Tumor vascularization is promoted by proangiogenic molecules such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and interleukin-8 (IL-8). Fischbach et al. investigated angiogenic signaling in oral squamous cell carcinoma cells (OSCC-3) cultured in a two- or three-dimensional matrix composed of alginate coupled to Arg-Gly-Asp (RGD) peptides, which constitute the primary integrin recognition site in many extracellular matrix (ECM) proteins. They found that OSCC-3 attached to RGD-alginate in an α5β1 integrin-dependent manner and proliferated when attached to RGD-alginate but not unmodified alginate. IL-8 secretion was increased 35 times in three-dimensional cultures compared with two-dimensional cultures, whereas VEGF secretion increased only slightly in three-dimensional cultures compared with two-dimensional cultures, and bFGF secretion was negligible under all culture conditions tested. Analysis of the relative contributions of these factors showed that VEGF was the major secreted angiogenic factor in two-dimensional culture, whereas IL-8 assumed this role in three-dimensional culture. Mathematical modeling of diffusion predicted that IL-8 would diffuse more readily than VEGF and, as predicted, mice implanted with tumors grown in RGD-alginate had higher concentrations of IL-8 than VEGF or bFGF in the tissue surrounding the tumor, as well as systemically. When locally injected into tumors grown in mice, an antibody that neutralized IL-8 reduced tumor growth more than one that neutralized VEGF. Moreover, mice with subcutaneously implanted porous scaffolds that released IL-8 exhibited increased blood vessel density at the interface between scaffold and muscle and showed recruitment of bone marrow–derived cells to the scaffold. The authors proposed that their findings suggest a greater role for IL-8 in tumor angiogenesis than has been previously appreciated.
C. Fischbach, H. J. Kong, S. X. Hsiong, M. B. Evangelista, W. Yuen, D. J. Mooney, Cancer cell angiogenic capability is regulated by 3D culture and integrin engagement. Proc. Natl. Acad. Sci. U.S.A. 106, 399–404 (2009). [Abstract] [Full Text]