{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T01:04:28Z","timestamp":1773191068008,"version":"3.50.1"},"reference-count":28,"publisher":"Proceedings of the National Academy of Sciences","issue":"39","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2008,9,30]]},"abstract":"<jats:p>Tumstatin is an angiogenesis inhibitor that binds to \u03b1v\u03b23 integrin and suppresses tumor growth. Previous deletion mutagenesis studies identified a 25-aa fragment of tumstatin (tumstatin peptide) with<jats:italic>in vitro<\/jats:italic>antiangiogenic activity. Here, we demonstrate that systemic administration of this tumstatin peptide inhibits tumor growth and angiogenesis. Site-directed mutagenesis identified amino acids L, V, and D as essential for the antiangiogenic activity of tumstatin. The tumstatin peptide binds to \u03b1v\u03b23 integrin on proliferating endothelial cells and localizes to select tumor endothelium<jats:italic>in vivo<\/jats:italic>. Using 3D molecular modeling, we identify a putative interaction interface for tumstatin peptide on \u03b1v\u03b23 integrin. The antitumor activity of the tumstatin peptide, in combination with bevacizumab (anti-VEGF antibody), displays significant improvement in efficacy against human renal cell carcinoma xenografts when compared with the single-agent use. Collectively, our results demonstrate that tumstatin peptide binds specifically to the tumor endothelium, and its antiangiogenic action is mediated by \u03b1v\u03b23 integrin, and, in combination with an anti-VEGF antibody it exhibits enhanced tumor suppression of renal cell carcinoma.<\/jats:p>","DOI":"10.1073\/pnas.0807055105","type":"journal-article","created":{"date-parts":[[2008,9,26]],"date-time":"2008-09-26T00:44:16Z","timestamp":1222389856000},"page":"15040-15045","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":56,"title":["Identification of amino acids essential for the antiangiogenic activity of tumstatin and its use in combination antitumor activity"],"prefix":"10.1073","volume":"105","author":[{"given":"Hans Petter","family":"Eikesdal","sequence":"first","affiliation":[{"name":"*Division of Matrix Biology, Department of Medicine, and"}]},{"given":"Hikaru","family":"Sugimoto","sequence":"additional","affiliation":[{"name":"*Division of Matrix Biology, Department of Medicine, and"}]},{"given":"Gabriel","family":"Birrane","sequence":"additional","affiliation":[{"name":"Division of Experimental Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215;"}]},{"given":"Yohei","family":"Maeshima","sequence":"additional","affiliation":[{"name":"*Division of Matrix Biology, Department of Medicine, and"}]},{"given":"Vesselina G.","family":"Cooke","sequence":"additional","affiliation":[{"name":"*Division of Matrix Biology, Department of Medicine, and"}]},{"given":"Mark","family":"Kieran","sequence":"additional","affiliation":[{"name":"Department of Pediatric Oncology, Dana\u2013Farber Cancer Institute, Boston, MA 02215; and"}]},{"given":"Raghu","family":"Kalluri","sequence":"additional","affiliation":[{"name":"*Division of Matrix Biology, Department of Medicine, and"},{"name":"Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston and Harvard\u2013Massachusetts Institute of Technology Division of Health Sciences and Technology, Cambridge, MA 02139"}]}],"member":"341","published-online":{"date-parts":[[2008,9,30]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81683-9"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M001956200"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M103024200"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.03098"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2005.08.010"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1535-6108(03)00133-8"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C000186200"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1065298"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1988.tb14321.x"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.11.8051"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1069040"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.062183499"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/prot.340110407"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0021889803006721"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2005.06.023"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1142946"},{"key":"e_1_3_3_17_2","first-page":"963","article-title":"Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis","volume":"57","author":"Relf M","year":"1997","unstructured":"M Relf, et al., Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. 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Cancer Res 61, 7375\u20137378 (2001).","journal-title":"Cancer Res"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-006-9259-z"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1993.1626"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1002\/prot.20573"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0807055105","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,20]],"date-time":"2023-05-20T02:33:27Z","timestamp":1684550007000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0807055105"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,9,30]]},"references-count":28,"journal-issue":{"issue":"39","published-print":{"date-parts":[[2008,9,30]]}},"alternative-id":["10.1073\/pnas.0807055105"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0807055105","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,9,30]]},"assertion":[{"value":"2008-04-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2008-09-30","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}