Stimulation of Host Bone Marrow Stromal Cells by Sympathetic Nerves Promotes Breast Cancer Bone Metastasis in Mice

被引:157
作者
Campbell, J. Preston [1 ,2 ]
Karolak, Matthew R. [1 ,2 ]
Ma, Yun [2 ,3 ]
Perrien, Daniel S. [2 ,4 ,5 ]
Masood-Campbell, S. Kathryn [2 ,3 ]
Penner, Niki L. [6 ]
Munoz, Steve A. [2 ,3 ]
Zijlstra, Andries [2 ,7 ,8 ]
Yang, Xiangli [1 ,2 ,3 ]
Sterling, Julie A. [2 ,3 ,8 ,9 ]
Elefteriou, Florent [1 ,2 ,3 ,8 ]
机构
[1] Vanderbilt Univ, Dept Pharmacol, Nashville, TN 37203 USA
[2] Vanderbilt Univ, Vanderbilt Ctr Bone Biol, Nashville, TN USA
[3] Vanderbilt Univ, Dept Med, Div Clin Pharmacol, Nashville, TN USA
[4] Vanderbilt Univ, Dept Orthopaed Surg & Rehabil, Nashville, TN USA
[5] Vanderbilt Univ, Inst Imaging Sci, Nashville, TN USA
[6] Vanderbilt Univ, Dept Med, Div Allergy Pulm & Crit Care Med, Nashville, TN USA
[7] Vanderbilt Univ, Dept Pathol Microbiol & Immunol, Nashville, TN USA
[8] Vanderbilt Univ, Dept Canc Biol, Nashville, TN USA
[9] Dept Vet Affairs VISN 9, Nashville, TN USA
关键词
BETA-ADRENERGIC-RECEPTORS; OSTEOBLAST-LIKE CELLS; NERVOUS-SYSTEM; TUMOR PROGRESSION; FREE SURVIVAL; MOUSE MODEL; EXPRESSION; INHIBITION; GROWTH; ACTIVATION;
D O I
10.1371/journal.pbio.1001363
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
070307 [化学生物学]; 071010 [生物化学与分子生物学];
摘要
Bone and lung metastases are responsible for the majority of deaths in patients with breast cancer. Following treatment of the primary cancer, emotional and psychosocial factors within this population precipitate time to recurrence and death, however the underlying mechanism(s) remain unclear. Using a mouse model of bone metastasis, we provide experimental evidence that activation of the sympathetic nervous system, which is one of many pathophysiological consequences of severe stress and depression, promotes MDA-231 breast cancer cell colonization of bone via a neurohormonal effect on the host bone marrow stroma. We demonstrate that induction of RANKL expression in bone marrow osteoblasts, following beta 2AR stimulation, increases the migration of metastatic MDA-231 cells in vitro, independently of SDF1-CXCR4 signaling. We also show that the stimulatory effect of endogenous (chronic stress) or pharmacologic sympathetic activation on breast cancer bone metastasis in vivo can be blocked with the beta-blocker propranolol, and by knockdown of RANK expression in MDA-231 cells. These findings indicate that RANKL promotes breast cancer cell metastasis to bone via its pro-migratory effect on breast cancer cells, independently of its effect on bone turnover. The emerging clinical implication, supported by recent epidemiological studies, is that beta AR-blockers and drugs interfering with RANKL signaling, such as Denosumab, could increase patient survival if used as adjuvant therapy to inhibit both the early colonization of bone by metastatic breast cancer cells and the initiation of the "vicious cycle" of bone destruction induced by these cells.
引用
收藏
页数:12
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