Cells isolated from residual intracranial tumors after treatment express iPSC genes and possess neural lineage differentiation plasticity.,EBioMedicine

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Cells isolated from residual intracranial tumors after treatment express iPSC genes and possess neural lineage differentiation plasticity.
EBioMedicine ( IF 9.7 ) Pub Date : 2018-09-27 , DOI: 10.1016/j.ebiom.2018.09.019
Kamalakannan Palanichamy ₁ , John R Jacob ₁ , Kevin T Litzenberg ₁ , Abhik Ray-Chaudhury ₂ , Arnab Chakravarti ₁

Affiliation

BACKGROUND The goal of this study is to identify and characterize treatment resistant tumor initiating cells (TRTICs) using orthotopic xenografts. METHODS TRTICs were enriched from GBM cell lines using mouse xenografts treated with fractionated doses of radiation and temozolomide. TRTICs were characterized by neurosphere clonogenicity and self-renewal, serial xenotransplantation, differentiation potential, and mRNA & miRNA transcriptomic profiling. We use an unbiased approach to identify antigens encoding TRTIC and glioma stem cells (GSC) populations. Co-culture experiments of TRTIC and differentiated cells were conducted to evaluate the reliance of TRTIC differentiation on the secretome of differentiated cells. FINDINGS TRTICs acquire stem-like gene expression signatures and increased side population staining resulting from the activation of multi-drug resistance genes. Genetic and functional characterization of TRTICs shows a striking resemblance with GSCs. TRTICs can differentiate towards specific progeny in the neural stem cell lineage. TRTIC-derived tumors display all the histological hallmarks of glioblastoma (GBM) and exhibit a miRNA-transcript and mRNA-transcriptomic profile associated with aggressiveness. We report that CD24+/CD44+ antigens are expressed in TRTICs and patient-derived GSCs. Double positive CD24+/CD44+ exhibit treatment resistance and enhanced tumorigenicity. Interestingly, co-culture experiments with TRTICs and differentiated cells indicated that the regulation of TRTIC differentiation could rely on the secretome in the tumor niche. INTERPRETATION Radiation and temozolomide treatment enriches a population of cells that have increased iPSC gene expression. As few as 500 cells produced aggressive intracranial tumors resembling patient GBM. CD24+/CD44+ antigens are increased in TRTICs and patient-derived GSCs. The enrichment for TRTICs may result in part from the secretome of differentiated cells. FUND: NIH/NCI 1RC2CA148190, 1R01CA108633, 1R01CA188228, and The Ohio State University Comprehensive Cancer Center.

中文翻译：

治疗后从残留颅内肿瘤中分离出的细胞表达iPSC基因，并具有神经谱系分化可塑性。

背景技术本研究的目的是使用原位异种移植物鉴定和表征治疗耐药的肿瘤起始细胞（TRTIC）。方法采用分次剂量放射和替莫唑胺处理的小鼠异种移植物从GBM细胞株中富集TRTICs。TRTICs的特征是神经球的克隆性和自我更新，连续异种移植，分化潜能以及mRNA和miRNA转录组谱。我们使用一种无偏见的方法来识别编码TRTIC和神经胶质瘤干细胞（GSC）群体的抗原。进行了TRTIC和分化细胞的共培养实验，以评估TRTIC分化对分化细胞分泌组的依赖性。结果TRTICs获得了茎样基因表达特征，并且由于多重耐药基因的激活而增加了侧群染色。TRTICs的遗传和功能表征与GSC极为相似。TRTICs可以分化为神经干细胞谱系中的特定子代。源自TRTIC的肿瘤显示出胶质母细胞瘤（GBM）的所有组织学特征，并表现出与侵略性相关的miRNA转录和mRNA转录组特征。我们报告CD24 + / CD44 +抗原在TRTICs和患者衍生的GSC中表达。双阳性CD24 + / CD44 +表现出治疗抗性和增强的致瘤性。有趣的是，TRTICs与分化细胞的共培养实验表明，TRITIC分化的调控可能依赖于肿瘤位点的分泌组。解释辐射和替莫唑胺治疗可丰富iPSC基因表达增加的细胞群体。仅有500个细胞产生类似于患者GBM的侵袭性颅内肿瘤。TRTICs和患者来源的GSC中CD24 + / CD44 +抗原增加。TRTICs的富集可能部分源于分化细胞的分泌组。资金：NIH / NCI 1RC2CA148190、1R01CA108633、1R01CA188228和俄亥俄州立大学综合癌症中心。仅有500个细胞产生类似于患者GBM的侵袭性颅内肿瘤。TRTICs和患者来源的GSC中CD24 + / CD44 +抗原增加。TRTICs的富集可能部分源于分化细胞的分泌组。资金：NIH / NCI 1RC2CA148190、1R01CA108633、1R01CA188228和俄亥俄州立大学综合癌症中心。仅有500个细胞产生类似于患者GBM的侵袭性颅内肿瘤。TRTICs和患者来源的GSC中CD24 + / CD44 +抗原增加。TRTICs的富集可能部分源于分化细胞的分泌组。资金：NIH / NCI 1RC2CA148190、1R01CA108633、1R01CA188228和俄亥俄州立大学综合癌症中心。

更新日期：2018-09-27

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