Cancer cell angiogenic capability is regulated by 3D culture and integrin engagement

Claudia Fischbach^a,b, Hyun Joon Kong^a,c, Susan X. Hsiong^a, Marta B. Evangelista^a,d,e, Will Yuen^a, and David J. Mooney^a,f,1

^aSchool of Engineering and Applied Sciences, Harvard University, 40 Oxford Street, Cambridge, MA 02138; ^bDepartment of Biomedical Engineering, Cornell University, 157 Weill Hall, Ithaca, NY 14853; ^cDepartment of Chemical and Biomolecular Engineering, University of Illinois at Urbana–Champaign, Urbana, IL 61801; ^dInstituto de Engenharia Biomedica, Divisao de Biomateriais, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal; ^eUniversidade do Porto, Faculdade de Engenharia, Departamento de Engenharia Metalúrgica e de Materiais, Rua Dr. Roberto Frias s/n, 4200-465 Porto, Portugal; and ^fWyss Institute of Biologically Inspired Engineering, Harvard University, Cambridge, MA 02138

Received for publication September 9, 2008.

Abstract: Three-dimensional culture alters cancer cell signaling; however, the underlying mechanisms and importance of these changes on tumor vascularization remain unclear. A hydrogel system was used to examine the role of the transition from 2D to 3D culture, with and without integrin engagement, on cancer cell angiogenic capability. 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.

Key Words: ECM • microenvironment • tumor vascularization • drug delivery • IL-8

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0808932106/DCSupplemental.

¹To whom correspondence should be addressed. E-mail: mooneyd{at}seas.harvard.edu

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