脑肿瘤干细胞致病机制的研究
|
摘要
脑肿瘤是致死率最高的人类肿瘤之一,其中IV级胶质瘤胶质母细胞瘤(glioblastoma multiforme,GBM)为成人最常见的原发性脑肿瘤,其患者的中位生存期仅有15个月左右。胶质膜细胞瘤呈现浸润性生长,可向正常脑组织广泛浸润,导致手术切除困难。其次,GBM对常规的放、化疗具有抵抗性,成为其致死率高和复发率高的重要原因。由于尚未完全阐明其发病机制,目前缺乏针对GBM的有效治疗方法。近年来,肿瘤干细胞的理论指出,胶质瘤中有一部分细胞具有极强的致瘤特性,且具有干细胞的特点,是GBM生长和复发的根源,称之为胶质瘤干细胞(glioma stem cell,GSC)。另外,GSCs还对放、化疗具有抵抗性,因而也是GBM复发的根源。
我们的研究包括了GSC的分离培养、GSC标志物的探索,以及探讨影响GSC致瘤性和干细胞特征的分子机制。
第一部分:采用手术切除的新鲜组织,利用神经干细胞(neural stem cell, NSC)培养基无血清培养基(serum free medium, SFM)培养出富含GSC的神经球。本课题分离培养了17例原发性脑肿瘤,其中7例形成了神经球样细胞系,并可传至5-20代。在此基础上,我们研究了神经干细胞标记物CD15标记GSC的情况。目前研究GSC的一个关键难题是尚缺乏特异性的GSC标记物。CD133(PROM1)是最早采用的GSC标记物,研究指出CD133~+的胶质瘤细胞富含有GSC。然而近期的研究指出也有部分的GSC呈现CD133~-。因而,进一步寻找GSC的标记物即成为研究GSC的重要课题。分析GSC的特点我们得出,GSC具有正常NSCs的特点,且目前的证据指出GBM起源于NSC。因而,我们提出假说,指出NSC的一些标记物也可用于标记GSC。CD15(SSEA-1/LeX)是常用的NSC标记物,我们此部分的目的即是探讨CD15是否可成为GSC的标记物。我们首先采用免疫组织化学的方法研究了CD15在胶质瘤组织中的表达。结果指出CD15广泛表达于胶质瘤,包括胶质母细胞瘤(GBM)、II和III级星形胶质细胞瘤以及室管膜细胞瘤。其次我们采用免疫磁珠分选出CD15~+的细胞,并比较了CD15~+细胞和CD15~-细胞的干细胞特性,发现,CD15~+细胞较CD15~-细胞具有更强的神经球形成能力。将分选的细胞移植入裸鼠脑内后,104的CD15~+细胞即可形成肿瘤而同样数目的CD15~-细胞则不能形成肿瘤。免疫组化研究指出CD15~+细胞形成的移植瘤与原发性的肿瘤具有相似的免疫组织特性。进一步,我们分选出CD133~-CD15~+细胞,发现CD133~-CD15~+细胞也具有GSC特性,即具有形成神经球以及在免疫缺陷小鼠脑内形成肿瘤的能力,进一步证明CD15可标记出部分CD133~-的GSC。同一时间发表的另一篇文章得到了与我们相似的结论(Cell Stem Cell. 2009 May 8;4(5):440-52)。
第二部分:癌基因ZNF217对GSC分化的影响。由于GSC对胶质瘤的致瘤性具有重要作用,因而针对GSC的治疗成为具有希望的治疗靶点。目前研究认为,通过促进GSC分化可抑制胶质瘤的生长,因而研究调节GSC干细胞特性以及分化的内在机制成为研究的一个重要方向。目前对控制GSC分化的分子机制尚知之甚少。本部分研究了新的癌基因ZNF217(锌指蛋白217)对GSC分化的影响。ZNF217在多种肿瘤中高表达,且具有抑制干细胞分化的作用。然而ZNF217在胶质瘤的研究尚未见报道。采用实时定量PCR(quantitative RT~-PCR,qPCR)结果指出ZNF217在胶质瘤中的表达显著高于正常脑组织,且在GBM中的表达显著高于低级别胶质瘤(p<0.001)。对一个分子数据库的分析指出,胶质瘤中ZNF217的表达水平与患者的预后负相关,因而是潜在的治疗靶点。其次,ZNF217在GSC中的表达高于正常NSC以及非GSCs(non-GSCs),且在血清培养集中诱导分化后ZNF217的表达降低。这些结果表明,ZNF217在GSC中的特异性高表达,因而可能对GSC的维持具有重要作用。采用siRNA沉默GSC中ZNF217表达可抑制GSC的生长并促进GSC向成熟的细胞分化。因而ZNF217在GBM中高表达对GSC的生长以及维持具有重要的作用。GSC在胶质瘤中处于一个特殊的缺氧微环境中。研究指出缺氧可增加GSC的致瘤性并增加干细胞的比例。因而,我们进一步探讨ZNF217是否也参与了缺氧调控的GSC致瘤性。采用GSC细胞系和常规的U87细胞系,我们研究指出在缺氧环境下ZNF217表达上调。由于缺氧诱导因子(hypoxia inducilble facors, HIFs)是缺氧环境下发挥作用的重要因子,我们进一步探讨了ZNF217是否受到HIFs的调控。利用qPCR对GBM标本的mRNA检测指出ZNF217表达与HIF1αα以及HIF2α呈正相关(p<0.01)。采用siRNA沉默U87和GSC中HIF1α或者HIF2α的表达,会显著降低ZNF217的表达水平,且HIF1α或者HIF2α沉默后ZNF217在缺氧环境中的上调也受到了抑制。因而ZNF217在缺氧环境中的表达上调受到HIFs的调控。
第三部分:干细胞因子LIN28对GSC发生的影响。本部分课题在约翰霍普金斯医学院Charles C. Eberhart实验室完成。LIN28可抑制Let-7 microRNA,后者可抑制K-ras、C-myc、HMGA2等癌基因。LIN28在多种癌组织中高表达,且高表达的肿瘤分化较差、患者预后较差。免疫组织化学结果指出LIN28在部分胶质瘤中过表达,而在正常脑组织中未检测到。采用慢病毒介导的shRNA沉默GSC细胞系JHH-GBM1中的LIN28后,MTT和软琼脂克隆试验结果指出沉默LIN28可显著抑制其生长以及克隆形成能力。其次,将LIN28在另一GBM细胞系JHH-GBM14中过表达可增加其侵袭性以及体内形成肿瘤的能力。因而LIN28对GSC的生长具有重要作用。为进一步探讨GSC的发生机制,我们分析了LIN28在GSC形成中的作用。我们采用了人源性的脑皮层神经干细胞(NSC-Ctx),然后利用慢病毒使其表达GBM中常见的癌基因,包括组成性活性K-RAS(constitutively activated KRAS,CA-KRAS),无活性的p53(dominant negative R248W p53,DN-p53),hTERT以及LIN28(NSC-KRAS/p53/hTERT/LIN28)。作为对照我们同时构建了NSC-GFP,NSC-p53/hTERT以及NSC-p53/hTERT/LIN28。值得注意的是我们试图构建的NSC-p53/hTERT/KRAS细胞无法存活,表明LIN28在NSC表达这些基因的过程这起着重要作用。体外实验表明NSC-KRAS/p53/hTERT/LIN28较正常NSC具有更强的增殖特性。体内结果表明,将NSC-KRAS/p53/hTERT/LIN28注射入裸鼠脑内4-5周即可长出肿瘤,且生长的移植瘤呈现胶质瘤的免疫组织特性,表达Nestin、GFAP、Ki67但不表达synaptophysin。而对照组NSC-GFP、NSC-p53/hTERT以及NSC-p53/hTERT/LIN28在移植入裸鼠脑内6个月后均无肿瘤形成。采用shRNA沉默NSC-KRAS/p53/hTERT/LIN28中的LIN28之后细胞无法继续存活。这些结果表明LIN28对NSC向胶质瘤细胞中的转化中起着重要作用。
总结:我们成功分离并鉴定出胶质瘤干细胞,且鉴定出新的GSC标志物CD15。在此基础上,我们探索出ZNF217是调控GSC干细胞和致瘤性的重要癌基因,且其表达受到缺氧环境的影响。最后在探讨GSC发生机制的研究中,我们发现干细胞因子LIN28对胶质瘤的形成具有重要作用。这些结果为进一步理解GBM的形成机制以及研发新的靶点提供了理论依据和实验基础。
Brain tumors have one of the poorest outcomes of all human cancers. Glioblastoma multiforme (GBM, World Health Organization grade IV glioma) is the most aggressive and, unfortunately, most common type of primary brain tumors in adults with a median survival of approximately 14 months, despite advances in surgery and adjuvant therapies. The failure of current treatments for GBMs primarily attributes to their invasiveness and resistance to chemo- and radio-therapies, resulting in frequent relapse or progression. Currently, the mechanisms underlying GBM tumorigenesis are not fully known. The cancer stem cell (CSC) hypothesis suggests that GBM is driven by a subpopulation of glioma stem cells (GSCs) which also contributes to their resistance to therapy. Therefore, it is important for both cancer research and clinical practice to further explore the intrinsic molecular basis behind the tumorigenicity of GSCs. Great efforts have been made to understand the mechanisms underlying the stem cell properties and tumorigenicity of GSCs.
