Cancer cell angiogenic capability is regulated by 3D culture and integrin engagement.
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.
Fischbach
Claudia
C
School of Engineering and Applied Sciences, Harvard University, 40 Oxford Street, Cambridge, MA 02138, USA.
Kong
Hyun Joon
HJ
Hsiong
Susan X
SX
Evangelista
Marta B
MB
Yuen
Will
W
Mooney
David J
DJ
D000818:Animals; D016026:Bone Marrow Transplantation; D018929:Cell Culture Techniques; D004058:Diffusion; D006801:Humans; D020100:Hydrogels / Q000737:chemistry; D016023:Integrins / Q000378:metabolism*; D016209:Interleukin-8 / Q000008:administration & dosage / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000473:pathology*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000502:physiology*
D020100:Hydrogels; D016023:Integrins; D016209:Interleukin-8; D042461:Vascular Endothelial Growth Factor A