T cells enhance stem-like properties and conditional malignancy in gliomas.
T cells enhance stem-like properties and conditional malignancy in gliomas.
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DOI：
10.1371/journal.pone.0010974
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发表时间：
2010-06-07
期刊：
影响因子：
3.7
通讯作者：
Wheeler CJ
中科院分区：
文献类型：
--
作者：
Irvin DK;Jouanneau E;Duvall G;Zhang XX;Zhai Y;Sarayba D;Seksenyan A;Panwar A;Black KL;Wheeler CJ
高度致瘤性干细胞样细胞（癌症干细胞; CSC）的小群体可以存在于癌症中，并且独特地再生癌症，包括恶性脑肿瘤（神经胶质瘤）。然而，胶质瘤CSC（GSC）的许多方面已经在非生理环境中表征。我们发现基因表达相似性更好地定义了胶质瘤的“干性”，并揭示了GSC相似性随着肿瘤级别的降低而增加。使用这种方法，我们检查了树突状细胞（DC）疫苗治疗前后人类IV级胶质瘤（GBM）的干性。随后对从裸、野生型或DC接种的宿主脑中回收的鼠GL 26肿瘤进行基因表达、表型和功能分析。GSC相似性在疫苗后GBM中特异性增加，并且与疫苗改变的基因表达和内源性抗肿瘤T细胞活性相关性最好。GL 26分析证实了免疫改变，干细胞标志物的特异性获得，对抗干细胞药物（环巴胺）的特异性增强的敏感性，以及在野生型宿主中增强的致瘤性，在肿瘤中与抗肿瘤T细胞活性成比例。尽管如此，在T细胞缺陷宿主中，疫苗暴露的GL 26细胞的致瘤性并不比亲本GL 26更强，尽管它们在其他方面似乎与通过化疗富集的GSC相似。最后，暴露于疫苗的GBM和GL 26表现出祖细胞和/或分化中表达的基因的相对均一的表达。T细胞活性代表能够在人和小鼠胶质瘤中按比例富集GSC的诱导性生理过程。然而，富含强T细胞活性的干细胞样胶质瘤可能与其他GSC不同，因为它们的干细胞样特性可能与特定宿主免疫条件下肿瘤恶性度和异质性增加无关。
Small populations of highly tumorigenic stem-like cells (cancer stem cells; CSCs) can exist within, and uniquely regenerate cancers including malignant brain tumors (gliomas). Many aspects of glioma CSCs (GSCs), however, have been characterized in non-physiological settings. We found gene expression similarity superiorly defined glioma “stemness”, and revealed that GSC similarity increased with lower tumor grade. Using this method, we examined stemness in human grade IV gliomas (GBM) before and after dendritic cell (DC) vaccine therapy. This was followed by gene expression, phenotypic and functional analysis of murine GL26 tumors recovered from nude, wild-type, or DC-vaccinated host brains. GSC similarity was specifically increased in post-vaccine GBMs, and correlated best to vaccine-altered gene expression and endogenous anti-tumor T cell activity. GL26 analysis confirmed immune alterations, specific acquisition of stem cell markers, specifically enhanced sensitivity to anti-stem drug (cyclopamine), and enhanced tumorigenicity in wild-type hosts, in tumors in proportion to anti-tumor T cell activity. Nevertheless, vaccine-exposed GL26 cells were no more tumorigenic than parental GL26 in T cell-deficient hosts, though they otherwise appeared similar to GSCs enriched by chemotherapy. Finally, vaccine-exposed GBM and GL26 exhibited relatively homogeneous expression of genes expressed in progenitor cells and/or differentiation. T cell activity represents an inducible physiological process capable of proportionally enriching GSCs in human and mouse gliomas. Stem-like gliomas enriched by strong T cell activity, however, may differ from other GSCs in that their stem-like properties may be disassociated from increased tumor malignancy and heterogeneity under specific host immune conditions.
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