In this study, we will isolate and identify GSCs from glioma tissues, and explore new markers for GSC. Then, the mechanisms underlying the tumorigenicity and the formation of GSCs will be studied.
Part I: Brain tumor stem like cells identified by neural stem cell marker CD15. In this part, we cultured 7 neurosphere cell lines derived from glioma tissues, which are enriched for GSCs, from 15 cases of primary brain tumors. These GSC cell lines can be maintained for 5-20 passages. At present, many studies used stem cell marker CD133 to identify GSCs. However, recent studies indicated that CD133 is not a universal marker for GSC and there are CD133 negative GSCs. Genetic mouse models demonstrated that gliomas are originated from transformed neural stem cells (NSCs), and there are many similarities between GSCs and NSCs. Therefore, we investigated the expression of CD15, one surface marker for NSCs, in GSCs derived from astrocytoma and ependymoma. CD15~+ cells isolated from these tumor spheres had properties of GSCs including self-renewal, multi-differentiation, and recapitulating the phenocopy of primary tumors. CD15 exhibited stable expression in long term cultured tumor spheres which sustained GSCs properties. Furthermore, CD15~+CD133- cells isolated from early or late passages of tumor spheres showed similar characteristics of GSCs. Examination of glioma samples by immunohistochemistry showed that CD15 was expressed in a subset of human brain tumors. Therefore, CD15 can be used as one marker of stem like cells derived from brain tumors which might contain CD133- GSCs.
Part II. Overexpression of ZNF217 in glioblastoma contributes to the maintenance of glioma stem cells regulated by hypoxia-inducible factors. It has been established that GSCs reside in a specialized hypoxic niche, which can regulate the tumorigenic capacity of GSCs primarily through the hypoxia-inducible factors (HIFs), HIF1αand HIF2α. ZNF217 is an oncogene frequently amplified in many kinds of tumors. It is associated with aggressive tumor behavior and poor clinical prognosis, but its role in gliomas is poorly known. Gene expression and copy number analysis from TCGA data reveal that ZNF217 is amplified in 32% and overexpressed in 71.2% of GBMs. Quantitative RT-PCR and Western blotting of a cohort of glioma samples showed that ZNF217 was highly expressed in gliomas and increased with tumor grade. Analysis of a molecular database demonstrated that ZNF217 expression correlated with poor survival of glioma patients. Investigation of ZNF217 expression in GSCs, non-GSCs and normal neural stem cells (NSCs) indicated that ZNF217 was more highly expressed in GSCs than in non-GSCs and NSCs. Knockdown of ZNF217 in GSCs by siRNA inhibited their growth and promoted their differentiation. Interestingly, ZNF217 was upregulated in GSCs and the GBM cell line U87 when exposed to the hypoxic environment of 1% oxygen. Knockdown of either HIF1αor HIF2α, which play a central role in the hypoxia induced responses of these cells, inhibited ZNF217 expression. In addition, ZNF217 upregulation was compromised under hypoxia in U87 and GSCs when either HIF1αor HIF2αwas targeted by siRNA. HIF2αknockdown inhibited ZNF217 expression more efficiently in both normoxia and hypoxia than HIF1αknockdown. Therefore, ZNF217 is overexpressed in GBMs and contributes to the maintenance of GSCs which is regulated by HIFs released by the hypoxic environment of the tumor.
Part III. LIN28 facilitates the transformation of human neural stem cells and promotes glioblastoma tumorgenicity. The pluripotency factor LIN28 is activated in many cancers arising outside the central nervous system, but its role in brain tumors is poorly understood. Using immunohistochemistry, we detected LIN28 protein in a subset of gliomas, with higher expression in GBMs than in lower grade tumors. Quantitative real-time PCR revealed that LIN28 is more highly expressed in glioma-derived stem like cells (GSCs) than in normal human neural stem cells (hNSC) and serum cultured GBM cell lines. Knockdown of LIN28 with lentivirus encoding LIN28 shRNA in GSC cell line HSR-GBM1 inhibited their growth and clonogenicity. Gain of function of LIN28 in GSC cell line JHH-GBM14 with LIN28 lentivirus caused larger and more invasive xenografts when injected into brains of immunocompromised mice. qPCR demonstrated that LIN28 over-expression in JHH-GBM14 resulted in down-regulation of let-7b and let-7g and up-regulation of HMGA2, one important target of let-7. LIN28 over-expression also increased the invasiveness of JHH-GBM14 as revealed by Matrigel invasion assay, which may contribute to the increased tumorigenicity of GBM14 in vivo. To find whether the stem cell factor LIN28 plays a role in the development of high grade gliomas, which are thought to arise from normal hNSC, we examined whether LIN28 would facilitate transformation of hNSC. We infected these cells with lentivirus encoding LIN28 together with dominant negative R248W p53 (DN-p53), constitutively active KRAS (CA-KRAS) and hTERT (hNSC-LIN28/DN-p53/CA-KRAS/hTERT), which are all commonly dysregulated in GBM. As controls, hNSC were also infected with DN-p53/CA-KRAS/hTERT, LIN28/DN-p53/hTERT, DN-p53/hTERT, or with GFP. To test their tumorigenecity in vivo, hNSC-LIN28/DN-p53/CA-KRAS/hTERT were injected into the brains of immunocompromised mice. Eight weeks after injection, 66.7% (12 of 18) of the mice developed invasive brain tumors resembling GBMs. In contrast, control
injections including hNSC-DN-p53/hTERT (10 mice), hNSC-LIN28/DN-p53/hTERT (5 mice) and hNSC-GFP (15 mice) did not generate tumors over 6 months. Interestingly, hNSC-DN-p53/CA-KRAS/hTERT cultures proliferated very poorly, suggesting that both LIN28 and activated KRAS may play key roles in transformation. Our data show that LIN28 is expressed in human GBMs and that LIN28 can promote tumorigenicity in orthotopic GBM mouse models and facilitates the transformation of human neural stem cells.
In summary, our study identified GSCs from brain tumor tissues, and elucidated that CD15 is one marker for GSCs. Based on these findings, we demonstrated that oncogene ZNF217 is important for the tumorigenicity of GSCs and is regulated by hypoxia condition, one of the critical factors of GSC microenvironment. Then we find that the pluripotency factor LIN28 promotes tumorigenicity of GSCs and facilitates the transformation of normal human NSCs. Our findings provide a deeper understanding of the machanisms of tumorigenicity of glioma and potential targets to eliminate GSCs.
我们的研究包括了GSC的分离培养、GSC标志物的探索,以及探讨影响GSC致瘤性和干细胞特征的分子机制。
