messengers secreted by the immune system in times of stress activate a metabolic pathway that encourages breast cancer cells to migrate from the site of the primary tumor into bone.

Bone and lung metastases are responsible for the majority of deaths in patients with breast cancer. Having previously shown that the sympathetic nervous system stimulated bone remodeling, and that it used some of the same signaling molecules that have been implicated in breast cancer metastasis to bone, investigators at Vanderbilt University (Nashville, TN, USA) examined the role of stress (stimulation of the sympathetic nervous system) in a mouse breast cancer model.

They reported in the July 17, 2012, online edition of the journal PLoS Biology that sympathetic nervous system activation increased bone levels of the signaling molecule RANKL, which was known to promote the formation of osteoclasts, bone cells that break down bone tissue. RANKL (receptor activator of nuclear factor kappa-B ligand) is a member of the tumor necrosis factor (TNF) cytokine family. It is a ligand for osteoprotegerin and functions as a key factor for osteoclast differentiation and activation. RANKL also has a function in the immune system, where it is expressed by T helper cells and is thought to be involved in dendritic cell maturation. T cell activation was reported to induce expression of this gene and lead to an increase in the number of osteoclasts and bone loss. Overproduction of RANKL has been implicated in a variety of degenerative bone diseases, such as rheumatoid arthritis and psoriatic arthritis.

Blocking sympathetic activation (i.e., lowering the level of stress) with a beta-blocker such as propranolol or inhibiting RANKL signaling in cancer cells with denosumab, reversed the stimulatory effect of sympathetic activation on bone metastasis in the mouse model. Denosumab, which was designed to target RANKL, is a fully human monoclonal antibody approved by the [US] Food and Drug Administration (FDA) for the treatment of osteoporosis, treatment-induced bone loss, bone metastases, rheumatoid arthritis, multiple myeloma, and giant cell tumor of bone.

"We came to the hypothesis that sympathetic activation might remodel the bone environment and make it more favorable for cancer cells to metastasize there," said senior author Dr. Florent Elefteriou, associate professor of medicine, pharmacology, and cancer biology at Vanderbilt University. "Preventing metastasis is really the goal we want to achieve. If something as simple as a beta-blocker could prevent cancer metastasis to bone, this would impact the treatment of millions of patients worldwide."

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