In this competitive renewal, five principal investigators, who have a strong track record in making novel contributions to angiogenesis research, propose to continue their collaborative efforts by studying novel activities of a set of endogenous molecules and structures that regulate angiogenesis by previously unknown mechanisms. J. Folkman (Project I) will elucidate new mechanisms by which specific endogenous angiogenesis regulatory proteins (e.g., thrombospondin-1 and endostatin) found in platelets, and in stromal cells and their extracellular matrix, suppress pathological angiogenesis, and oppose the tumorigenic activity of activated oncogenes. M. Klagsbrun (Project II) will study new angiogenesis regulatory functions of two proteins, neuropilin and semaphorin, that were previously thought to exclusively regulate neuronal growth and migration. D. Ingber (Project III) will investigate how physical interactions between cells and extracellular matrix regulate the small GTPases Rho and Rac, and thereby govern directional migration of capillary cells during tumor angiogenesis in vitro and in vivo. Patricia D'Amore (Project IV) will examine the potential antiadhesive function of endomucin, a down stream target of VEGF, in vascular lumen formation. Marsha Moses (Project V) will analyze the mechanism by which the metalloproteinase ADAM12 regulates angiogenesis, as well as tumor growth and metastasis. She will also determine whether ADAM 12 may be used as an early biomarker of recurrent cancer, disease status or efficacy of therapy in cancer patients. Together, the five research programs in this application cover a broad range of investigation that should significantly enhance our understanding of how angiogenesis is regulated. The results of these experiments are likely to provide a broader spectrum of targets for antiangiogenic therapy, and lead to the development of new diagnostic and prognostic biomarkers. Summary: The body has a variety of defenses against cancer. One of the strongest defenses consists of special proteins that prevent early tumors smaller than a pinhead from recruiting new blood vessels. These are called endogenous angiogenesis inhibitors. Many of them were first discovered by the five principal investigators who are working together on this Program Project. These investigators will now study the different mechanisms by which a set of these proteins operate to prevent tumor angiogenesis. The expected result from this body of work should be the possibility of new angiogenesis inhibitors for which there would be less risk of the development of resistance by a tumor, and the possibility of developing blood tests and urine tests that could detect recurrent cancer long before symptoms appear, or before a tumor can be seen by current methods.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA045548-25
Application #
8129688
Study Section
Special Emphasis Panel (ZCA1-RPRB-O (M1))
Program Officer
Ault, Grace S
Project Start
1997-07-09
Project End
2013-02-28
Budget Start
2011-09-01
Budget End
2013-02-28
Support Year
25
Fiscal Year
2011
Total Cost
$1,629,082
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Adapala, R K; Thoppil, R J; Ghosh, K et al. (2016) Activation of mechanosensitive ion channel TRPV4 normalizes tumor vasculature and improves cancer therapy. Oncogene 35:314-22
Pelton, Kristine; Coticchia, Christine M; Curatolo, Adam S et al. (2014) Hypercholesterolemia induces angiogenesis and accelerates growth of breast tumors in vivo. Am J Pathol 184:2099-110
German, Alexandra E; Mammoto, Tadanori; Jiang, Elisabeth et al. (2014) Paxillin controls endothelial cell migration and tumor angiogenesis by altering neuropilin 2 expression. J Cell Sci 127:1672-83
Ingber, Donald E; Wang, Ning; Stamenovic, Dimitrije (2014) Tensegrity, cellular biophysics, and the mechanics of living systems. Rep Prog Phys 77:046603
Procaccia, Vera; Nakayama, Hironao; Shimizu, Akio et al. (2014) Gleevec/imatinib, an ABL2 kinase inhibitor, protects tumor and endothelial cells from semaphorin-induced cytoskeleton collapse and loss of cell motility. Biochem Biophys Res Commun 448:134-8
Roy, R; Zurakowski, D; Wischhusen, J et al. (2014) Urinary TIMP-1 and MMP-2 levels detect the presence of pancreatic malignancies. Br J Cancer 111:1772-9
Battinelli, Elisabeth M; Markens, Beth A; Kulenthirarajan, Rajesh A et al. (2014) Anticoagulation inhibits tumor cell-mediated release of platelet angiogenic proteins and diminishes platelet angiogenic response. Blood 123:101-12
Li, Wenliang; Ai, Nanping; Wang, Suming et al. (2014) GRK3 is essential for metastatic cells and promotes prostate tumor progression. Proc Natl Acad Sci U S A 111:1521-6
Panigrahy, Dipak; Kalish, Brian T; Huang, Sui et al. (2013) Epoxyeicosanoids promote organ and tissue regeneration. Proc Natl Acad Sci U S A 110:13528-33
Shimizu, Akio; Nakayama, Hironao; Wang, Priscilla et al. (2013) Netrin-1 promotes glioblastoma cell invasiveness and angiogenesis by multiple pathways including activation of RhoA, cathepsin B, and cAMP-response element-binding protein. J Biol Chem 288:2210-22

Showing the most recent 10 out of 277 publications