INSERM UMR 911, Faculté de Médecine Timone, 13385 Marseille, France.
Eur J Cancer. 2011 Jul;47(11):1727-35. doi: 10.1016/j.ejca.2011.02.021. Epub 2011 Mar 31.
Clinical and experimental studies suggest that angiogenesis is a prerequisite for solid tumour growth. Glioblastoma (GBM) and pilocytic astrocytoma (PA), both angiogenic tumours display strong contrast enhancement associated with peripheral oedema in GBM but not in PA indicating differences in vascular permeability in these two types of gliomas. Here we show that expression of adrenomedullin (AM) mRNA is induced in GBM whereas is barely detectable in PA. In situ analysis of tumour specimens undergoing neovascularisation shows that the production of AM is specifically induced in a subset of GBM cells distinguished by their immediate proximity to necrotic foci (presumably hypoxic regions), suggesting a hypoxic induction of AM expression in GBM. Vascular endothelial growth factor (VEGF) mRNA levels are increased in GBM and moderate in PA. Immunohistochemical study showed that cytoplasmic AM, VEGF and HIF-1α nuclear immunoreactivity were recorded in GBM located near large necrotic areas whereas they were not expressed by PA tumour cells. Interestingly, double fluorescence immunostaining demonstrated that 85% of AM immunoreactivity colocalised with VEGF. AM transduces its effects through calcitonin receptor-like receptor/receptor activity modifying protein-2 and -3 (CLR/RAMP2 and CLR/RAMP3). Real-time quantitative RT-PCR showed expression of RAMP2, RAMP3 and CLR in PA and GBM, suggesting that AM may function as an autocrine/paracrine growth factor for GBM cells. These observations strongly support the concept that tumour angiogenesis is regulated by paracrine mechanisms and identify beside VEGF, AM as a potential tumour angiogenesis factor in vivo which constitutes a potential interesting molecular target in GBM treatment.
临床和实验研究表明血管生成是实体瘤生长的必要条件。神经胶质瘤（GBM）和毛细胞星形细胞瘤（PA）都是血管生成肿瘤，均表现出强烈的对比增强，与 GBM 外周水肿相关，但在 PA 中则没有，这表明这两种类型的神经胶质瘤的血管通透性存在差异。在这里，我们表明 AM 信使 RNA 的表达在 GBM 中被诱导，而在 PA 中则几乎检测不到。对正在发生新血管形成的肿瘤标本进行原位分析表明，AM 的产生是在 GBM 细胞的一个亚群中特异性诱导的，这些细胞与坏死灶（推测为缺氧区域）的临近程度密切相关，表明在 GBM 中存在缺氧诱导 AM 表达。GBM 中血管内皮生长因子（VEGF）信使 RNA 水平升高，而 PA 中则适中。免疫组织化学研究表明，细胞质 AM、VEGF 和 HIF-1α 核免疫反应性记录在靠近大的坏死区域的 GBM 中，而在 PA 肿瘤细胞中则不表达。有趣的是，双荧光免疫染色表明 85%的 AM 免疫反应性与 VEGF 共定位。AM 通过降钙素受体样受体/受体活性修饰蛋白-2 和 -3（CLR/RAMP2 和 CLR/RAMP3）传递其作用。实时定量 RT-PCR 显示 PA 和 GBM 中表达 RAMP2、RAMP3 和 CLR，表明 AM 可能作为 GBM 细胞的自分泌/旁分泌生长因子发挥作用。这些观察结果强烈支持肿瘤血管生成受旁分泌机制调节的概念，并确定除了 VEGF 之外，AM 作为体内潜在的肿瘤血管生成因子，这为 GBM 治疗构成了一个潜在的有趣的分子靶点。
