PLoS Biol：抑制交感神经具有抗乳腺癌转移功效

近日，Vanderbilt骨生物学研究中心发现应激可以促进乳腺癌定植于骨细胞。这项研究发表于7月17的PLoS Biology杂志上，研究证明在小鼠体内，激活交感神经系统会促进乳腺癌细胞转移到骨。研究人员使用心血管药普萘洛尔抑制交感神经系统的信号后，发现可以防止骨乳腺癌细胞病变。

骨生物学中心主任Florent Elefteriou表示：癌细胞扩散到远处器官即转移比原发性乳房癌更有可能杀死肿瘤患者。

Elefteriou和他的同事们都的早期研究发现交感神经系统刺激骨重塑，而这些刺激信号已被证实在乳腺癌转移至骨中发挥作用。

Elefteriou说，我们来假设交感神经的活化可能重塑骨环境，使其更利于癌细胞转移。

研究人员研究了小鼠体癌细胞的转移过程。用荧光标记人乳腺癌细胞后注射到小鼠心脏建模，观察乳腺癌细胞通过血液循环离开原发位和移动情况。
 
他们发现，激活交感神经系统的药物给予小鼠后，结果小鼠骨内更多癌症病变部位。激活老鼠自身体内的交感神经系统也引起骨更多的癌病变。给予普萘洛尔治疗的小鼠可以减少骨病变的数目。

研究表明交感神经系统的激活增加RANKL信号分子，促进破骨细胞的形成，骨组织被破坏后有利于癌细胞转移。RANKL也与细胞迁移有关，Elefteriou和他的同事们证实乳腺癌细胞移植到骨依赖RANKL信号分子。

如果β受体阻滞剂可以防止癌细胞转移到骨骼，那这会影响全世界数百万患者的治疗。研究人员补充说，尽量减少癌症患者的压力和抑郁症状可能有预防肿瘤转移。

拓展阅读:

JCO：β受体阻滞剂普萘洛尔降低乳腺癌死亡率

JCO：β受体阻滞剂改善乳腺癌患者RFS而非OS

Cancer: β受体阻滞剂并不降低结直肠癌风险

doi:10.1371/journal.pbio.1001363
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Stimulation of Host Bone Marrow Stromal Cells by Sympathetic Nerves Promotes Breast Cancer Bone Metastasis in Mice.

J. Preston Campbell, Matthew R. Karolak, Yun Ma, Daniel S. Perrien, S. Kathryn Masood-Campbell, Niki L. Penner, Steve A. Munoz, Andries Zijlstra, Xiangli Yang, Julie A. Sterling, Florent Elefteriou.

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.