Abstract 2682: Sympathetic activation alters the bone vasculature: implication for osteotropic breast cancer metastasis

Emotional stresses chronically activate the Hypothalamic-Pituitary-Adrenal axis and the sympathetic nervous system (SNS), and have been associated with the progression and recurrence of breast cancer, as well as with reduced survival of breast cancer patients. We observed that isoproterenol (ISO), a β1/2 adrenergic receptor (βAR) agonist used to mimic sympathetic activation, induced the expression of Vegfa in mouse bone in vivo and in osteoblast cultures in vitro. Because VEGF is pro-angiogenic, and tumor cells depend on the vasculature to form distant metastases, we hypothesized that SNS chronic activation may increase bone marrow vascular density via an effect on β2AR-expressing osteoblasts, thus promoting the possibility of metastatic breast cancer establishment in the skeleton. To address this question, we measured the formation of CD31+ vessels in femurs in vivo by histomorphometric analyses, following daily ISO treatment of adult mice for 6 weeks. Vessel number was significantly increased by ISO treatment in WT mouse femurs, and this effect was blunted in mice lacking the β2AR. Further supporting our hypothesis, we found that the conditioned media (CM) from MC3T3 osteoblasts treated with ISO augmented blood vessel formation in an ex vivo metatarsal assay as compared to the CM of PBS-treated osteoblasts. Lastly, the CM of ISO-treated MC3T3 osteoblasts promoted primary bone endothelial cell tube formation, and inhibition of Vegf:Vegfr2 interaction with the antibody mcr84 reduced this formation. These results suggest that the effect of chronic stress on metastatic breast cancer cell establishment in the skeleton may be mediated in part due to changes in the bone microenvironment, specifically an increase in osteoblastic VEGF that changes host bone marrow vascular density. Citation Format: Patrick L. Mulcrone, J. Preston Campbell, Ana Lia Anbinder, Julie A. Sterling, Florent Elefteriou. Sympathetic activation alters the bone vasculature: implication for osteotropic breast cancer metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2682.