第一部分:采用手术切除的新鲜组织,利用神经干细胞(neural stem cell, NSC)培养基无血清培养基(serum free medium, SFM)培养出富含GSC的神经球。本课题分离培养了17例原发性脑肿瘤,其中7例形成了神经球样细胞系,并可传至5-20代。在此基础上,我们研究了神经干细胞标记物CD15标记GSC的情况。目前研究GSC的一个关键难题是尚缺乏特异性的GSC标记物。CD133(PROM1)是最早采用的GSC标记物,研究指出CD133~+的胶质瘤细胞富含有GSC。然而近期的研究指出也有部分的GSC呈现CD133~-。因而,进一步寻找GSC的标记物即成为研究GSC的重要课题。分析GSC的特点我们得出,GSC具有正常NSCs的特点,且目前的证据指出GBM起源于NSC。因而,我们提出假说,指出NSC的一些标记物也可用于标记GSC。CD15(SSEA-1/LeX)是常用的NSC标记物,我们此部分的目的即是探讨CD15是否可成为GSC的标记物。我们首先采用免疫组织化学的方法研究了CD15在胶质瘤组织中的表达。结果指出CD15广泛表达于胶质瘤,包括胶质母细胞瘤(GBM)、II和III级星形胶质细胞瘤以及室管膜细胞瘤。其次我们采用免疫磁珠分选出CD15~+的细胞,并比较了CD15~+细胞和CD15~-细胞的干细胞特性,发现,CD15~+细胞较CD15~-细胞具有更强的神经球形成能力。将分选的细胞移植入裸鼠脑内后,104的CD15~+细胞即可形成肿瘤而同样数目的CD15~-细胞则不能形成肿瘤。免疫组化研究指出CD15~+细胞形成的移植瘤与原发性的肿瘤具有相似的免疫组织特性。进一步,我们分选出CD133~-CD15~+细胞,发现CD133~-CD15~+细胞也具有GSC特性,即具有形成神经球以及在免疫缺陷小鼠脑内形成肿瘤的能力,进一步证明CD15可标记出部分CD133~-的GSC。同一时间发表的另一篇文章得到了与我们相似的结论(Cell Stem Cell. 2009 May 8;4(5):440-52)。
第二部分:癌基因ZNF217对GSC分化的影响。由于GSC对胶质瘤的致瘤性具有重要作用,因而针对GSC的治疗成为具有希望的治疗靶点。目前研究认为,通过促进GSC分化可抑制胶质瘤的生长,因而研究调节GSC干细胞特性以及分化的内在机制成为研究的一个重要方向。目前对控制GSC分化的分子机制尚知之甚少。本部分研究了新的癌基因ZNF217(锌指蛋白217)对GSC分化的影响。ZNF217在多种肿瘤中高表达,且具有抑制干细胞分化的作用。然而ZNF217在胶质瘤的研究尚未见报道。采用实时定量PCR(quantitative RT~-PCR,qPCR)结果指出ZNF217在胶质瘤中的表达显著高于正常脑组织,且在GBM中的表达显著高于低级别胶质瘤(p<0.001)。对一个分子数据库的分析指出,胶质瘤中ZNF217的表达水平与患者的预后负相关,因而是潜在的治疗靶点。其次,ZNF217在GSC中的表达高于正常NSC以及非GSCs(non-GSCs),且在血清培养集中诱导分化后ZNF217的表达降低。这些结果表明,ZNF217在GSC中的特异性高表达,因而可能对GSC的维持具有重要作用。采用siRNA沉默GSC中ZNF217表达可抑制GSC的生长并促进GSC向成熟的细胞分化。因而ZNF217在GBM中高表达对GSC的生长以及维持具有重要的作用。GSC在胶质瘤中处于一个特殊的缺氧微环境中。研究指出缺氧可增加GSC的致瘤性并增加干细胞的比例。因而,我们进一步探讨ZNF217是否也参与了缺氧调控的GSC致瘤性。采用GSC细胞系和常规的U87细胞系,我们研究指出在缺氧环境下ZNF217表达上调。由于缺氧诱导因子(hypoxia inducilble facors, HIFs)是缺氧环境下发挥作用的重要因子,我们进一步探讨了ZNF217是否受到HIFs的调控。利用qPCR对GBM标本的mRNA检测指出ZNF217表达与HIF1αα以及HIF2α呈正相关(p<0.01)。采用siRNA沉默U87和GSC中HIF1α或者HIF2α的表达,会显著降低ZNF217的表达水平,且HIF1α或者HIF2α沉默后ZNF217在缺氧环境中的上调也受到了抑制。因而ZNF217在缺氧环境中的表达上调受到HIFs的调控。
第三部分:干细胞因子LIN28对GSC发生的影响。本部分课题在约翰霍普金斯医学院Charles C. Eberhart实验室完成。LIN28可抑制Let-7 microRNA,后者可抑制K-ras、C-myc、HMGA2等癌基因。LIN28在多种癌组织中高表达,且高表达的肿瘤分化较差、患者预后较差。免疫组织化学结果指出LIN28在部分胶质瘤中过表达,而在正常脑组织中未检测到。采用慢病毒介导的shRNA沉默GSC细胞系JHH-GBM1中的LIN28后,MTT和软琼脂克隆试验结果指出沉默LIN28可显著抑制其生长以及克隆形成能力。其次,将LIN28在另一GBM细胞系JHH-GBM14中过表达可增加其侵袭性以及体内形成肿瘤的能力。因而LIN28对GSC的生长具有重要作用。为进一步探讨GSC的发生机制,我们分析了LIN28在GSC形成中的作用。我们采用了人源性的脑皮层神经干细胞(NSC-Ctx),然后利用慢病毒使其表达GBM中常见的癌基因,包括组成性活性K-RAS(constitutively activated KRAS,CA-KRAS),无活性的p53(dominant negative R248W p53,DN-p53),hTERT以及LIN28(NSC-KRAS/p53/hTERT/LIN28)。作为对照我们同时构建了NSC-GFP,NSC-p53/hTERT以及NSC-p53/hTERT/LIN28。值得注意的是我们试图构建的NSC-p53/hTERT/KRAS细胞无法存活,表明LIN28在NSC表达这些基因的过程这起着重要作用。体外实验表明NSC-KRAS/p53/hTERT/LIN28较正常NSC具有更强的增殖特性。体内结果表明,将NSC-KRAS/p53/hTERT/LIN28注射入裸鼠脑内4-5周即可长出肿瘤,且生长的移植瘤呈现胶质瘤的免疫组织特性,表达Nestin、GFAP、Ki67但不表达synaptophysin。而对照组NSC-GFP、NSC-p53/hTERT以及NSC-p53/hTERT/LIN28在移植入裸鼠脑内6个月后均无肿瘤形成。采用shRNA沉默NSC-KRAS/p53/hTERT/LIN28中的LIN28之后细胞无法继续存活。这些结果表明LIN28对NSC向胶质瘤细胞中的转化中起着重要作用。
总结:我们成功分离并鉴定出胶质瘤干细胞,且鉴定出新的GSC标志物CD15。在此基础上,我们探索出ZNF217是调控GSC干细胞和致瘤性的重要癌基因,且其表达受到缺氧环境的影响。最后在探讨GSC发生机制的研究中,我们发现干细胞因子LIN28对胶质瘤的形成具有重要作用。这些结果为进一步理解GBM的形成机制以及研发新的靶点提供了理论依据和实验基础。
Brain tumors have one of the poorest outcomes of all human cancers. Glioblastoma multiforme (GBM, World Health Organization grade IV glioma) is the most aggressive and, unfortunately, most common type of primary brain tumors in adults with a median survival of approximately 14 months, despite advances in surgery and adjuvant therapies. The failure of current treatments for GBMs primarily attributes to their invasiveness and resistance to chemo- and radio-therapies, resulting in frequent relapse or progression. Currently, the mechanisms underlying GBM tumorigenesis are not fully known. The cancer stem cell (CSC) hypothesis suggests that GBM is driven by a subpopulation of glioma stem cells (GSCs) which also contributes to their resistance to therapy. Therefore, it is important for both cancer research and clinical practice to further explore the intrinsic molecular basis behind the tumorigenicity of GSCs. Great efforts have been made to understand the mechanisms underlying the stem cell properties and tumorigenicity of GSCs.
In this study, we will isolate and identify GSCs from glioma tissues, and explore new markers for GSC. Then, the mechanisms underlying the tumorigenicity and the formation of GSCs will be studied.
Part I: Brain tumor stem like cells identified by neural stem cell marker CD15. In this part, we cultured 7 neurosphere cell lines derived from glioma tissues, which are enriched for GSCs, from 15 cases of primary brain tumors. These GSC cell lines can be maintained for 5-20 passages. At present, many studies used stem cell marker CD133 to identify GSCs. However, recent studies indicated that CD133 is not a universal marker for GSC and there are CD133 negative GSCs. Genetic mouse models demonstrated that gliomas are originated from transformed neural stem cells (NSCs), and there are many similarities between GSCs and NSCs. Therefore, we investigated the expression of CD15, one surface marker for NSCs, in GSCs derived from astrocytoma and ependymoma. CD15~+ cells isolated from these tumor spheres had properties of GSCs including self-renewal, multi-differentiation, and recapitulating the phenocopy of primary tumors. CD15 exhibited stable expression in long term cultured tumor spheres which sustained GSCs properties. Furthermore, CD15~+CD133- cells isolated from early or late passages of tumor spheres showed similar characteristics of GSCs. Examination of glioma samples by immunohistochemistry showed that CD15 was expressed in a subset of human brain tumors. Therefore, CD15 can be used as one marker of stem like cells derived from brain tumors which might contain CD133- GSCs.
Part II. Overexpression of ZNF217 in glioblastoma contributes to the maintenance of glioma stem cells regulated by hypoxia-inducible factors. It has been established that GSCs reside in a specialized hypoxic niche, which can regulate the tumorigenic capacity of GSCs primarily through the hypoxia-inducible factors (HIFs), HIF1αand HIF2α. ZNF217 is an oncogene frequently amplified in many kinds of tumors. It is associated with aggressive tumor behavior and poor clinical prognosis, but its role in gliomas is poorly known. Gene expression and copy number analysis from TCGA data reveal that ZNF217 is amplified in 32% and overexpressed in 71.2% of GBMs. Quantitative RT-PCR and Western blotting of a cohort of glioma samples showed that ZNF217 was highly expressed in gliomas and increased with tumor grade. Analysis of a molecular database demonstrated that ZNF217 expression correlated with poor survival of glioma patients. Investigation of ZNF217 expression in GSCs, non-GSCs and normal neural stem cells (NSCs) indicated that ZNF217 was more highly expressed in GSCs than in non-GSCs and NSCs. Knockdown of ZNF217 in GSCs by siRNA inhibited their growth and promoted their differentiation. Interestingly, ZNF217 was upregulated in GSCs and the GBM cell line U87 when exposed to the hypoxic environment of 1% oxygen. Knockdown of either HIF1αor HIF2α, which play a central role in the hypoxia induced responses of these cells, inhibited ZNF217 expression. In addition, ZNF217 upregulation was compromised under hypoxia in U87 and GSCs when either HIF1αor HIF2αwas targeted by siRNA. HIF2αknockdown inhibited ZNF217 expression more efficiently in both normoxia and hypoxia than HIF1αknockdown. Therefore, ZNF217 is overexpressed in GBMs and contributes to the maintenance of GSCs which is regulated by HIFs released by the hypoxic environment of the tumor.
