Department of Neurosurgery, The 2nd Affiliated Hospital of Suzhou University, 1055 Sanxiang Road, Suzhou 215004, People's Republic of China.
Stem Cell Rev Rep. 2011 Mar;7(1):141-52. doi: 10.1007/s12015-010-9169-7.
Previous studies suggest that tumor cells might be the progenitor for tumor vasculature. Whether vascular tube formation from transdifferentiation of human glioma stem/progenitor cells (hGSPCs) contribute to angiogenesis of gliomas remain largely uncertain.
hGSPCs were isolated from thirteen surgical specimens of gliomas and cultured in medium favored for stem cell growth. In vitro transdifferentiation of hGSPCs was performed under hypoxia. Expression of vascular endothelial cells (VECs) markers CD31, CD34, kinase insert domain receptor (KDR), and von Willebrand factor (vWF) were analyzed with real-time quantitative RT-PCR and immunofluorescence techniques. Vasculogenic mimicry of hGSPCs was evaluated in a tumor stem cell xenograft model in vivo. Relationships between content of hGSPCs and expression levels of both VECs markers and proangiogenic factors in large number of clinical specimens were further investigated in glioma tissue microarray.
In vitro, hGSPCs can transdifferentiate into VECs under hypoxia, they manifested typical "flagstone" pattern when cultivated in medium containing VEGF for a few days; when cultivated on Matrigel they were capable of forming capillary-like structures. Expression of VECs markers including CD31, CD34, KDR, and vWF were significantly up-regulated after transdifferentiation. Human leukocyte antigen (HLA) positively stained vessels were observed inside the xenograft tumors after intracerebral transplantation of hGSPCs in athymic nude mice, implied part of tumor cells with human origin were involved in formation of tumor vessels. In surgical specimens of human glioma, tumor vascular cells coexpressing the markers of early VECs (CD34) and markers of hGSPCs (ABCG2 and nestin) suggest that these vascular cells may stemmed from hGSPCs.
Our observations suggest the functional role of hGSPCs as endothelial progenitors, which have properties that give rise to VECs, and have the ability to form vascular endothelial tubes. However, unspecific markers (ABCG2, nestin) that stain for both endothelial as well as glioma stem cells, were found to be expressed in tumor vasculature of human specimen, and limit further interpretation of this finding.
先前的研究表明，肿瘤细胞可能是肿瘤血管的前体细胞。人神经胶质瘤干细胞/祖细胞（hGSPCs）的血管管腔形成是否有助于神经胶质瘤的血管生成仍存在很大的不确定性。
从 13 例神经胶质瘤手术标本中分离出 hGSPCs，并在有利于干细胞生长的培养基中培养。在缺氧条件下进行 hGSPCs 的体外转分化。用实时定量 RT-PCR 和免疫荧光技术分析血管内皮细胞（VECs）标志物 CD31、CD34、激酶插入结构域受体（KDR）和血管性血友病因子（vWF）的表达。在体内肿瘤干细胞异种移植模型中评估 hGSPCs 的血管生成拟态。进一步在神经胶质瘤组织微阵列中研究了大量临床标本中 hGSPCs 含量与 VECs 标志物和促血管生成因子表达水平之间的关系。
体外，hGSPCs 在缺氧条件下可向 VECs 转分化，在含 VEGF 的培养基中培养数天后表现出典型的“石板”样形态；在 Matrigel 上培养时，能够形成类似毛细血管的结构。转分化后 VECs 标志物 CD31、CD34、KDR 和 vWF 的表达明显上调。将 hGSPCs 颅内移植入裸鼠后，在异种移植肿瘤内观察到 HLA 阳性染色的血管，提示部分具有人源性的肿瘤细胞参与了肿瘤血管的形成。在人神经胶质瘤的手术标本中，肿瘤血管细胞共同表达早期 VECs 标志物（CD34）和 hGSPCs 标志物（ABCG2 和巢蛋白），提示这些血管细胞可能源自 hGSPCs。
我们的观察表明，hGSPCs 作为内皮祖细胞具有功能性作用，可分化为 VECs，并具有形成血管内皮管的能力。然而，在人标本的肿瘤血管中发现了既表达内皮细胞又表达神经胶质瘤干细胞的非特异性标志物（ABCG2、巢蛋白），限制了对这一发现的进一步解释。
