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.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-07252017-105749 |
| Date | 31 July 2017 |
| Creators | Mulcrone, Patrick Louis |
| Contributors | Florent Elefteriou, John S. Penn, Ginger E. Holt, Jin Chen, Julie A. Sterling |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-07252017-105749/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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