Glioma initiating cells form a differentiation niche via the induction of extracellular matrices and integrin αV.
Glioma initiating cells form a differentiation niche via the induction of extracellular matrices and integrin αV.
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DOI：
10.1371/journal.pone.0059558
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Araki N
中科院分区：
文献类型：
--
作者：
Niibori-Nambu A;Midorikawa U;Mizuguchi S;Hide T;Nagai M;Komohara Y;Nagayama M;Hirayama M;Kobayashi D;Tsubota N;Takezaki T;Makino K;Nakamura H;Takeya M;Kuratsu J;Araki N
胶质瘤起始细胞（GIC）被认为是恶性胶质瘤耐药和复发的原因。为了阐明GIC维持/分化的分子机制，我们建立了具有分化为恶性胶质瘤的潜力的GIC克隆，并进行基于DNA微阵列/iTRAQ的整合蛋白质组学。鉴定了21，857种mRNA和8，471种蛋白质，并整合到基因/蛋白质表达分析图中。基因本体分析显示，细胞粘附分子，包括整合素亚家族，如α2和αV，和细胞外基质（ECM），如胶原IV（COL 4），层粘连蛋白α2（LAMA 2）和纤连蛋白1（FN）的表达，在血清诱导的GIC分化过程中显著上调。这种分化过程伴随着MAPK以及GIC中胶质瘤特异性蛋白的上调，在这些ECM（特别是FN）包被的培养皿中显著加速。整合素αV阻断抗体和RGD肽显著抑制GIC分化的早期事件，表明ECM与整合素αV的偶联是GIC分化所必需的。此外，整合素αV及其强配体FN的表达在小鼠颅内GIC异种移植物形成的胶质母细胞瘤中显著增加。有趣的是，在GIC分化的初始阶段，RGD处理显著抑制GIC增殖并提高其对抗癌药物替莫唑胺（TMZ）的敏感性。我们还发现，TMZ和RGD的组合治疗抑制胶质瘤的进展，并导致小鼠颅内GIC异种移植模型的存活时间更长。这些结果表明，GIC诱导/分泌ECM以形成具有血清因子的微环境，即通过整联蛋白识别基序RGD进一步刺激GIC分化和增殖的分化小生境。联合应用RGD和TMZ对胶质瘤的复发有更高的抑制作用，这可能是由分化小生境中的GIC调节的。本研究为早期GIC相关胶质瘤的治疗提供了新的思路。
Glioma initiating cells (GICs) are considered responsible for the therapeutic resistance and recurrence of malignant glioma. To clarify the molecular mechanism of GIC maintenance/differentiation, we established GIC clones having the potential to differentiate into malignant gliomas, and subjected to DNA microarray/iTRAQ based integrated proteomics. 21,857 mRNAs and 8,471 proteins were identified and integrated into a gene/protein expression analysis chart. Gene Ontology analysis revealed that the expression of cell adhesion molecules, including integrin subfamilies, such as α2 and αV, and extracellular matrices (ECMs), such as collagen IV (COL4), laminin α2 (LAMA2), and fibronectin 1 (FN), was significantly upregulated during serum-induced GIC differentiation. This differentiation process, accompanied by the upregulation of MAPK as well as glioma specific proteins in GICs, was dramatically accelerated in these ECM (especially FN)-coated dishes. Integrin αV blocking antibody and RGD peptide significantly suppressed early events in GIC differentiation, suggesting that the coupling of ECMs to integrin αV is necessary for GIC differentiation. In addition, the expression of integrin αV and its strong ligand FN was prominently increased in glioblastomas developed from mouse intracranial GIC xenografts. Interestingly, during the initial phase of GIC differentiation, the RGD treatment significantly inhibited GIC proliferation and raised their sensitivity against anti-cancer drug temozolomide (TMZ). We also found that combination treatments of TMZ and RGD inhibit glioma progression and lead the longer survival of mouse intracranial GIC xenograft model. These results indicate that GICs induce/secrete ECMs to develop microenvironments with serum factors, namely differentiation niches that further stimulate GIC differentiation and proliferation via the integrin recognition motif RGD. A combination of RGD treatment with TMZ could have the higher inhibitory potential against the glioma recurrence that may be regulated by the GICs in the differentiation niche. This study provides a new perspective for developing therapeutic strategies against the early onset of GIC-associated glioma.
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DOI：
10.1016/j.bbrc.2007.06.094
发表时间：
2007-08-31
影响因子：
3.1
作者：
Oka, Naoki;Soeda, Akio;Iwama, Toru
通讯作者：
Iwama, Toru
影响因子：
5.2
作者：
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影响因子：
5.2
作者：
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通讯作者：
Ffrench-Constant, Charles
影响因子：
3.2
作者：
Pimton, Pimchanok;Sarkar, Saheli;Lelkes, Peter I.
通讯作者：
Lelkes, Peter I.
影响因子：
3.5
作者：
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通讯作者：
Smith, Austin