Part III. LIN28 facilitates the transformation of human neural stem cells and promotes glioblastoma tumorgenicity. The pluripotency factor LIN28 is activated in many cancers arising outside the central nervous system, but its role in brain tumors is poorly understood. Using immunohistochemistry, we detected LIN28 protein in a subset of gliomas, with higher expression in GBMs than in lower grade tumors. Quantitative real-time PCR revealed that LIN28 is more highly expressed in glioma-derived stem like cells (GSCs) than in normal human neural stem cells (hNSC) and serum cultured GBM cell lines. Knockdown of LIN28 with lentivirus encoding LIN28 shRNA in GSC cell line HSR-GBM1 inhibited their growth and clonogenicity. Gain of function of LIN28 in GSC cell line JHH-GBM14 with LIN28 lentivirus caused larger and more invasive xenografts when injected into brains of immunocompromised mice. qPCR demonstrated that LIN28 over-expression in JHH-GBM14 resulted in down-regulation of let-7b and let-7g and up-regulation of HMGA2, one important target of let-7. LIN28 over-expression also increased the invasiveness of JHH-GBM14 as revealed by Matrigel invasion assay, which may contribute to the increased tumorigenicity of GBM14 in vivo. To find whether the stem cell factor LIN28 plays a role in the development of high grade gliomas, which are thought to arise from normal hNSC, we examined whether LIN28 would facilitate transformation of hNSC. We infected these cells with lentivirus encoding LIN28 together with dominant negative R248W p53 (DN-p53), constitutively active KRAS (CA-KRAS) and hTERT (hNSC-LIN28/DN-p53/CA-KRAS/hTERT), which are all commonly dysregulated in GBM. As controls, hNSC were also infected with DN-p53/CA-KRAS/hTERT, LIN28/DN-p53/hTERT, DN-p53/hTERT, or with GFP. To test their tumorigenecity in vivo, hNSC-LIN28/DN-p53/CA-KRAS/hTERT were injected into the brains of immunocompromised mice. Eight weeks after injection, 66.7% (12 of 18) of the mice developed invasive brain tumors resembling GBMs. In contrast, control
injections including hNSC-DN-p53/hTERT (10 mice), hNSC-LIN28/DN-p53/hTERT (5 mice) and hNSC-GFP (15 mice) did not generate tumors over 6 months. Interestingly, hNSC-DN-p53/CA-KRAS/hTERT cultures proliferated very poorly, suggesting that both LIN28 and activated KRAS may play key roles in transformation. Our data show that LIN28 is expressed in human GBMs and that LIN28 can promote tumorigenicity in orthotopic GBM mouse models and facilitates the transformation of human neural stem cells.
In summary, our study identified GSCs from brain tumor tissues, and elucidated that CD15 is one marker for GSCs. Based on these findings, we demonstrated that oncogene ZNF217 is important for the tumorigenicity of GSCs and is regulated by hypoxia condition, one of the critical factors of GSC microenvironment. Then we find that the pluripotency factor LIN28 promotes tumorigenicity of GSCs and facilitates the transformation of normal human NSCs. Our findings provide a deeper understanding of the machanisms of tumorigenicity of glioma and potential targets to eliminate GSCs.
引文
[1] Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW and Kleihues P (2007). The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114, 97-109.
[2] DeAngelis LM (2001). Brain tumors. N Engl J Med 344, 114-123.
[3] Fortin D, Cairncross GJ and Hammond RR (1999). Oligodendroglioma: an appraisal of recent data pertaining to diagnosis and treatment. Neurosurgery 45, 1279-1291; discussion 1191.
[4] Ohgaki H and Kleihues P (2007). Genetic pathways to primary and secondary glioblastoma. Am J Pathol 170, 1445-1453.
[5] Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U et al. (2005). Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352, 987-996.
[6] TCGA (2008). Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061-1068.
[7] Dai C, Celestino JC, Okada Y, Louis DN, Fuller GN and Holland EC (2001). PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo. Genes Dev 15, 1913-1925.
[8] Bachoo RM, Maher EA, Ligon KL, Sharpless NE, Chan SS, You MJ, Tang Y, DeFrances J, Stover E, Weissleder R et al. (2002). Epidermal growth factor receptor and Ink4a/Arf: convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. Cancer Cell 1, 269-277.
[9] Holland EC, Celestino J, Dai C, Schaefer L, Sawaya RE and Fuller GN (2000). Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat Genet 25, 55-57.
[10] Marumoto T, Tashiro A, Friedmann-Morvinski D, Scadeng M, Soda Y, Gage FH and Verma IM (2009). Development of a novel mouse glioma model using lentiviral vectors. Nat Med 15, 110-116.
[11] Reilly KM, Loisel DA, Bronson RT, McLaughlin ME and Jacks T (2000). Nf1;Trp53 mutant mice develop glioblastoma with evidence of strain-specific effects. Nat Genet 26, 109-113.
[12] Zhu Y, Guignard F, Zhao D, Liu L, Burns DK, Mason RP, Messing A and Parada LF (2005). Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. Cancer Cell 8, 119-130.
[13] Zheng H, Ying H, Yan H, Kimmelman AC, Hiller DJ, Chen AJ, Perry SR, Tonon G, ChuGC, Ding Z et al. (2008). p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation. Nature 455, 1129-1133.
[14] Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP et al. (2010). Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17, 98-110.
[15] Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD, Misra A, Nigro JM, Colman H, Soroceanu L et al. (2006). Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 9, 157-173.
[16] Carro MS, Lim WK, Alvarez MJ, Bollo RJ, Zhao X, Snyder EY, Sulman EP, Anne SL, Doetsch F, Colman H et al. (2010). The transcriptional network for mesenchymal transformation of brain tumours. Nature 463, 318-325.
[17] Doetsch F (2003). The glial identity of neural stem cells. Nat Neurosci 6, 1127-1134.
[18] Capela A and Temple S (2002). LeX/ssea-1 is expressed by adult mouse CNS stem cells, identifying them as nonependymal. Neuron 35, 865-875.
[19] Doetsch F, Petreanu L, Caille I, Garcia-Verdugo JM and Alvarez-Buylla A (2002). EGF converts transit-amplifying neurogenic precursors in the adult brain into multipotent stem cells. Neuron 36, 1021-1034.
[20] Alvarez-Buylla A, Seri B and Doetsch F (2002). Identification of neural stem cells in the adult vertebrate brain. Brain Res Bull 57, 751-758.
[21] Temple S (2001). The development of neural stem cells. Nature 414, 112-117.
[22] Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM and Alvarez-Buylla A (1999). Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97, 703-716.
[23] Alvarez-Buylla A, Garcia-Verdugo JM and Tramontin AD (2001). A unified hypothesis on the lineage of neural stem cells. Nat Rev Neurosci 2, 287-293.
[24] Barnabe-Heider F, Goritz C, Sabelstrom H, Takebayashi H, Pfrieger FW, Meletis K and Frisen J (2010). Origin of new glial cells in intact and injured adult spinal cord. Cell Stem Cell 7, 470-482.
[25] Reynolds BA and Weiss S (1992). Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255, 1707-1710.
[26] Reynolds BA and Rietze RL (2005). Neural stem cells and neurospheres--re-evaluating the relationship. Nat Methods 2, 333-336.
[27] Ming GL and Song H (2005). Adult neurogenesis in the mammalian central nervous system. Annu Rev Neurosci 28, 223-250.
[28] Sanai N, Berger MS, Garcia-Verdugo JM and Alvarez-Buylla A (2007). Comment on "Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension". Science 318, 393; author reply 393.
[29] Sanai N, Tramontin AD, Quinones-Hinojosa A, Barbaro NM, Gupta N, Kunwar S,Lawton MT, McDermott MW, Parsa AT, Manuel-Garcia Verdugo J et al. (2004). Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature 427, 740-744.
[30] Curtis MA, Kam M, Nannmark U, Anderson MF, Axell MZ, Wikkelso C, Holtas S, van Roon-Mom WM, Bjork-Eriksson T, Nordborg C et al. (2007). Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension. Science 315, 1243-1249.
[31] Shen Q, Wang Y, Kokovay E, Lin G, Chuang SM, Goderie SK, Roysam B and Temple S (2008). Adult SVZ stem cells lie in a vascular niche: a quantitative analysis of niche cell-cell interactions. Cell Stem Cell 3, 289-300.
[32] Tavazoie M, Van der Veken L, Silva-Vargas V, Louissaint M, Colonna L, Zaidi B, Garcia-Verdugo JM and Doetsch F (2008). A specialized vascular niche for adult neural stem cells. Cell Stem Cell 3, 279-288.
[33] Hansen DV, Lui JH, Parker PR and Kriegstein AR (2010). Neurogenic radial glia in the outer subventricular zone of human neocortex. Nature 464, 554-561.
[34] Aguirre A, Rubio ME and Gallo V (2010). Notch and EGFR pathway interaction regulates neural stem cell number and self-renewal. Nature 467, 323-327.
[35] Mizutani K, Yoon K, Dang L, Tokunaga A and Gaiano N (2007). Differential Notch signalling distinguishes neural stem cells from intermediate progenitors. Nature 449, 351-355.
[36] Androutsellis-Theotokis A, Leker RR, Soldner F, Hoeppner DJ, Ravin R, Poser SW, Rueger MA, Bae SK, Kittappa R and McKay RD (2006). Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 442, 823-826.
[37] Mazumdar J, O'Brien WT, Johnson RS, Lamanna JC, Chavez JC, Klein PS and Simon MC (2010). O(2) regulates stem cells through Wnt/beta-catenin signalling. Nat Cell Biol 12, 1007-1013.
[38] Zheng H, Ying H, Wiedemeyer R, Yan H, Quayle SN, Ivanova EV, Paik JH, Zhang H, Xiao Y, Perry SR et al. (2010). PLAGL2 regulates Wnt signaling to impede differentiation in neural stem cells and gliomas. Cancer Cell 17, 497-509.
[39] Kalani MY, Cheshier SH, Cord BJ, Bababeygy SR, Vogel H, Weissman IL, Palmer TD and Nusse R (2008). Wnt-mediated self-renewal of neural stem/progenitor cells. Proc Natl Acad Sci U S A 105, 16970-16975.
