Our long-term objective is to understand the mechanisms of angiogenesis in sufficient detail at the cellular, biochemical and molecular level so that this knowledge can be applied clinically to inhibit angiogenesis in tumors as a means of controlling tumor growth and metastasis. Three strategies of angiogenesis inhibition are in various stages of discovery and development: (i) inhibition of capillary blood vessel growth per se (e.g., angiostatic steroids); (ii) inhibition of specific angiogenic molecules in body fluids or on the endothelial cell surface, (e.g., antibodies to FGF); and (iii) inhibition of expression or production of angiogenic factors by tumor cells or other sources. It is now well accepted that tumor growth is angiogenesis-dependent. However, it is not clear when or how angiogenic capability appears, nor what its role is in the development of a tumor. These questions are the subject of this application. A transgenic mouse tumor system will be used in conjunction with a novel in vitro assay to elucidate the biochemical, molecular and genetic mechanisms of the switch to the angiogenic state during the transition from hyperplasia to neoplasia. Additional experiments will test the hypothesis that there is a causal relationship between induction of angiogenesis and tumorigenesis, and thereby establish whether or not neovascularization is a rate-limiting secondary event in tumorigenesis. As part of this aim, transgenic mice will be treated with angiogenesis inhibitors in order to test the efficacy of these drugs for blocking neovascularization and consequently the development of cancers which otherwise inevitably arise. We will examine the generality of angiogenesis in tumorigenesis by characterizing a second tumor progression model in which fibrosarcomas develop in transgenic mice harboring the bovine papilloma virus genome. These studies will be conducted as a collaboration between the laboratories of Judah Folkman and Douglas Hanahan.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA037395-16
Application #
2330708
Study Section
Special Emphasis Panel (NSS)
Project Start
1983-01-01
Project End
2000-01-31
Budget Start
1997-02-01
Budget End
1998-01-31
Support Year
16
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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Zhao, H; Bojanowski, K; Ingber, D E et al. (1999) New role for tRNA and its fragment purified from human urinary bladder carcinoma conditioned medium: inhibition of endothelial cell growth. J Cell Biochem 76:109-17
O'Reilly, M S; Brem, H; Folkman, J (1995) Treatment of murine hemangioendotheliomas with the angiogenesis inhibitor AGM-1470. J Pediatr Surg 30:325-9;discussion 329-30
Nguyen, M; Shing, Y; Folkman, J (1994) Quantitation of angiogenesis and antiangiogenesis in the chick embryo chorioallantoic membrane. Microvasc Res 47:31-40
Nguyen, M; Watanabe, H; Budson, A E et al. (1994) Elevated levels of an angiogenic peptide, basic fibroblast growth factor, in the urine of patients with a wide spectrum of cancers. J Natl Cancer Inst 86:356-61
Li, V W; Folkerth, R D; Watanabe, H et al. (1994) Microvessel count and cerebrospinal fluid basic fibroblast growth factor in children with brain tumours. Lancet 344:82-6
Nguyen, M; Watanabe, H; Budson, A E et al. (1993) Elevated levels of the angiogenic peptide basic fibroblast growth factor in urine of bladder cancer patients. J Natl Cancer Inst 85:241-2
Brem, H; Gresser, I; Grosfeld, J et al. (1993) The combination of antiangiogenic agents to inhibit primary tumor growth and metastasis. J Pediatr Surg 28:1253-7
Weidner, N; Semple, J P; Welch, W R et al. (1991) Tumor angiogenesis and metastasis--correlation in invasive breast carcinoma. N Engl J Med 324:1-8
Folkman, J; Szabo, S; Stovroff, M et al. (1991) Duodenal ulcer. Discovery of a new mechanism and development of angiogenic therapy that accelerates healing. Ann Surg 214:414-25;discussion 426-7

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