{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2022,6,18]],"date-time":"2022-06-18T18:41:22Z","timestamp":1655577682576},"reference-count":0,"publisher":"American Association for Cancer Research (AACR)","issue":"19_Supplement","content-domain":{"domain":["aacrjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2010,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Background: Glioblastoma is the most common and lethal central nervous system malignancy with a median survival often less than 18 months. Despite promising initial responses to anti-angiogenic therapies many patients with this disease develop resistance to treatment via poorly understood mechanisms. Here we demonstrate that glioblastoma cell lines grown under growth factor antagonizing conditions exhibit an altered phenotype with changes in growth factor signaling, gene expression as well as in vivo tumorigenesis.<\/jats:p>\n               <jats:p>Methods: U87 cells were cultured under constant pressure with bevacizumab (3.0 mg\/mL), AMG102 (1.0 \u00b5g\/mL), or a combination of both drugs long term (seven or more passages) in adherent culture. In vitro expression analysis was carried out by growth factor and receptor tyrosine kinase arrays, cDNA microarray, and ELISA. Intracranial xenograft studies demonstrated resultant differences in growth kinetics and survival.<\/jats:p>\n               <jats:p>Results: Hepatocyte growth factor (HGF), glial derived neurotrophic factor (GDNF), and platelet-derived growth factor AA (PDGFAA) were elevated at 5.3, 4.5, and 3.9 fold in combinatorially treated cells versus controls, respectively. These changes correlated with relative increases in corresponding receptor mRNA and protein expression. Furthermore, AMG102 and combinatorially pressured cells were highly tumorigenic as compared to control and bevacizumab treated cells in vivo (Median survival 10 \u00b1 1 vs. 32 \u00b1 2 days, respectively).<\/jats:p>\n               <jats:p>Conclusion: Herein we describe concomitant increases of various oncogenic growth factors which might potentiate tumor survival and therapeutic resistance. These results suggest several potential molecular bypass mechanisms facing proposed angiogenic strategies. Evaluation of resistant phenotypes provides insight on the adaptive complexity of glioblastoma and offers potential for targeting recurrent disease.<\/jats:p>","DOI":"10.1158\/diag-10-b13","type":"journal-article","created":{"date-parts":[[2015,5,4]],"date-time":"2015-05-04T16:54:37Z","timestamp":1430758477000},"page":"B13-B13","update-policy":"http:\/\/dx.doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pathways of angiogenic resistance in glioblastoma: Adaptations in growth factor signaling in response to VEGF and HGF attenuation"],"prefix":"10.1158","volume":"16","author":[{"given":"Christian A.","family":"Graves","sequence":"first","affiliation":[{"name":"National Cancer Institute, Bethesda, MD"}]},{"given":"Kevin","family":"Camphausen","sequence":"additional","affiliation":[{"name":"National Cancer Institute, Bethesda, MD"}]}],"member":"1086","published-online":{"date-parts":[[2014,8,15]]},"container-title":["Clinical Cancer Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/aacrjournals.org\/clincancerres\/article\/16\/19_Supplement\/B13\/196695\/Pathways-of-angiogenic-resistance-in-glioblastoma","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/aacrjournals.org\/clincancerres\/article\/16\/19_Supplement\/B13\/196695\/Pathways-of-angiogenic-resistance-in-glioblastoma","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,18]],"date-time":"2022-06-18T18:25:18Z","timestamp":1655576718000},"score":1,"resource":{"primary":{"URL":"https:\/\/aacrjournals.org\/clincancerres\/article\/16\/19_Supplement\/B13\/196695\/Pathways-of-angiogenic-resistance-in-glioblastoma"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,10,1]]},"references-count":0,"journal-issue":{"issue":"19_Supplement","published-online":{"date-parts":[[2014,8,15]]},"published-print":{"date-parts":[[2010,10,1]]}},"URL":"https:\/\/doi.org\/10.1158\/diag-10-b13","relation":{},"ISSN":["1078-0432","1557-3265"],"issn-type":[{"value":"1078-0432","type":"print"},{"value":"1557-3265","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,10,1]]}}}