Mulcrone Patrick L, Campbell J Preston, Clément-Demange Lise, Anbinder Ana Lia, Merkel Alyssa R, Brekken Rolf A, Sterling Julie A, Elefteriou Florent
Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA.
Vanderbilt Center for Bone Biology, Vanderbilt University, Nashville, TN, USA.
J Bone Miner Res. 2017 Jul;32(7):1442-1454. doi: 10.1002/jbmr.3133. Epub 2017 Apr 28.
The skeleton is a common site for breast cancer metastasis. Although significant progress has been made to manage osteolytic bone lesions, the mechanisms driving the early steps of the bone metastatic process are still not sufficiently understood to design efficacious strategies needed to inhibit this process and offer preventative therapeutic options. Progression and recurrence of breast cancer, as well as reduced survival of patients with breast cancer, are associated with chronic stress, a condition known to stimulate sympathetic nerve outflow. In this study, we show that stimulation of the beta 2-adrenergic receptor (β2AR) by isoproterenol, used as a pharmacological surrogate of sympathetic nerve activation, led to increased blood vessel density and Vegf-a expression in bone. It also raised levels of secreted Vegf-a in osteoblast cultures, and accordingly, the conditioned media from isoproterenol-treated osteoblast cultures promoted new vessel formation in two ex vivo models of angiogenesis. Blocking the interaction between Vegf-a and its receptor, Vegfr2, blunted the increase in vessel density induced by isoproterenol. Genetic loss of the β2AR globally, or specifically in type 1 collagen-expressing osteoblasts, diminished the increase in Vegf-positive osteoblast number and bone vessel density induced by isoproterenol, and reduced the higher incidence of bone metastatic lesions induced by isoproterenol after intracardiac injection of an osteotropic variant of MDA-MB-231 breast cancer cells. Inhibition of the interaction between Vegf-a and Vegfr2 with the blocking antibody mcr84 also prevented the increase in bone vascular density and bone metastasis triggered by isoproterenol. Together, these results indicate that stimulation of the β2AR in osteoblasts triggers a Vegf-dependent neo-angiogenic switch that promotes bone vascular density and the colonization of the bone microenvironment by metastatic breast cancer cells. © 2017 American Society for Bone and Mineral Research.
骨骼是乳腺癌转移的常见部位。尽管在治疗溶骨性骨病变方面已取得显著进展，但对于驱动骨转移过程早期步骤的机制仍了解不足，难以设计出抑制该过程并提供预防性治疗选择所需的有效策略。乳腺癌的进展和复发以及乳腺癌患者生存率的降低与慢性应激有关，慢性应激是一种已知会刺激交感神经输出的状态。在本研究中，我们表明，使用异丙肾上腺素作为交感神经激活的药理学替代物刺激β2肾上腺素能受体（β2AR），会导致骨中血管密度增加和Vegf-a表达升高。它还提高了成骨细胞培养物中分泌的Vegf-a水平，因此，来自异丙肾上腺素处理的成骨细胞培养物的条件培养基在两种体外血管生成模型中促进了新血管形成。阻断Vegf-a与其受体Vegfr2之间的相互作用，可减弱异丙肾上腺素诱导的血管密度增加。β2AR在整体上的基因缺失，或在表达I型胶原蛋白的成骨细胞中的特异性缺失，会减少异丙肾上腺素诱导的Vegf阳性成骨细胞数量增加和骨血管密度，并降低心内注射MDA-MB-231乳腺癌骨趋向性变体后异丙肾上腺素诱导的骨转移病变的较高发生率。用阻断抗体mcr84抑制Vegf-a与Vegfr2之间的相互作用，也可防止异丙肾上腺素引发的骨血管密度增加和骨转移。总之，这些结果表明，成骨细胞中β2AR的刺激会触发一个依赖Vegf的新血管生成开关，促进骨血管密度以及转移性乳腺癌细胞对骨微环境的定植。© 2017美国骨与矿物质研究学会
