Greenfield Jeffrey P, Jin David K, Young Lauren M, Christos Paul J, Abrey Lauren, Rafii Shahin, Gutin Philip H
Department of Neurological Surgery, NewYork-Presbyterian Hospital, Weill Cornell Medical Center, New York, New York, USA.
Neurosurgery. 2009 May;64(5):819-26; discussion 826-7. doi: 10.1227/01.NEU.0000343742.06625.DB.
The neovascularization of malignant brain tumors is a poorly understood phenomenon. Radiographic and histological evidence of increased vascularity correlate with clinical grade of gliomas. However, a quantitative noninvasive assay to assess glioma vascularity and associated clinical aggressiveness has not been developed. Circulating endothelial progenitor cells are unique vascular precursors recruited from the bone marrow through the circulation to form new tumor blood vessels. These cells were measured in patients undergoing surgery for glioblastoma multiforme (GBM). We hypothesized that this might reflect the extent of tumor vascularity, predict prognosis, or be useful as an assay to assess response to antiangiogenesis therapies. In addition, we report on a novel in vitro assay to assess the proangiogenic activity within the plasma samples obtained from glioma patients.
Fifty-six patients with various-grade gliomas had peripheral venous blood collected at the time of surgery and at subsequent visits during the follow-up period. The blood was separated into plasma and cellular fractions. The plasma was utilized in a human umbilical vein endothelial cell-based angiogenic assay. The cellular fraction containing endothelial progenitor cells was isolated, and specific cellular phenotypes were immunologically separated and counted using flow cytometry. Pathological samples were reviewed at the time of initial resection, and each patient's clinical course was monitored until the time of manuscript submission.
Plasma derived from peripheral blood of patients with GBM scored significantly higher on the functional angiogenic scale compared with plasma derived from patients with low-grade gliomas and from controls. In addition, all patients with GBM had measurable numbers of bone marrow-derived endothelial precursor cells coexpressing CD133 and vascular endothelial growth factor receptor 2 in their peripheral circulation at the time of tumor resection. These cells range from less than 0.1% to 1.6% of the entire circulating mononuclear white blood cell population, or approximately 200,000 cells in some patients. A statistically significant relationship was observed between the percentage of endothelial progenitor cells in the peripheral blood at the time of initial GBM resection and survival.
These studies suggest that plasma and circulating CD133+ vascular endothelial growth factor receptor 2+ proangiogenic cells are present in the peripheral blood of patients with glioma and can be used as a surrogate biomarker to measure tumor angiogenicity. These cells can be measured at the time of diagnosis and monitored in the postoperative period. These assays can be used to predict tumor aggressiveness. Also promising is their potential to identify patients with increased angiogenic activity who might respond maximally to antiangiogenesis therapies or to assess tumor response in patients using those therapies as the use of these adjuvant molecular modalities becomes more prevalent in neuro-oncology.
恶性脑肿瘤的新生血管形成是一个尚未被充分理解的现象。影像学和组织学上血管增多的证据与胶质瘤的临床分级相关。然而，尚未开发出一种定量的非侵入性检测方法来评估胶质瘤血管生成及相关的临床侵袭性。循环内皮祖细胞是从骨髓中募集并通过循环形成新的肿瘤血管的独特血管前体细胞。对多形性胶质母细胞瘤（GBM）手术患者的这些细胞进行了检测。我们推测这可能反映肿瘤血管生成的程度、预测预后，或作为评估抗血管生成治疗反应的一种检测方法。此外，我们报告了一种新的体外检测方法，用于评估从胶质瘤患者获得的血浆样本中的促血管生成活性。
56例不同分级的胶质瘤患者在手术时及随访期间的后续就诊时采集外周静脉血。血液被分离成血浆和细胞部分。血浆用于基于人脐静脉内皮细胞的血管生成检测。分离出含有内皮祖细胞的细胞部分，使用流式细胞术对特定细胞表型进行免疫分离和计数。在初次切除时复查病理样本，并监测每位患者的临床病程直至稿件提交时。
与低级别胶质瘤患者和对照组患者的血浆相比，GBM患者外周血来源的血浆在功能性血管生成量表上的得分显著更高。此外，所有GBM患者在肿瘤切除时外周循环中均有可测量数量的共表达CD133和血管内皮生长因子受体2的骨髓来源的内皮祖细胞。这些细胞占整个循环单核白细胞群体的比例从不到0.1%到1.6%不等，在一些患者中约为200,000个细胞。在初次GBM切除时外周血中内皮祖细胞的百分比与生存率之间观察到统计学上的显著关系。
这些研究表明，胶质瘤患者外周血中存在血浆和循环中的CD133 +血管内皮生长因子受体2 +促血管生成细胞，可作为测量肿瘤血管生成的替代生物标志物。这些细胞可以在诊断时进行检测，并在术后进行监测。这些检测方法可用于预测肿瘤的侵袭性。同样有前景的是，随着这些辅助分子模式在神经肿瘤学中的应用越来越普遍，它们有可能识别出血管生成活性增加、可能对抗血管生成治疗反应最大的患者，或评估使用这些治疗方法的患者的肿瘤反应。
