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Influence of Stress on Bone Vasculature and Bone Metastasis

Award Number: F31CA192748
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/01/2015
PERIOD OF PERFORMANCE END DATE: 07/31/2017

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Influence of Stress on Bone Vasculature and Bone Metastasis - ¿ DESCRIPTION (provided by applicant): 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2021 ( Subtotal = -$975 )
2021	2017	VANDERBILT UNIVERSITY, THE	2301 VANDERBILT PL	NASHVILLE	TN	37235	DAVIDSON	USA	Cancer Research Manpower	000	3	12/31/2020	NON-COMPETING CONTINUATION	-$975
														Subtotal = -$975

Issue Date FY: 2017 ( Subtotal = $12,395 )
2017	2017	VANDERBILT UNIVERSITY, THE	211 KIRKLAND HALL	NASHVILLE	TN	37240	DAVIDSON	USA	Cancer Research Manpower	002	3	8/8/2017	NON-COMPETING CONTINUATION	-$16,009
2017	2017	VANDERBILT UNIVERSITY, THE	211 KIRKLAND HALL	NASHVILLE	TN	37240	DAVIDSON	USA	Cancer Research Manpower	001	3	7/17/2017	NON-COMPETING CONTINUATION	$468
2017	2017	VANDERBILT UNIVERSITY, THE	211 KIRKLAND HALL	NASHVILLE	TN	37240	DAVIDSON	USA	Cancer Research Manpower	000	3	2/17/2017	NON-COMPETING CONTINUATION	$27,936
														Subtotal = $12,395

Issue Date FY: 2016 ( Subtotal = $27,936 )
2016	2016	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Research Manpower	001	2	2/8/2016	NON-COMPETING CONTINUATION	$456
2016	2016	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Research Manpower	000	2	12/18/2015	NON-COMPETING CONTINUATION	$27,480
														Subtotal = $27,936

Issue Date FY: 2015 ( Subtotal = $27,480 )
2015	2015	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Research Manpower	000	1	2/23/2015	NEW	$0
2015	2015	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Research Manpower	001	1	2/23/2015	NEW	$27,480
														Subtotal = $27,480

Grand Total All Awards = $66,836

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Influence of Stress on Bone Vasculature and Bone Metastasis

Award Number: F31CA192748

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/01/2015

PERIOD OF PERFORMANCE END DATE: 07/31/2017

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