Cancer metastasis is a rare biological event, yet it is responsible for approximately 80% of all cancer deaths. Breast cancer, the second deadliest cancer among women, often metastasizes to bone, an organ that is highly vascularized and innervated by the sympathetic nervous system (SNS). Emotional and psychosocial stimuli that cause stress activate the SNS and are linked to shorter patient survival and increased recurrence in multiple cancer types including breast cancer. Our laboratory has shown that SNS activation primes the bone microenvironment to favor breast cancer cell establishment, and that receptor activator of NF-kB ligand (RANKL)/RANK signaling contributes to this process by promoting breast cancer cell migration. Furthermore, clinical data indicates a correlation between breast cancer bone metastases and increase bone marrow angiogenesis, suggesting a vascular mechanism might contribute. Because the circulatory system is the major conduit through which metastatic tumor cells colonization distant organs, stress may promote breast cancer metastasis via alterations in the bone vasculature. My preliminary data revealed that VEGFA and IL6 expression levels in osteoblasts are increased following SNS activation. These cytokines affect endothelial cells in distinct ways that could promote bone metastasis. We thus hypothesize that stress-induced osteoblastic ADRB2 signaling transmutes bone vasculature to facilitate extravasation of metastatic breast cancer.
In aim one of this proposal, changes in vascular density will be assessed under SNS activation. Vessel number and size will be measured in order to determine whether SNS activation transforms the layout of bone vasculature. Genetic mouse models lacking components of SNS activation as well as treatments will different inhibitors of angiogenesis will elucidate the role of vessel density in bone metastases. How stress affects tumor cell adhesion to bone marrow endothelial cells is the focus of aim two. These interactions will be assessed through gene expression of selected adhesion proteins, functional in vitro assays, as well as through loss of function genetic mouse models.
The goal of this proposal is to determine if there is a connection between sympathetic nerve activation, the bone vasculature and the increase in breast cancer metastases to the skeleton triggered by chronic stress. Understanding how stress, bone vasculature, and osteotropic metastases are intertwined will lead to a better understanding of why chronic stress and severe depression are associated with increased relapse incidence and reduced survival in women with breast cancer, and potentially lead to the discovery of new targets for cancer therapies.
| Clément-Demange, Lise; Mulcrone, Patrick L; Tabarestani, Troy Q et al. (2018) ?2ARs stimulation in osteoblasts promotes breast cancer cell adhesion to bone marrow endothelial cells in an IL-1? and selectin-dependent manner. J Bone Oncol 13:1-10 |
| Mulcrone, Patrick L; Campbell, J Preston; Clément-Demange, Lise et al. (2017) Skeletal Colonization by Breast Cancer Cells Is Stimulated by an Osteoblast and ?2AR-Dependent Neo-Angiogenic Switch. J Bone Miner Res 32:1442-1454 |
