Influence of Stress on Bone Vasculature and Breast Cancer Bone Metastasis

Abstract

The skeleton is a common site for breast cancer metastasis. Although significant progress has been made to manage osteolytic bone lesions caused by breast tumors, patients still die of the disease, and the current treatments for these lesions are palliative. Thus, there is a need to identify the early determinants of the breast cancer bone metastatic process in order to treat these lesions more effectively. 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. Interestingly, the bone is innervated by nerves of the sympathetic nervous system (SNS), and previous data from our lab show that chronic SNS stimulation promotes breast cancer colonization of bone. What has not been explored is how chronic SNS activity alters the bone vasculature, a key component in successful osteotropic breast cancer metastases. The research presented in this dissertation shows that stimulation of the beta 2-adrenergic receptors (b2AR) specifically on osteoblasts alters bone vascular density and the adhesion protein profile of bone marrow endothelium via increased osetoblastic Vegf-a and Il-6. These results support the notion that chronic stress affects not only colonization of bone by breast cancer cells, but also the interaction between endothelium and tumor cells that occurs during extravasation. Potential clinical benefits of beta-blockers, anti-angiogenics, and inhibitors that target adhesion need to be investigated further regarding breast cancer bone metastases.