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Three-dimensional culture recreated tumor microenvironmental cues and led to enhanced interleukin 8 (IL-8) secretion that depended on integrin engagement with adhesion peptides coupled to the polymer. In contrast, vascular endothelial growth factor (VEGF) secretion was unaffected by 3D culture with or without substrate adhesion. IL-8 diffused greater distances and was present in higher concentrations in the systemic circulation, relative to VEGF. Implantation of a polymeric IL-8 delivery system into GFP bone marrow-transplanted mice revealed that localized IL-8 up-regulation was critical to both the local and systemic control of tumor vascularization in vivo. In summary, 3D integrin engagement within tumor microenvironments regulates cancer cell angiogenic signaling, and controlled local and systemic blockade of both IL-8 and VEGF signaling may improve antiangiogenic therapies.<\/jats:p>","DOI":"10.1073\/pnas.0808932106","type":"journal-article","created":{"date-parts":[[2009,1,7]],"date-time":"2009-01-07T03:19:01Z","timestamp":1231298341000},"page":"399-404","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":260,"title":["Cancer cell angiogenic capability is regulated by 3D culture and integrin engagement"],"prefix":"10.1073","volume":"106","author":[{"given":"Claudia","family":"Fischbach","sequence":"first","affiliation":[{"name":"School of Engineering and Applied Sciences, Harvard University, 40 Oxford Street, Cambridge, MA 02138;"},{"name":"Department of Biomedical Engineering, Cornell University, 157 Weill Hall, Ithaca, NY 14853;"}]},{"given":"Hyun Joon","family":"Kong","sequence":"additional","affiliation":[{"name":"School of Engineering and Applied Sciences, Harvard University, 40 Oxford Street, Cambridge, MA 02138;"},{"name":"Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana\u2013Champaign, Urbana, IL 61801;"}]},{"given":"Susan X.","family":"Hsiong","sequence":"additional","affiliation":[{"name":"School of Engineering and Applied Sciences, Harvard University, 40 Oxford Street, Cambridge, MA 02138;"}]},{"given":"Marta B.","family":"Evangelista","sequence":"additional","affiliation":[{"name":"School of Engineering and Applied Sciences, Harvard University, 40 Oxford Street, Cambridge, MA 02138;"},{"name":"Instituto de Engenharia Biomedica, Divisao de Biomateriais, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal;"},{"name":"Universidade do Porto, Faculdade de Engenharia, Departamento de Engenharia Metal\u00fargica e de Materiais, Rua Dr. Roberto Frias s\/n, 4200-465 Porto, Portugal; and"}]},{"given":"Will","family":"Yuen","sequence":"additional","affiliation":[{"name":"School of Engineering and Applied Sciences, Harvard University, 40 Oxford Street, Cambridge, MA 02138;"}]},{"given":"David J.","family":"Mooney","sequence":"additional","affiliation":[{"name":"School of Engineering and Applied Sciences, Harvard University, 40 Oxford Street, Cambridge, MA 02138;"},{"name":"Wyss Institute of Biologically Inspired Engineering, Harvard University, Cambridge, MA 02138"}]}],"member":"341","published-online":{"date-parts":[[2009,1,13]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1695"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.25.14821"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth1085"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2005.08.010"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81683-9"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0502935102"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6602132"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1064829"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0142-9612(98)00107-0"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1177\/10454411990100020301"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1007\/12_070"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.2821619"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0605960103"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc704"},{"key":"e_1_3_3_15_2","first-page":"5822","article-title":"Hypoxia-induced elevation in interleukin-8 expression by human ovarian carcinoma cells","volume":"59","author":"Xu L","year":"1999","unstructured":"L Xu, et al., Hypoxia-induced elevation in interleukin-8 expression by human ovarian carcinoma cells. 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