[40] Lie DC, Colamarino SA, Song HJ, Desire L, Mira H, Consiglio A, Lein ES, Jessberger S, Lansford H, Dearie AR et al. (2005). Wnt signalling regulates adult hippocampal neurogenesis. Nature 437, 1370-1375.
[41] Ille F and Sommer L (2005). Wnt signaling: multiple functions in neural development. Cell Mol Life Sci 62, 1100-1108.
[42] Wexler EM, Paucer A, Kornblum HI, Plamer TD and Geschwind DH (2009). Endogenous Wnt signaling maintains neural progenitor cell potency. Stem Cells 27, 1130-1141.
[43] Fasano CA, Phoenix TN, Kokovay E, Lowry N, Elkabetz Y, Dimos JT, Lemischka IR,Studer L and Temple S (2009). Bmi-1 cooperates with Foxg1 to maintain neural stem cell self-renewal in the forebrain. Genes Dev 23, 561-574.
[44] Molofsky AV, Pardal R, Iwashita T, Park IK, Clarke MF and Morrison SJ (2003). Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425, 962-967.
[45] He S, Iwashita T, Buchstaller J, Molofsky AV, Thomas D and Morrison SJ (2009). Bmi-1 over-expression in neural stem/progenitor cells increases proliferation and neurogenesis in culture but has little effect on these functions in vivo. Dev Biol 328, 257-272.
[46] Armesilla-Diaz A, Bragado P, Del Valle I, Cuevas E, Lazaro I, Martin C, Cigudosa JC and Silva A (2009). p53 regulates the self-renewal and differentiation of neural precursors. Neuroscience 158, 1378-1389.
[47] Groszer M, Erickson R, Scripture-Adams DD, Lesche R, Trumpp A, Zack JA, Kornblum HI, Liu X and Wu H (2001). Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo. Science 294, 2186-2189.
[48] Abdouh M, Facchino S, Chatoo W, Balasingam V, Ferreira J and Bernier G (2009). BMI1 sustains human glioblastoma multiforme stem cell renewal. J Neurosci 29, 8884-8896.
[49] Fan X, Khaki L, Zhu TS, Soules ME, Talsma CE, Gul N, Koh C, Zhang J, Li YM, Maciaczyk J et al. (2010). Notch Pathway Blockade Depletes CD133-Positive Glioblastoma Cells and Inhibits Growth of Tumor Neurospheres and Xenografts. Stem Cells 28, 5-16.
[50] Charles N, Ozawa T, Squatrito M, Bleau AM, Brennan CW, Hambardzumyan D and Holland EC (2010). Perivascular Nitric Oxide Activates Notch Signaling and Promotes Stem-like Character in PDGF-Induced Glioma Cells. Cell Stem Cell 6, 141-152.
[51] Hoeck JD, Jandke A, Blake SM, Nye E, Spencer-Dene B, Brandner S and Behrens A (2010). Fbw7 controls neural stem cell differentiation and progenitor apoptosis via Notch and c-Jun. Nat Neurosci 13, 1365-1372.
[52] Fan X, Matsui W, Khaki L, Stearns D, Chun J, Li YM and Eberhart CG (2006). Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res 66, 7445-7452.
[53] Sareddy GR, Panigrahi M, Challa S, Mahadevan A and Babu PP (2009). Activation of Wnt/beta-catenin/Tcf signaling pathway in human astrocytomas. Neurochem Int 55, 307-317.
[54] Yu JM, Jun ES, Jung JS, Suh SY, Han JY, Kim JY and Kim KW (2007). Role of Wnt5a in the proliferation of human glioblastoma cells. Cancer Lett 257, 172-181.
[55] Facchino S, Abdouh M, Chatoo W and Bernier G (2010). BMI1 confers radioresistance to normal and cancerous neural stem cells through recruitment of the DNA damage response machinery. J Neurosci 30, 10096-10111.
[56] Bruggeman SW, Hulsman D, Tanger E, Buckle T, Blom M, Zevenhoven J, van Tellingen O and van Lohuizen M (2007). Bmi1 controls tumor development in anInk4a/Arf-independent manner in a mouse model for glioma. Cancer Cell 12, 328-341.
[57] Globus J and Kuhlenbeck H (1942). Tumors of the striato thalamic and related regions: their probable source of origin and more common forms. Arch Pathol 24, 674-734.
[58] Tohyama T, Lee VM, Rorke LB, Marvin M, McKay RD and Trojanowski JQ (1992). Nestin expression in embryonic human neuroepithelium and in human neuroepithelial tumor cells. Lab Invest 66, 303-313.
[59] Hopewell JW (1975). The subependymal plate and the genesis of gliomas. J Pathol 117, 101-103.
[60] Lantos PL and Cox DJ (1976). The origin of experimental brain tumours: a sequential study. Experientia 32, 1467-1468.
[61] Lim DA, Cha S, Mayo MC, Chen MH, Keles E, VandenBerg S and Berger MS (2007). Relationship of glioblastoma multiforme to neural stem cell regions predicts invasive and multifocal tumor phenotype. Neuro Oncol 9, 424-429.
[62] Persson AI, Petritsch C, Swartling FJ, Itsara M, Sim FJ, Auvergne R, Goldenberg DD, Vandenberg SR, Nguyen KN, Yakovenko S et al. (2010). Non-stem cell origin for oligodendroglioma. Cancer Cell 18, 669-682.
[63] Alcantara Llaguno S, Chen J, Kwon CH, Jackson EL, Li Y, Burns DK, Alvarez-Buylla A and Parada LF (2009). Malignant astrocytomas originate from neural stem/progenitor cells in a somatic tumor suppressor mouse model. Cancer Cell 15, 45-56.
[64] Wang Y, Yang J, Zheng H, Tomasek GJ, Zhang P, McKeever PE, Lee EY and Zhu Y (2009). Expression of mutant p53 proteins implicates a lineage relationship between neural stem cells and malignant astrocytic glioma in a murine model. Cancer Cell 15, 514-526.
[65] Bonnet D (2005). Cancer stem cells: lessons from leukaemia. Cell Prolif 38, 357-361.
[66] Bonnet D and Dick JE (1997). Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3, 730-737.
[67] Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, Paterson B, Caligiuri MA and Dick JE (1994). A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367, 645-648.
[68] Ignatova TN, Kukekov VG, Laywell ED, Suslov ON, Vrionis FD and Steindler DA (2002). Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia 39, 193-206.
[69] Hemmati HD, Nakano I, Lazareff JA, Masterman-Smith M, Geschwind DH, Bronner-Fraser M and Kornblum HI (2003). Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci U S A 100, 15178-15183.
[70] Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J and Dirks PB (2003). Identification of a cancer stem cell in human brain tumors. Cancer Res 63, 5821-5828.
[71] Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD and Dirks PB (2004). Identification of human brain tumour initiating cells. Nature 432, 396-401.
[72] Singh SK, Clarke ID, Hide T and Dirks PB (2004). Cancer stem cells in nervous system tumors. Oncogene 23, 7267-7273.
[73]邓永文,方加胜,李茗初,陈风华,刘劲芳,伍军,周向阳,方芳,卢明,陈成et al. (2005).胶质瘤中肿瘤干细胞的分离、培养及鉴定.中国现代医学杂志15, 2449-2452.
[74]李茗初,邓永文,伍军,陈风华,刘劲芳and方加胜(2006).髓母细胞瘤中脑肿瘤干细胞的分离培养及鉴定.癌症25, 241-246.
[75]方加胜,邓永文,李茗初,陈风华,王延金,卢明,方芳,伍军,杨转移,周向阳et al. (2007).神经上皮来源脑肿瘤中肿瘤干细胞的分离培养与鉴定.中华医学杂志87, 298-303.
[76] Collins AT, Berry PA, Hyde C, Stower MJ and Maitland NJ (2005). Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 65, 10946-10951.
[77] Seigel GM, Campbell LM, Narayan M and Gonzalez-Fernandez F (2005). Cancer stem cell characteristics in retinoblastoma. Mol Vis 11, 729-737.
[78] Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M, Haegebarth A, Korving J, Begthel H, Peters PJ et al. (2007). Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003-1007.
[79] Dou J, Pan M, Wen P, Li Y, Tang Q, Chu L, Zhao F, Jiang C, Hu W, Hu K et al. (2007). Isolation and identification of cancer stem-like cells from murine melanoma cell lines. Cell Mol Immunol 4, 467-472.
[80] Ma S, Chan KW, Hu L, Lee TK, Wo JY, Ng IO, Zheng BJ and Guan XY (2007). Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology 132, 2542-2556.
[81] Monzani E, Facchetti F, Galmozzi E, Corsini E, Benetti A, Cavazzin C, Gritti A, Piccinini A, Porro D, Santinami M et al. (2007). Melanoma contains CD133 and ABCG2 positive cells with enhanced tumourigenic potential. Eur J Cancer 43, 935-946.
[82] Olempska M, Eisenach PA, Ammerpohl O, Ungefroren H, Fandrich F and Kalthoff H (2007). Detection of tumor stem cell markers in pancreatic carcinoma cell lines. Hepatobiliary Pancreat Dis Int 6, 92-97.
[83] Yin S, Li J, Hu C, Chen X, Yao M, Yan M, Jiang G, Ge C, Xie H, Wan D et al. (2007). CD133 positive hepatocellular carcinoma cells possess high capacity for tumorigenicity. Int J Cancer 120, 1444-1450.
[84] O'Brien CA, Pollett A, Gallinger S and Dick JE (2007). A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445, 106-110.
