We have found that loss of Vascular Endothelial Growth Factor-A expression in myeloid cells has profound and unexpected effects in a mouse model of breast cancer. Our recent findings illustrate how inflammatory cells act to induce vascular changes in tumors, and how these changes alter tumor perfusion and oxygenation, as well as tumor cell survival and malignant progression. The work proposed here will allow us to explore and exploit these new and novel findings, in order to: determine the mechanisms of myeloid cell interactions with endothelial cells during tumor angiogenesis;better understand the relationship between myeloid cell VEGF expression and metastasis;and determine how these findings could be used to increase the efficacy of chemotherapy.
The aims we propose to further our understanding of these phenomena are: 1: Determine the molecular mechanisms for differential VEGF signaling through innate immune cells in tumors. 2: Determine how VEGF expression from myeloid cells impacts metastasis. 3: Determine how VEGF from myeloid cells impacts chemotherapy delivery and efficacy. In sum, we believe this application will address key questions surrounding the processes of inflammation, angiogenesis, and tumor growth, with a particular emphasis on how these influence mammary tumorigenesis and metastasis.

Public Health Relevance

These findings speak directly to breast cancer therapies currently used in the clinic, and will explore ways in which these therapies can be improved through modulation of inflammatory response.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA153983-02
Application #
8210931
Study Section
Special Emphasis Panel (ZRG1-OBT-Z (02))
Program Officer
Woodhouse, Elizabeth
Project Start
2011-01-06
Project End
2012-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
2
Fiscal Year
2012
Total Cost
$222,907
Indirect Cost
$15,407
Name
University of Cambridge
Department
Type
DUNS #
226552610
City
Cambridge
State
Country
United Kingdom
Zip Code
CB2 1-TN
Cowburn, Andrew S; Takeda, Norihiko; Boutin, Adam T et al. (2013) HIF isoforms in the skin differentially regulate systemic arterial pressure. Proc Natl Acad Sci U S A 110:17570-5