Side population in human glioblastoma is non-tumorigenic and characterizes brain endothelial cells.
Side population in human glioblastoma is non-tumorigenic and characterizes brain endothelial cells.
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DOI：
10.1093/brain/awt025
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发表时间：
2013-05
期刊：
影响因子：
--
通讯作者：
Niclou SP
中科院分区：
文献类型：
--
作者：
Golebiewska A;Bougnaud S;Stieber D;Brons NH;Vallar L;Hertel F;Klink B;Schröck E;Bjerkvig R;Niclou SP
恶性胶质瘤中癌症干细胞样细胞的鉴定和意义仍然存在争议。有人提出，癌症干细胞样细胞通过表达 ATP 结合盒转运蛋白，通过流出外源化合物对细胞进行解毒，从而表现出更高的耐药性。在这里，我们根据新鲜分离的人胶质母细胞瘤样本及其衍生的颅内异种移植物中 ATP 结合盒转运蛋白的外排特性，研究了“侧群”表型。通过对从胶质母细胞瘤活组织检查中获得的分选细胞以及在表达免疫缺陷的增强型绿色荧光蛋白的小鼠中开发的人类肿瘤异种移植物进行荧光原位杂交分析，可以明确地区分肿瘤-基质，我们发现人类胶质母细胞瘤中的侧群细胞是非肿瘤性的并且完全源自基质。无论其遗传背景、肿瘤倍性或干细胞相关标记物表达如何，肿瘤细胞始终缺乏外排特性。使用多参数流式细胞术，我们确定人胶质母细胞瘤中的基质侧群体是脑源性内皮细胞，星形胶质细胞的贡献较小。与胎儿的对应物相比，成人大脑中的神经干/祖细胞没有表现出侧群表型。值得注意的是，我们发现 CD133 阳性细胞通常与胶质母细胞瘤活检中的癌症干细胞样细胞相关，并不代表同质细胞群，并且包括 CD31 阳性内皮细胞。有趣的是，用抗血管生成剂贝伐珠单抗治疗脑肿瘤可降低总血管密度，但不影响内皮细胞的流出特性。总之，我们的研究结果有助于公正地识别脑肿瘤中的癌症干细胞样细胞和基质细胞，并为大脑药物输送的复杂问题提供新的见解。由于内皮细胞的流出特性可能会影响药物的利用度，因此瞬时靶向 ATP 结合盒转运蛋白可能是改善脑肿瘤治疗效果的一种有价值的治疗策略。
The identification and significance of cancer stem-like cells in malignant gliomas remains controversial. It has been proposed that cancer stem-like cells display increased drug resistance, through the expression of ATP-binding cassette transporters that detoxify cells by effluxing exogenous compounds. Here, we investigated the ‘side population’ phenotype based on efflux properties of ATP-binding cassette transporters in freshly isolated human glioblastoma samples and intracranial xenografts derived thereof. Using fluorescence in situ hybridization analysis on sorted cells obtained from glioblastoma biopsies, as well as human tumour xenografts developed in immunodeficient enhanced green fluorescence protein-expressing mice that allow an unequivocal tumour-stroma discrimination, we show that side population cells in human glioblastoma are non-neoplastic and exclusively stroma-derived. Tumour cells were consistently devoid of efflux properties regardless of their genetic background, tumour ploidy or stem cell associated marker expression. Using multi-parameter flow cytometry we identified the stromal side population in human glioblastoma to be brain-derived endothelial cells with a minor contribution of astrocytes. In contrast with their foetal counterpart, neural stem/progenitor cells in the adult brain did not display the side population phenotype. Of note, we show that CD133-positive cells often associated with cancer stem-like cells in glioblastoma biopsies, do not represent a homogenous cell population and include CD31-positive endothelial cells. Interestingly, treatment of brain tumours with the anti-angiogenic agent bevacizumab reduced total vessel density, but did not affect the efflux properties of endothelial cells. In conclusion our findings contribute to an unbiased identification of cancer stem-like cells and stromal cells in brain neoplasms, and provide novel insight into the complex issue of drug delivery to the brain. Since efflux properties of endothelial cells are likely to compromise drug availability, transiently targeting ATP-binding cassette transporters may be a valuable therapeutic strategy to improve treatment effects in brain tumours.
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影响因子：
37.3
作者：
Beier D;Schulz JB;Beier CP
通讯作者：
Beier CP
影响因子：
4.8
作者：
Ogden, Alfred T.;Waziri, Allen E.;Bruce, Jeffrey N.
通讯作者：
Bruce, Jeffrey N.
影响因子：
50.3
作者：
Chen, Ruihuan;Nishimura, Merry C.;Phillips, Heidi S.
通讯作者：
Phillips, Heidi S.
影响因子：
4.8
作者：
Niclou, Simone P.;Danzeisen, Claude;Bjerkvig, Rolf
通讯作者：
Bjerkvig, Rolf
影响因子：
5.2
作者：
Challen, GA;Little, MH
通讯作者：
Little, MH