Dedifferentiation of Glioma Cells to Glioma Stem-like Cells By Therapeutic Stress-induced HIF Signaling in the Recurrent GBM Model.
Dedifferentiation of Glioma Cells to Glioma Stem-like Cells By Therapeutic Stress-induced HIF Signaling in the Recurrent GBM Model.
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DOI：
10.1158/1535-7163.mct-15-0675
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发表时间：
2016-12
影响因子：
5.7
通讯作者：
Ahmed AU
中科院分区：
文献类型：
--
作者：
Lee G;Auffinger B;Guo D;Hasan T;Deheeger M;Tobias AL;Kim JY;Atashi F;Zhang L;Lesniak MS;James CD;Ahmed AU
越来越多的证据表明，癌细胞的亚群，称为癌症干细胞（CSC），是几种人类恶性肿瘤，包括多形性胶质母细胞瘤（GBM）的进展至关重要。CSC具有高度致瘤性，能够自我更新，并且对常规疗法具有抗性，因此被认为是疾病复发的关键因素之一。为了阐明肿瘤复发的进化路径以及CSC在此过程中的作用，我们开发了由抗胶质瘤化疗，替莫唑胺（TMZ）诱导的患者来源的异种移植GBM复发模型。在这个模型中，我们观察到一个显着的表型转变向未分化的人口。我们在体外证实了这些发现，因为发现在分化促进培养基中培养的分选的CD133阴性群体在化疗治疗后获得CD133表达。为了在单细胞水平上研究这种表型转换，设计了基于GSC特异性启动子的报告系统，以真实的时间跟踪GSC群体的变化。我们观察到单个非干细胞胶质瘤细胞向干细胞样状态的活跃表型和功能转换，并且TMZ治疗显著增加了单个细胞转换的速率。重要的是，我们发现治疗诱导的缺氧诱导因子（HIF）1α和HIF 2 α在允许非干细胞胶质瘤细胞获得干细胞样特征中起关键作用，因为两种HIF的表达在TMZ治疗后增加，并且HIF表达的敲低抑制了治疗后非干细胞胶质瘤细胞和GSC之间的相互转化。基于我们的研究结果，我们提出抗胶质瘤化疗促进了HIF在GBM细胞中的积累，从而诱导了负责复发的治疗抗性GSC的形成。
Increasing evidence exposes a subpopulation of cancer cells, known as cancer stem cells (CSCs), to be critical for the progression of several human malignancies, including glioblastoma multiforme (GBM). CSCs are highly tumorigenic, capable of self-renewal, and resistant to conventional therapies, and thus considered to be one of the key contributors to disease recurrence. In order to elucidate the poorly understood evolutionary path of tumor recurrence and the role of CSCs in this process, we developed patient-derived xenograft GBM recurrent models induced by anti-glioma chemotherapy, temozolomide (TMZ). In this model, we observed a significant phenotypic shift towards an undifferentiated population. We confirmed these findings in vitro as sorted CD133-negative populations cultured in differentiation-forcing media were found to acquire CD133 expression following chemotherapy treatment. To investigate this phenotypic switch at the single cell level, GSC-specific promoter-based reporter systems were engineered to track changes in the GSC population in real time. We observed the active phenotypic and functional switch of single non-stem glioma cells to a stem-like state and that TMZ therapy significantly increased the rate of single-cell conversions. Importantly, we showed the therapy induced hypoxia inducible factors (HIF) 1α and HIF2α play key roles in allowing non-stem glioma cells to acquire stem-like traits, as the expression of both HIFs increase upon TMZ therapy and knockdown of HIFs expression inhibits the interconversion between non-stem glioma cells and GSCs post-therapy. Based on our results, we propose that anti-glioma chemotherapy promotes the accumulation of HIFs in the GBM cells that induces the formation of therapy-resistant GSCs responsible for recurrence.