RAGE expression in tumor-associated macrophages promotes angiogenesis in glioma.
RAGE expression in tumor-associated macrophages promotes angiogenesis in glioma.
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DOI：
10.1158/0008-5472.can-14-1240
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发表时间：
2014-12-15
期刊：
影响因子：
11.2
通讯作者：
Badie B
中科院分区：
文献类型：
--
作者：
Chen X;Zhang L;Zhang IY;Liang J;Wang H;Ouyang M;Wu S;da Fonseca ACC;Weng L;Yamamoto Y;Yamamoto H;Natarajan R;Badie B
它与配体的相互作用可以促进肿瘤的进展、侵袭和血管生成。虽然阻断CD 45信号传导已被提出作为一种潜在的抗癌策略，但CD 45在肿瘤微环境（TME）中的表达的功能贡献尚未详细研究。在这里，我们评估了TME中的基因缺失对胶质瘤生长的影响。在侵袭性和非侵袭性神经胶质瘤模型中，Ager基因敲除（Ager−/−）小鼠的动物生存期延长。然而，Ager−/−小鼠存活率的提高并不是由于肿瘤生长速率的变化，而是由于肿瘤相关炎症的减少。此外，TME中的血管消融通过下调阻止正常血管形成的促血管生成因子的表达来消除血管生成，从而产生渗漏的脉管系统。这些变化在非侵袭性胶质瘤中最为突出，其中VEGF和促炎细胞因子的表达在Ager−/−小鼠的肿瘤相关巨噬细胞（TAM）中也较低。有趣的是，用野生型小胶质细胞或巨噬细胞重建Ager−/− TAM使肿瘤血管正常化。我们的研究结果表明，胶质瘤相关的小胶质细胞和TAM的信号转导驱动血管生成，强调了神经胶质瘤及其配体的复杂作用。
Interaction of RAGE with its ligands can promote tumor progression, invasion and angiogenesis. Although blocking RAGE signaling has been proposed as a potential anti-cancer strategy, functional contributions of RAGE expression in the tumor microenvironment (TME) 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 knockout (Ager−/−) mice. However, the improvement in survival in Ager−/− mice was not due to changes in tumor growth rate but rather to a reduction in tumor-associated inflammation. Furthermore, RAGE ablation in the TME abrogated angiogenesis by downregulating the expression of pro-angiogenic factors which prevented normal vessel formation, thereby generating a leaky vasculature. These alterations were most prominent in non-invasive gliomas, where the expression of VEGF and pro-inflammatory cytokines were also lower in tumor-associated macrophages (TAM) in Ager−/− mice. Interestingly, reconstitution of Ager−/− TAM with wild-type microglia or macrophages normalized tumor vascularity. Our results establish that RAGE signaling in glioma-associated microglia and TAM drives angiogenesis, underscoring the complex role of RAGE and its ligands in gliomagenesis.