Lee Ok-Hee, Fueyo Juan, Xu Jing, Yung W K Alfred, Lemoine Michael G, Lang Frederick F, Bekele B Nebiyou, Zhou Xian, Alonso Marta A, Aldape Kenneth D, Fuller Gregory N, Gomez-Manzano Candelaria
Department of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Neoplasia. 2006 May;8(5):419-28. doi: 10.1593/neo.06109.
Systematic analyses of the expression of angiogenic regulators in cancer models should yield useful information for the development of novel therapies for malignant gliomas. In this study, we analyzed tumor growth, vascularization, and angiopoietin-2 (Ang2) expression during the development of U-87 MG xenografts. We found that tumoral angiogenesis in this model follows a multistage process characterized by avascular, prolific peripheral angiogenesis, and late vascular phases. On day 4, we observed an area of central necrosis, a peripheral ring of Ang2-positive glioma cells, and reactive Ang2-positive vascular structures in the tumor/brain interface. When the tumor had developed a vascular network, Ang2 was expressed only in peripheral vascular structures. Because Ang2 expression was downmodulated in the late stages of development, probably to maintain a stable tumoral vasculature, we next studied whether sustained Ang2 expression might impair vascular development and, ultimately, tumor growth. Ang2 prevented the formation of capillary-like structures by and impaired angiogenesis in a chorioallantoic membrane chicken model. Finally, we tested the effect of sustained Ang2 expression on U-87 MG xenograft development. Ang2 significantly prolonged the survival of intracranial U-87 MG tumor-bearing animals. Examination of Ang2-treated xenografts revealed areas of tumor necrosis and vascular damage. We therefore conclude that deregulated Ang2 expression during gliomagenesis hindered successful angiogenesis and that therapies that sustain Ang2 expression might be effective against malignant gliomas.
对癌症模型中血管生成调节因子表达的系统分析应为恶性胶质瘤新疗法的开发提供有用信息。在本研究中，我们分析了U - 87 MG异种移植瘤生长过程中的肿瘤生长、血管生成以及血管生成素-2（Ang2）的表达。我们发现该模型中的肿瘤血管生成遵循一个多阶段过程，其特征为无血管、丰富的外周血管生成以及晚期血管阶段。在第4天，我们在肿瘤/脑界面观察到中央坏死区域、Ang2阳性胶质瘤细胞的外周环以及反应性Ang2阳性血管结构。当肿瘤形成血管网络时，Ang2仅在外周血管结构中表达。由于Ang2表达在发育后期被下调，可能是为了维持稳定的肿瘤脉管系统，我们接下来研究持续的Ang2表达是否可能损害血管发育并最终影响肿瘤生长。在鸡尿囊膜模型中，Ang2阻止了毛细血管样结构的形成并损害了血管生成。最后，我们测试了持续的Ang2表达对U - 87 MG异种移植瘤生长的影响。Ang2显著延长了颅内接种U - 87 MG肿瘤动物的生存期。对经Ang2处理的异种移植瘤的检查显示出肿瘤坏死和血管损伤区域。因此，我们得出结论，胶质瘤发生过程中Ang2表达失调阻碍了成功的血管生成，并且持续Ang2表达的疗法可能对恶性胶质瘤有效。