[85] Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C and De Maria R (2007). Identification and expansion of human colon-cancer-initiating cells. Nature 445, 111-115.
[86] Sakariassen PO, Immervoll H and Chekenya M (2007). Cancer stem cells as mediators of treatment resistance in brain tumors: status and controversies. Neoplasia 9, 882-892.
[87] Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, Jacquemier J,Viens P, Kleer CG, Liu S et al. (2007). ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1, 555-567.
[88] Wright MH, Calcagno AM, Salcido CD, Carlson MD, Ambudkar SV and Varticovski L (2008). Brca1 breast tumors contain distinct CD44+/CD24- and CD133+ cells with cancer stem cell characteristics. Breast Cancer Res 10, R10.
[89] Wong DJ, Liu H, Ridky TW, Cassarino D, Segal E and Chang HY (2008). Module map of stem cell genes guides creation of epithelial cancer stem cells. Cell Stem Cell 2, 333-344.
[90] Fan X and Eberhart CG (2008). Medulloblastoma stem cells. J Clin Oncol 26, 2821-2827.
[91] Bertolini G, Roz L, Perego P, Tortoreto M, Fontanella E, Gatti L, Pratesi G, Fabbri A, Andriani F, Tinelli S et al. (2009). Highly tumorigenic lung cancer CD133+ cells display stem-like features and are spared by cisplatin treatment. Proc Natl Acad Sci U S A 106, 16281-16286.
[92] Zhang Q, Shi S, Yen Y, Brown J, Ta JQ and Le AD (2009). A subpopulation of CD133(+) cancer stem-like cells characterized in human oral squamous cell carcinoma confer resistance to chemotherapy. Cancer Lett,
[93] Zhu Z, Hao X, Yan M, Yao M, Ge C, Gu J and Li J (2009). Cancer stem/progenitor cells are highly enriched in CD133(+)CD44(+) population in hepatocellular carcinoma. Int J Cancer,
[94] Rutella S, Bonanno G, Procoli A, Mariotti A, Corallo M, Prisco MG, Eramo A, Napoletano C, Gallo D, Perillo A et al. (2009). Cells with characteristics of cancer stem/progenitor cells express the CD133 antigen in human endometrial tumors. Clin Cancer Res 15, 4299-4311.
[95] Friedman S, Lu M, Schultz A, Thomas D and Lin RY (2009). CD133+ anaplastic thyroid cancer cells initiate tumors in immunodeficient mice and are regulated by thyrotropin. PLoS One 4, e5395.
[96] Suva ML, Riggi N, Stehle JC, Baumer K, Tercier S, Joseph JM, Suva D, Clement V, Provero P, Cironi L et al. (2009). Identification of cancer stem cells in Ewing's sarcoma. Cancer Res 69, 1776-1781.
[97] Kelly PN, Dakic A, Adams JM, Nutt SL and Strasser A (2007). Tumor growth need not be driven by rare cancer stem cells. Science 317, 337.
[98] Quintana E, Shackleton M, Sabel MS, Fullen DR, Johnson TM and Morrison SJ (2008). Efficient tumour formation by single human melanoma cells. Nature 456, 593-598.
[99] Richardson GD, Robson CN, Lang SH, Neal DE, Maitland NJ and Collins AT (2004). CD133, a novel marker for human prostatic epithelial stem cells. J Cell Sci 117, 3539-3545.
[100] Vander Griend DJ, Karthaus WL, Dalrymple S, Meeker A, DeMarzo AM and Isaacs JT (2008). The role of CD133 in normal human prostate stem cells and malignantcancer-initiating cells. Cancer Res 68, 9703-9711.
[101] Coskun V, Wu H, Blanchi B, Tsao S, Kim K, Zhao J, Biancotti JC, Hutnick L, Krueger RC, Jr., Fan G et al. (2008). CD133+ neural stem cells in the ependyma of mammalian postnatal forebrain. Proc Natl Acad Sci U S A 105, 1026-1031.
[102] Cheng JX, Liu BL and Zhang X (2009). How powerful is CD133 as a cancer stem cell marker in brain tumors? Cancer Treat Rev 35, 403-408.
[103] Clement V, Dutoit V, Marino D, Dietrich PY and Radovanovic I (2009). Limits of CD133 as a marker of glioma self-renewing cells. Int J Cancer 125, 244-248.
[104] Snippert HJ, van Es JH, van den Born M, Begthel H, Stange DE, Barker N and Clevers H (2009). Prominin-1/CD133 marks stem cells and early progenitors in mouse small intestine. Gastroenterology 136, 2187-2194 e2181.
[105] Zhu L, Gibson P, Currle DS, Tong Y, Richardson RJ, Bayazitov IT, Poppleton H, Zakharenko S, Ellison DW and Gilbertson RJ (2009). Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation. Nature 457, 603-607.
[106] Bakondi B, Shimada IS, Perry A, Munoz JR, Ylostalo J, Howard AB, Gregory CA and Spees JL (2009). CD133 identifies a human bone marrow stem/progenitor cell sub-population with a repertoire of secreted factors that protect against stroke. Mol Ther 17, 1938-1947.
[107] Tsuchiya A, Kamimura H, Takamura M, Yamagiwa S, Matsuda Y, Sato Y, Nomoto M, Ichida T and Aoyagi Y (2009). Clinicopathological analysis of CD133 and NCAM human hepatic stem/progenitor cells in damaged livers and hepatocellular carcinomas. Hepatol Res 39, 1080-1090.
[108] Curley MD, Therrien VA, Cummings CL, Sergent PA, Koulouris CR, Friel AM, Roberts DJ, Seiden MV, Scadden DT, Rueda BR et al. (2009). CD133 Expression Defines a Tumor Initiating Cell Population in Primary Human Ovarian Cancer. Stem Cells 27, 2875-2883.
[109] Ding W, Mouzaki M, You H, Laird JC, Mato J, Lu SC and Rountree CB (2009). CD133+ liver cancer stem cells from methionine adenosyl transferase 1A-deficient mice demonstrate resistance to transforming growth factor (TGF)-beta-induced apoptosis. Hepatology 49, 1277-1286.
[110] Wei XD, Zhou L, Cheng L, Tian J, Jiang JJ and Maccallum J (2009). In vivo investigation of CD133 as a putative marker of cancer stem cells in Hep-2 cell line. Head Neck 31, 94-101.
[111] Quintana E, Shackleton M, Foster HR, Fullen DR, Sabel MS, Johnson TM and Morrison SJ (2010). Phenotypic heterogeneity among tumorigenic melanoma cells from patients that is reversible and not hierarchically organized. Cancer Cell 18, 510-523.
[112] Yeung J, Esposito MT, Gandillet A, Zeisig BB, Griessinger E, Bonnet D and So CW (2010). beta-Catenin mediates the establishment and drug resistance of MLL leukemic stem cells. Cancer Cell 18, 606-618.
[113] Goardon N, Marchi E, Atzberger A, Quek L, Schuh A, Soneji S, Woll P, Mead A, AlfordKA, Rout R et al. (2011). Coexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia. Cancer Cell 19, 138-152.
[114] Majeti R and Weissman IL (2011). Human acute myelogenous leukemia stem cells revisited: there's more than meets the eye. Cancer Cell 19, 9-10.
[115] Yuan X, Curtin J, Xiong Y, Liu G, Waschsmann-Hogiu S, Farkas DL, Black KL and Yu JS (2004). Isolation of cancer stem cells from adult glioblastoma multiforme. Oncogene 23, 9392-9400.
[116] Wang J, Sakariassen PO, Tsinkalovsky O, Immervoll H, Boe SO, Svendsen A, Prestegarden L, Rosland G, Thorsen F, Stuhr L et al. (2008). CD133 negative glioma cells form tumors in nude rats and give rise to CD133 positive cells. Int J Cancer 122, 761-768.
[117] Sun Y, Kong W, Falk A, Hu J, Zhou L, Pollard S and Smith A (2009). CD133 (Prominin) negative human neural stem cells are clonogenic and tripotent. PLoS One 4, e5498.
[118] Beier D, Hau P, Proescholdt M, Lohmeier A, Wischhusen J, Oefner PJ, Aigner L, Brawanski A, Bogdahn U and Beier CP (2007). CD133(+) and CD133(-) glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res 67, 4010-4015.
[119] Ogden AT, Waziri AE, Lochhead RA, Fusco D, Lopez K, Ellis JA, Kang J, Assanah M, McKhann GM, Sisti MB et al. (2008). Identification of A2B5+CD133- tumor-initiating cells in adult human gliomas. Neurosurgery 62, 505-514; discussion 514-505.
[120] Son MJ, Woolard K, Nam DH, Lee J and Fine HA (2009). SSEA-1 is an enrichment marker for tumor-initiating cells in human glioblastoma. Cell Stem Cell 4, 440-452.
[121] Ward RJ, Lee L, Graham K, Satkunendran T, Yoshikawa K, Ling E, Harper L, Austin R, Nieuwenhuis E, Clarke ID et al. (2009). Multipotent CD15+ cancer stem cells in patched-1-deficient mouse medulloblastoma. Cancer Res 69, 4682-4690.
[122] Read TA, Fogarty MP, Markant SL, McLendon RE, Wei Z, Ellison DW, Febbo PG and Wechsler-Reya RJ (2009). Identification of CD15 as a marker for tumor-propagating cells in a mouse model of medulloblastoma. Cancer Cell 15, 135-147.
