Department of Biochemistry and Cancer Biology, Meharry Medical College, The Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Int J Cancer. 2010 Nov 1;127(9):2063-75. doi: 10.1002/ijc.25249.
Glioblastoma multiforme (GBM) remains the most devastating neoplasm of the central nervous system and has a dismal prognosis. Ionizing radiation represents an effective therapy for GBM, but radiotherapy remains only palliative because of radioresistance. In this study, we demonstrate that glioma cells participate in tumor vascularization and contribute to vascular radioresistance. Using a 3-dimensional coculture system, we observed an intimate interaction of glioma cells with endothelial cells whereby endothelial cells form vascular structures, followed by the recruitment and vascular patterning of glioma cells. In addition, tumor cells stabilize the vascular structures and render them radioresistant. Blocking initial endothelial vascular formation with endothelial-specific inhibitors prevented tumor cells from forming any structures. However, these inhibitors exhibited minimum effects on vascular structures formed by tumor cells, due to the absence of the targeted receptors on tumor cells. Consistent with the in vitro findings, we show that glioma cells form perfused blood vessels in xenograft tumor models. Together, these data suggest that glioma cells mimic endothelial cells and incorporate into tumor vasculature, which may contribute to radioresistance observed in GBM. Therefore, interventions aimed at the glioma vasculature should take into consideration the chimeric nature of the tumor vasculature.
多形性胶质母细胞瘤（GBM）仍然是中枢神经系统最具破坏性的肿瘤，预后不良。电离辐射是治疗 GBM 的有效方法，但由于存在放射抵抗，放疗仍然只是姑息性的。在这项研究中，我们证明了神经胶质瘤细胞参与肿瘤血管生成，并有助于血管放射抵抗。使用三维共培养系统，我们观察到神经胶质瘤细胞与内皮细胞之间存在密切的相互作用，内皮细胞形成血管结构，随后招募和血管形成神经胶质瘤细胞。此外，肿瘤细胞稳定血管结构并使其具有放射抗性。用内皮特异性抑制剂阻断初始内皮血管形成可防止肿瘤细胞形成任何结构。然而，由于肿瘤细胞上缺乏靶向受体，这些抑制剂对肿瘤细胞形成的血管结构的影响最小。与体外研究结果一致，我们表明神经胶质瘤细胞在异种移植肿瘤模型中形成灌注血管。总之，这些数据表明，神经胶质瘤细胞模拟内皮细胞并整合到肿瘤血管中，这可能导致 GBM 中观察到的放射抵抗。因此，针对神经胶质瘤血管的干预措施应考虑到肿瘤血管的嵌合性质。
