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 β2AR 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 β-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 βAR-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.
Source: Stimulation
of host bone marrow stromal cells by sympathetic nerves promotes breast cancer
bone metastasis in mice. Campbell JP, Karolak MR, Ma Y, Perrien DS,
Masood-Campbell SK, Penner NL, Munoz SA, Zijlstra A, Yang X, Sterling JA,
Elefteriou F (florent.elefteriou@vanderbilt.edu).
PLoS Biol. 2012 Jul;10(7):e1001363.
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