Overexpression of calcium-permeable glutamate receptors in glioblastoma derived brain tumor initiating cells.
Overexpression of calcium-permeable glutamate receptors in glioblastoma derived brain tumor initiating cells.
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DOI：
10.1371/journal.pone.0047846
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Parsa AT
中科院分区：
文献类型：
--
作者：
Oh MC;Kim JM;Safaee M;Kaur G;Sun MZ;Kaur R;Celli A;Mauro TM;Parsa AT
多形性胶质母细胞瘤是最恶性的原发性脑肿瘤，预后差。这些肿瘤由恶性细胞的异质群体组成，包括分化良好的肿瘤细胞和具有干细胞特性的分化较低的细胞。这些癌症干细胞，被称为脑肿瘤起始细胞，可能有助于胶质瘤复发，因为它们具有高度侵袭性，移动的，对放疗和化疗具有抗性，并且具有自我更新的能力。胶质母细胞瘤肿瘤细胞释放兴奋毒性水平的谷氨酸，这可能是肿瘤周围神经元死亡、坏死形成、局部炎症和胶质瘤相关癫痫发作的关键过程。此外，肿瘤中升高的谷氨酸水平可能以旁分泌和自分泌方式激活胶质母细胞瘤肿瘤细胞上的谷氨酸受体，导致增殖和侵袭。使用先前描述的选择性促进表达干细胞标记物巢蛋白和SOX-2的脑肿瘤起始细胞生长的培养条件，我们表征了源自胶质母细胞瘤的脑肿瘤起始细胞中α-氨基-3-羟基-5-甲基-4-异唑丙酸（AMPA）型谷氨酸受体亚单位的表达。在这里，我们第一次表明，胶质母细胞瘤脑肿瘤起始细胞表达高浓度的功能性钙渗透AMPA受体相比，分化的肿瘤培养物组成的非干细胞。通过免疫印迹、免疫细胞化学和细胞内钙成像对特异性激动剂的反应，证实了钙渗透性AMPA受体表达上调。我们的发现提高了GBM肿瘤微环境中谷氨酸分泌可能刺激脑肿瘤源性癌症干细胞的可能性。
Glioblastoma multiforme is the most malignant type of primary brain tumor with a poor prognosis. These tumors consist of a heterogeneous population of malignant cells, including well-differentiated tumor cells and less differentiated cells with stem cell properties. These cancer stem cells, known as brain tumor initiating cells, likely contribute to glioma recurrence, as they are highly invasive, mobile, resistant to radiation and chemotherapy, and have the capacity to self-renew. Glioblastoma tumor cells release excitotoxic levels of glutamate, which may be a key process in the death of peritumoral neurons, formation of necrosis, local inflammation, and glioma-related seizures. Moreover, elevated glutamate levels in the tumor may act in paracrine and autocrine manner to activate glutamate receptors on glioblastoma tumor cells, resulting in proliferation and invasion. Using a previously described culturing condition that selectively promotes the growth of brain tumor initiating cells, which express the stem cell markers nestin and SOX-2, we characterize the expression of α-amino-3-hydroxy-5-methyl-4-isozolepropionic acid (AMPA)-type glutamate receptor subunits in brain tumor initiating cells derived from glioblastomas. Here we show for the first time that glioblastoma brain tumor initiating cells express high concentrations of functional calcium-permeable AMPA receptors, compared to the differentiated tumor cultures consisting of non-stem cells. Up-regulated calcium-permeable AMPA receptor expression was confirmed by immunoblotting, immunocytochemistry, and intracellular calcium imaging in response to specific agonists. Our findings raise the possibility that glutamate secretion in the GBM tumor microenvironment may stimulate brain tumor derived cancer stem cells.
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影响因子：
45.3
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Fine, Howard A.
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