Tumors are angiogenesis-dependent as they require blood supply to grow and metastasize. Angiogenesis is regulated by a multitude of stimulators and inhibitors that maintain vascular homeostasis under physiological conditions. This angiogenic balance is tipped in favor of proangiogenic factors in cancer. The proangiogenic factors include many growth factors among which vascular endothelial growth factor (VEGF) plays a prominent role. Among endogenous antiangiogenic factors several whole proteins, e.g. thrombospondin-1, as well as protein fragments have been identified;most of the known fragments reside in the extracellular matrix. A quantitative understanding of how these factors interact to result in a growing vasculature and how to control this growth is presently lacking. To achieve a better understanding of these processes, the development of predictive experiment-based molecular-detailed multiscale computational models of tumor angiogenesis is necessary. This research will focus on breast cancer. The long-term goal of this project is to develop such models of the breast cancer angiogenesis physiome. The computational developments will be tightly coupled to state of the art breast cancer imaging at the molecular, cellular, microvascular, and tissue levels using animal models. The invasive human breast cancer cell line MDA-MB-231 and the less invasive human breast cancer cell line MCF-7 will be used to generate orthotopic xenografts in the mammary fat pad in female severe combined immune deficient (SCID) mice. The measurements will include the characterization and localization of receptor and ligand expression at the different stages of tumor development;temporal and spatial development of hypoxia and microvasculature in growing tumor;and functional characteristics of the tumor microvasculature such as blood volume and vascular permeability, and the extracellular matrix. Part of these data will serve as input to the computational models whereas other data will serve as a means for their validation. The models will be extended to human disease. The research will contribute to a better fundamental understanding of the tumor vascular biology and to the design of novel therapeutics and quantitative interpretation of clinical data. The synergistic combination of computational and experimental studies should provide significant insights into the nature of the disease.

Public Health Relevance

Breast cancer is the most commonly diagnosed female malignancy in the United States. Angiogenesis or neovascular growth plays a key role in breast cancer development, invasion and metastasis. Using synergistic combination of computational and experimental methods, the project will provide a better quantitative understanding of angiogenesis stimulation and inhibition, leading to translation of fundamental knowledge into novel therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA138264-04
Application #
8206806
Study Section
Special Emphasis Panel (ZRG1-BST-E (51))
Program Officer
Couch, Jennifer A
Project Start
2009-02-13
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
4
Fiscal Year
2012
Total Cost
$571,079
Indirect Cost
$222,860
Name
Johns Hopkins University
Department
Biomedical Engineering
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Finley, Stacey D; Chu, Liang-Hui; Popel, Aleksander S (2015) Computational systems biology approaches to anti-angiogenic cancer therapeutics. Drug Discov Today 20:187-97
Stamatelos, Spyros K; Kim, Eugene; Pathak, Arvind P et al. (2014) A bioimage informatics based reconstruction of breast tumor microvasculature with computational blood flow predictions. Microvasc Res 91:8-21
Norton, Kerri-Ann; Popel, Aleksander S (2014) An agent-based model of cancer stem cell initiated avascular tumour growth and metastasis: the effect of seeding frequency and location. J R Soc Interface 11:20140640
Lee, Esak; Pandey, Niranjan B; Popel, Aleksander S (2014) Lymphatic endothelial cells support tumor growth in breast cancer. Sci Rep 4:5853
Chu, Liang-Hui; Lee, Esak; Bader, Joel S et al. (2014) Angiogenesis interactome and time course microarray data reveal the distinct activation patterns in endothelial cells. PLoS One 9:e110871
Vempati, Prakash; Popel, Aleksander S; Mac Gabhann, Feilim (2014) Extracellular regulation of VEGF: isoforms, proteolysis, and vascular patterning. Cytokine Growth Factor Rev 25:1-19
Lee, Esak; Pandey, Niranjan B; Popel, Aleksander S (2014) Pre-treatment of mice with tumor-conditioned media accelerates metastasis to lymph nodes and lungs: a new spontaneous breast cancer metastasis model. Clin Exp Metastasis 31:67-79
Lee, Esak; Fertig, Elana J; Jin, Kideok et al. (2014) Breast cancer cells condition lymphatic endothelial cells within pre-metastatic niches to promote metastasis. Nat Commun 5:4715
Rosca, Elena V; Penet, Marie-France; Mori, Noriko et al. (2014) A biomimetic collagen derived peptide exhibits anti-angiogenic activity in triple negative breast cancer. PLoS One 9:e111901
Imoukhuede, Princess I; Popel, Aleksander S (2014) Quantitative fluorescent profiling of VEGFRs reveals tumor cell and endothelial cell heterogeneity in breast cancer xenografts. Cancer Med 3:225-44

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