IB-04 * EXPRESSION OF RAGE BY TUMOR MACROPHAGES PROMOTES ANGIOGENESIS IN GLIOMAS

Abstract

Interaction of RAGE with its ligands can promote tumor progression, invasion and angiogenesis. Although blockage of RAGE signaling has been proposed as a potential anti-cancer therapy, the contribution of RAGE expression in tumor microenvironement (TME) to tumorigenesis has not been investigated in detail. Here, we evaluated the effect of genetic depletion of RAGE in TME on the growth of gliomas. In both invasive and non-invasive glioma models, animal survival was prolonged in Rage−/- mice. This improvement in animal survival, however, was not due to changes in tumor growth rate, but a reduction in tumor-associated inflammation in Rage−/- mice. Furthermore, RAGE ablation in TME abrogated angiogenesis by downregulating the expression of pro-angiogenic factors which prevented vessel pruning, and resulted in the generation of leaky vasculature. These alterations, however, were most prominent in non-invasive gliomas where the expression of VEGF and pro-inflammatory cytokines were also lower in Rage−/- tumor-associated macrophages. Interestingly, reconstituting Rage−/- tumor macrophages with either wild-type microglia or macrophages normalized tumor vascularity. This is the first report to demonstrate the pro-angiogenic function of RAGE signaling in tumor macrophages and underscores the complex role of RAGE and its ligands in gliomagenesis.