[123] Mao XG, Zhang X, Xue XY, Guo G, Wang P, Zhang W, Fei Z, Zhen HN, You SW and Yang H (2009). Brain Tumor Stem-Like Cells Identified by Neural Stem Cell Marker CD15. Transl Oncol 2, 247-257.
[124] Chen R, Nishimura MC, Bumbaca SM, Kharbanda S, Forrest WF, Kasman IM, Greve JM, Soriano RH, Gilmour LL, Rivers CS et al. (2010). A hierarchy of self-renewing tumor-initiating cell types in glioblastoma. Cancer Cell 17, 362-375.
[125] Capela A and Temple S (2006). LeX is expressed by principle progenitor cells in the embryonic nervous system, is secreted into their environment and binds Wnt-1. Dev Biol 291, 300-313.
[126] Harris MA, Yang H, Low BE, Mukherjee J, Guha A, Bronson RT, Shultz LD, Israel MA and Yun K (2008). Cancer stem cells are enriched in the side population cells in a mouse model of glioma. Cancer Res 68, 10051-10059.
[127] Bleau AM, Huse JT and Holland EC (2009). The ABCG2 resistance network of glioblastoma. Cell Cycle 8, 2936-2944.
[128] Hirschmann-Jax C, Foster AE, Wulf GG, Nuchtern JG, Jax TW, Gobel U, Goodell MA and Brenner MK (2004). A distinct "side population" of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci U S A 101, 14228-14233.
[129] Bleau AM, Hambardzumyan D, Ozawa T, Fomchenko EI, Huse JT, Brennan CW and Holland EC (2009). PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells. Cell Stem Cell 4, 226-235.
[130] Broadley KW, Hunn MK, Farrand KJ, Price KM, Grasso C, Miller RJ, Hermans IF and McConnell MJ (2010). Side Population is not Necessary or Sufficient for a Cancer Stem Cell Phenotype in Glioblastoma Multiforme. Stem Cells,
[131] Christensen K, Schroder HD and Kristensen BW (2008). CD133 identifies perivascular niches in grade II-IV astrocytomas. J Neurooncol 90, 157-170.
[132] Calabrese C, Poppleton H, Kocak M, Hogg TL, Fuller C, Hamner B, Oh EY, Gaber MW, Finklestein D, Allen M et al. (2007). A perivascular niche for brain tumor stem cells. Cancer Cell 11, 69-82.
[133] Mirzadeh Z, Merkle FT, Soriano-Navarro M, Garcia-Verdugo JM and Alvarez-Buylla A (2008). Neural stem cells confer unique pinwheel architecture to the ventricular surface in neurogenic regions of the adult brain. Cell Stem Cell 3, 265-278.
[134] Wang R, Chadalavada K, Wilshire J, Kowalik U, Hovinga KE, Geber A, Fligelman B, Leversha M, Brennan C and Tabar V (2010). Glioblastoma stem-like cells give rise to tumour endothelium. Nature 468, 829-833.
[135] Ricci-Vitiani L, Pallini R, Biffoni M, Todaro M, Invernici G, Cenci T, Maira G, Parati EA, Stassi G, Larocca LM et al. (2010). Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 468, 824-828.
[136] Rodrigues CA, Diogo MM, da Silva CL and Cabral JM (2009). Hypoxia enhances proliferation of mouse embryonic stem cell-derived neural stem cells. Biotechnol Bioeng,
[137] Chen X, Tian Y, Yao L, Zhang J and Liu Y (2009). Hypoxia stimulates proliferation of rat neural stem cells with influence on the expression of cyclin D1 and c-Jun N-terminal protein kinase signaling pathway in vitro. Neuroscience,
[138] Li Z, Bao S, Wu Q, Wang H, Eyler C, Sathornsumetee S, Shi Q, Cao Y, Lathia J, McLendon RE et al. (2009). Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell 15, 501-513.
[139] Bertout JA, Patel SA and Simon MC (2008). The impact of O2 availability on human cancer. Nat Rev Cancer 8, 967-975.
[140] Chen HL, Pistollato F, Hoeppner DJ, Ni HT, McKay RD and Panchision DM (2007). Oxygen tension regulates survival and fate of mouse central nervous system precursors at multiple levels. Stem Cells 25, 2291-2301.
[141] Keith B and Simon MC (2007). Hypoxia-inducible factors, stem cells, and cancer. Cell 129, 465-472.
[142] Semenza GL (2007). Life with oxygen. Science 318, 62-64.
[143] Seidel S, Garvalov BK, Wirta V, von Stechow L, Schanzer A, Meletis K, Wolter M, Sommerlad D, Henze AT, Nister M et al. (2010). A hypoxic niche regulates glioblastoma stem cells through hypoxia inducible factor 2 alpha. Brain 133, 983-995.
[144] Heddleston JM, Li Z, McLendon RE, Hjelmeland AB and Rich JN (2009). The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype. Cell Cycle 8, 3274-3284.
[145] Bar EE, Lin A, Mahairaki V, Matsui W and Eberhart CG (2010). Hypoxia increases the expression of stem-cell markers and promotes clonogenicity in glioblastoma neurospheres. Am J Pathol 177, 1491-1502.
[146] Soeda A, Park M, Lee D, Mintz A, Androutsellis-Theotokis A, McKay RD, Engh J, Iwama T, Kunisada T, Kassam AB et al. (2009). Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1alpha. Oncogene 28, 3949-3959.
[147] McCord AM, Jamal M, Shankavaram UT, Lang FF, Camphausen K and Tofilon PJ (2009). Physiologic oxygen concentration enhances the stem-like properties of CD133+ human glioblastoma cells in vitro. Mol Cancer Res 7, 489-497.
[148] Mole DR, Blancher C, Copley RR, Pollard PJ, Gleadle JM, Ragoussis J and Ratcliffe PJ (2009). Genome-wide association of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha DNA binding with expression profiling of hypoxia-inducible transcripts. J Biol Chem 284, 16767-16775.
[149] Mao XG, Zhang X and Zhen HN (2009). Progress on potential strategies to target brain tumor stem cells. Cell Mol Neurobiol 29, 141-155.
[150]毛星刚and章翔(2009).脑肿瘤干细胞研究进展.中华神经外科疾病研究杂志8, 84-86.
[151]章翔and毛星刚(2008).靶向消除脑肿瘤干细胞的潜在治疗策略.中华神经外科疾病研究杂志7, 481-484.
[152] Lee J, Kotliarova S, Kotliarov Y, Li A, Su Q, Donin NM, Pastorino S, Purow BW, Christopher N, Zhang W et al. (2006). Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 9, 391-403.
[153] Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD and Rich JN (2006). Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444, 756-760.
[154] Lu C and Shervington A (2008). Chemoresistance in gliomas. Mol Cell Biochem 312, 71-80.
[155] Kang MK and Kang SK (2007). Tumorigenesis of chemotherapeutic drug-resistant cancer stem-like cells in brain glioma. Stem Cells Dev 16, 837-847.
[156] Eramo A, Ricci-Vitiani L, Zeuner A, Pallini R, Lotti F, Sette G, Pilozzi E, Larocca LM, Peschle C and De Maria R (2006). Chemotherapy resistance of glioblastoma stem cells.Cell Death Differ 13, 1238-1241.
[157] Bar EE, Chaudhry A, Lin A, Fan X, Schreck K, Matsui W, Piccirillo S, Vescovi AL, DiMeco F, Olivi A et al. (2007). Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma. Stem Cells 25, 2524-2533.
[158] Frank RT, Najbauer J and Aboody KS (2010). Concise review: stem cells as an emerging platform for antibody therapy of cancer. Stem Cells 28, 2084-2087.
[159] Frank RT, Edmiston M, Kendall SE, Najbauer J, Cheung CW, Kassa T, Metz MZ, Kim SU, Glackin CA, Wu AM et al. (2009). Neural stem cells as a novel platform for tumor-specific delivery of therapeutic antibodies. PLoS One 4, e8314.
[160] Aboody KS, Najbauer J and Danks MK (2008). Stem and progenitor cell-mediated tumor selective gene therapy. Gene Ther 15, 739-752.
[161] Aboody KS, Brown A, Rainov NG, Bower KA, Liu S, Yang W, Small JE, Herrlinger U, Ourednik V, Black PM et al. (2000). Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc Natl Acad Sci U S A 97, 12846-12851.
[162] Mapara KY, Stevenson CB, Thompson RC and Ehtesham M (2007). Stem cells as vehicles for the treatment of brain cancer. Neurosurg Clin N Am 18, 71-80, ix.
[163] Kabos P, Ehtesham M, Black KL and Yu JS (2003). Neural stem cells as delivery vehicles. Expert Opin Biol Ther 3, 759-770.
[164] Dickson PV, Hamner JB, Burger RA, Garcia E, Ouma AA, Kim SU, Ng CY, Gray JT, Aboody KS, Danks MK et al. (2007). Intravascular administration of tumor tropic neural progenitor cells permits targeted delivery of interferon-beta and restricts tumor growth in a murine model of disseminated neuroblastoma. J Pediatr Surg 42, 48-53.
[165] Benedetti S, Pirola B, Pollo B, Magrassi L, Bruzzone MG, Rigamonti D, Galli R, Selleri S, Di Meco F, De Fraja C et al. (2000). Gene therapy of experimental brain tumors using neural progenitor cells. Nat Med 6, 447-450.
