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We investigated the roles of three EAIs during de novo tumorigenesis to further test the angiogenic balance hypothesis, which suggests that blood vessel development in the tumor microenvironment can be governed by a net loss of negative regulators of angiogenesis in addition to the well-established principle of up-regulated angiogenesis inducers. In a mouse model of pancreatic neuroendocrine cancer, administration of endostatin, thrombospondin-1, and tumstatin peptides, as well as deletion of their genes, reveal neoplastic stage-specific effects on angiogenesis, tumor progression, and survival, correlating with endothelial expression of their receptors. Deletion of tumstatin and thrombospondin-1 in mice lacking the p53 tumor suppressor gene leads to increased incidence and reduced latency of angiogenic lymphomas associated with diminished overall survival. The results demonstrate that EAIs are part of a balance mechanism regulating tumor angiogenesis, serving as intrinsic microenvironmental barriers to tumorigenesis.<\/jats:p>","DOI":"10.1073\/pnas.1105041108","type":"journal-article","created":{"date-parts":[[2011,5,28]],"date-time":"2011-05-28T03:05:19Z","timestamp":1306551919000},"page":"9939-9944","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":43,"title":["Counterbalancing angiogenic regulatory factors control the rate of cancer progression and survival in a stage-specific manner"],"prefix":"10.1073","volume":"108","author":[{"given":"Liang","family":"Xie","sequence":"first","affiliation":[{"name":"Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215;"}]},{"given":"Michael B.","family":"Duncan","sequence":"additional","affiliation":[{"name":"Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215;"}]},{"given":"Jessica","family":"Pahler","sequence":"additional","affiliation":[{"name":"Diabetes and Comprehensive Cancer Centers, University of California, San Francisco, CA 94143;"}]},{"given":"Hikaru","family":"Sugimoto","sequence":"additional","affiliation":[{"name":"Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215;"}]},{"given":"Margot","family":"Martino","sequence":"additional","affiliation":[{"name":"Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215;"}]},{"given":"Julie","family":"Lively","sequence":"additional","affiliation":[{"name":"Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215;"}]},{"given":"Thomas","family":"Mundel","sequence":"additional","affiliation":[{"name":"Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215;"}]},{"given":"Mary","family":"Soubasakos","sequence":"additional","affiliation":[{"name":"Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215;"}]},{"given":"Kristofer","family":"Rubin","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Microbiology, Uppsala University, 75105 Uppsala, Sweden;"},{"name":"Howard Hughes Medical Institute, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139;"}]},{"given":"Takaaki","family":"Takeda","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537-8511, Japan;"}]},{"given":"Masahiro","family":"Inoue","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537-8511, Japan;"}]},{"given":"Jack","family":"Lawler","sequence":"additional","affiliation":[{"name":"Division of Cancer Biology and Angiogenesis, Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215;"}]},{"given":"Richard O.","family":"Hynes","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139;"}]},{"given":"Douglas","family":"Hanahan","sequence":"additional","affiliation":[{"name":"Diabetes and Comprehensive Cancer Centers, University of California, San Francisco, CA 94143;"}]},{"given":"Raghu","family":"Kalluri","sequence":"additional","affiliation":[{"name":"Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215;"},{"name":"Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215; 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