BoneKEy Reports | BoneKEy Watch

Blocking the impact of chronic stress on bone metastasis

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DOI:10.1038/bonekey.2012.190

Severe stress and depression, both of which occur in some women diagnosed with primary breast cancer, can activate the sympathetic nervous system and can result in physiological consequences. Studies using a murine model of bone metastasis revealed that sympathetic activation influences the bone marrow stroma through a neurohormonal effect, increasing the level of bone colonization by MDA-231 breast cancer cells.

The mechanism involved centers on bone marrow osteoblasts, which express RANKL after being stimulated by β2AR. In vitro, this promotes migration of metastatic MDA-231 cells, an effect that does not depend on DSF1-CXCR4 signaling.

Of therapeutic interest was the observation that endogenous stress or pharmacological activation of the sympathetic system increased bone metastasis in vivo in the mouse model, but this effect was blocked if the mice were treated with propranolol. This β-blocker rendered MDA-231 cells unable to express RANK. The authors suggest that β2AR blockers, denosumab and other drugs that block RANKL signaling may be useful adjuvant therapies to reduce bone metastasis.

Editor's comment: Campbell and colleagues provide strong evidence that sympathetic activation increases RANKL production in the bone microenvironment and stimulates breast cancer bone metastasis formation. This suggests that the use of β-blockers combined with standard antiresorptive therapies may be an interesting strategy for the treatment of advanced breast cancer.

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