[166] Ehtesham M, Kabos P, Kabosova A, Neuman T, Black KL and Yu JS (2002). The use of interleukin 12-secreting neural stem cells for the treatment of intracranial glioma. Cancer Res 62, 5657-5663.
[167] Schmidt NO, Przylecki W, Yang W, Ziu M, Teng Y, Kim SU, Black PM, Aboody KS and Carroll RS (2005). Brain tumor tropism of transplanted human neural stem cells is induced by vascular endothelial growth factor. Neoplasia 7, 623-629.
[168] Ehtesham M, Yuan X, Kabos P, Chung NH, Liu G, Akasaki Y, Black KL and Yu JS (2004). Glioma tropic neural stem cells consist of astrocytic precursors and their migratory capacity is mediated by CXCR4. Neoplasia 6, 287-293.
[169] Ziu M, Schmidt NO, Cargioli TG, Aboody KS, Black PM and Carroll RS (2006). Glioma-produced extracellular matrix influences brain tumor tropism of human neural stem cells. J Neurooncol 79, 125-133.
[170] Zhao D, Najbauer J, Garcia E, Metz MZ, Gutova M, Glackin CA, Kim SU and Aboody KS (2008). Neural stem cell tropism to glioma: critical role of tumor hypoxia. MolCancer Res 6, 1819-1829.
[171] Nakamizo A, Marini F, Amano T, Khan A, Studeny M, Gumin J, Chen J, Hentschel S, Vecil G, Dembinski J et al. (2005). Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas. Cancer Res 65, 3307-3318.
[172] Ferrari N, Glod J, Lee J, Kobiler D and Fine HA (2003). Bone marrow-derived, endothelial progenitor-like cells as angiogenesis-selective gene-targeting vectors. Gene Ther 10, 647-656.
[173] Tabatabai G, Hasenbach K, Herrmann C, Maurer G, Mohle R, Marini P, Grez M, Wick W and Weller M (2010). Glioma tropism of lentivirally transduced hematopoietic progenitor cells. Int J Oncol 36, 1409-1417.
[174] Tabatabai G, Herrmann C, von Kurthy G, Mittelbronn M, Grau S, Frank B, Mohle R, Weller M and Wick W (2008). VEGF-dependent induction of CD62E on endothelial cells mediates glioma tropism of adult haematopoietic progenitor cells. Brain 131, 2579-2595.
[175] Vescovi AL, Galli R and Reynolds BA (2006). Brain tumour stem cells. Nat Rev Cancer 6, 425-436.
[176] Liu G, Yuan X, Zeng Z, Tunici P, Ng H, Abdulkadir IR, Lu L, Irvin D, Black KL and Yu JS (2006). Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer 5, 67.
[177] Griguer CE, Oliva CR, Gobin E, Marcorelles P, Benos DJ, Lancaster JR, Jr. and Gillespie GY (2008). CD133 is a marker of bioenergetic stress in human glioma. PLoS One 3, e3655.
[178] Weiss S, Dunne C, Hewson J, Wohl C, Wheatley M, Peterson AC and Reynolds BA (1996). Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuroaxis. J Neurosci 16, 7599-7609.
[179] Sanai N, Alvarez-Buylla A and Berger MS (2005). Neural stem cells and the origin of gliomas. N Engl J Med 353, 811-822.
[180] Moore KA and Lemischka IR (2006). Stem cells and their niches. Science 311, 1880-1885.
[181] Clark PA, Treisman DM, Ebben J and Kuo JS (2007). Developmental signaling pathways in brain tumor-derived stem-like cells. Dev Dyn 236, 3297-3308.
[182] Reifenberger G, Sieth P, Niederhaus M and Wechsler W (1992). Expression of CD15 in tumours of the nervous system. Histochem J 24, 890-901.
[183] Martin K, Akinwunmi J, Rooprai HK, Kennedy AJ, Linke A, Ognjenovic N and Pilkington GJ (1995). Nonexpression of CD15 by neoplastic glia: a barrier to metastasis? Anticancer Res 15, 1159-1166.
[184] Gocht A, Struckhoff G and Lhler J (1996). CD15-containing glycoconjugates in the central nervous system. Histol Histopathol 11, 1007-1028.
[185] Budka H and Majdic O (1985). Shared antigenic determinants between human hemopoietic cells and nervous tissues and tumors. Acta Neuropathol 67, 58-66.
[186] Tropepe V, Sibilia M, Ciruna BG, Rossant J, Wagner EF and van der Kooy D (1999). Distinct neural stem cells proliferate in response to EGF and FGF in the developing mouse telencephalon. Dev Biol 208, 166-188.
[187] Yi L, Zhou ZH, Ping YF, Chen JH, Yao XH, Feng H, Lu JY, Wang JM and Bian XW (2007). Isolation and characterization of stem cell-like precursor cells from primary human anaplastic oligoastrocytoma. Mod Pathol 20, 1061-1068.
[188] Zheng X, Shen G, Yang X and Liu W (2007). Most C6 cells are cancer stem cells: evidence from clonal and population analyses. Cancer Res 67, 3691-3697.
[189] Joo KM, Kim SY, Jin X, Song SY, Kong DS, Lee JI, Jeon JW, Kim MH, Kang BG, Jung Y et al. (2008). Clinical and biological implications of CD133-positive and CD133-negative cells in glioblastomas. Lab Invest 88, 808-815.
[190] Stiles CD and Rowitch DH (2008). Glioma stem cells: a midterm exam. Neuron 58, 832-846.
[191] Pfenninger CV, Roschupkina T, Hertwig F, Kottwitz D, Englund E, Bengzon J, Jacobsen SE and Nuber UA (2007). CD133 is not present on neurogenic astrocytes in the adult subventricular zone, but on embryonic neural stem cells, ependymal cells, and glioblastoma cells. Cancer Res 67, 5727-5736.
[192] Platet N, Liu SY, Atifi ME, Oliver L, Vallette FM, Berger F and Wion D (2007). Influence of oxygen tension on CD133 phenotype in human glioma cell cultures. Cancer Lett 258, 286-290.
[193] Zeppernick F, Ahmadi R, Campos B, Dictus C, Helmke BM, Becker N, Lichter P, Unterberg A, Radlwimmer B and Herold-Mende CC (2008). Stem cell marker CD133 affects clinical outcome in glioma patients. Clin Cancer Res 14, 123-129.
[194] Pouyssegur J, Dayan F and Mazure NM (2006). Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 441, 437-443.
[195] Kaelin WG, Jr. and Ratcliffe PJ (2008). Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell 30, 393-402.
[196] Mendez O, Zavadil J, Esencay M, Lukyanov Y, Santovasi D, Wang SC, Newcomb EW and Zagzag D (2010). Knock down of HIF-1alpha in glioma cells reduces migration in vitro and invasion in vivo and impairs their ability to form tumor spheres. Mol Cancer 9, 133.
[197] Krig SR, Miller JK, Frietze S, Beckett LA, Neve RM, Farnham PJ, Yaswen PI and Sweeney CA (2010). ZNF217, a candidate breast cancer oncogene amplified at 20q13, regulates expression of the ErbB3 receptor tyrosine kinase in breast cancer cells. Oncogene 29, 5500-5510.
[198] Sun G, Zhou J, Yin A, Ding Y and Zhong M (2008). Silencing of ZNF217 gene influences the biological behavior of a human ovarian cancer cell line. Int J Oncol 32, 1065-1071.
[199] Quinlan KG, Verger A, Yaswen P and Crossley M (2007). Amplification of zinc finger gene 217 (ZNF217) and cancer: when good fingers go bad. Biochim Biophys Acta 1775,333-340.
[200] Li P, Maines-Bandiera S, Kuo WL, Guan Y, Sun Y, Hills M, Huang G, Collins CC, Leung PC, Gray JW et al. (2007). Multiple roles of the candidate oncogene ZNF217 in ovarian epithelial neoplastic progression. Int J Cancer 120, 1863-1873.
[201] Nonet GH, Stampfer MR, Chin K, Gray JW, Collins CC and Yaswen P (2001). The ZNF217 gene amplified in breast cancers promotes immortalization of human mammary epithelial cells. Cancer Res 61, 1250-1254.
[202] Collins C, Rommens JM, Kowbel D, Godfrey T, Tanner M, Hwang SI, Polikoff D, Nonet G, Cochran J, Myambo K et al. (1998). Positional cloning of ZNF217 and NABC1: genes amplified at 20q13.2 and overexpressed in breast carcinoma. Proc Natl Acad Sci U S A 95, 8703-8708.
[203] Krig SR, Jin VX, Bieda MC, O'Geen H, Yaswen P, Green R and Farnham PJ (2007). Identification of genes directly regulated by the oncogene ZNF217 using chromatin immunoprecipitation (ChIP)-chip assays. J Biol Chem 282, 9703-9712.
[204] Cowger JJ, Zhao Q, Isovic M and Torchia J (2007). Biochemical characterization of the zinc-finger protein 217 transcriptional repressor complex: identification of a ZNF217 consensus recognition sequence. Oncogene 26, 3378-3386.
[205] Mao XG, Guo G, Wang P, Zhang X, Xue XY, Zhang W, Fei Z, Jiang XF and Yan M (2010). Maintenance of critical properties of brain tumor stem like cells after cryopreservation. Cell Mol Neurobiol 30, 775-786.
[206] Jordan CT (2009). Cancer stem cells: controversial or just misunderstood? Cell Stem Cell 4, 203-205.
[207] Lottaz C, Beier D, Meyer K, Kumar P, Hermann A, Schwarz J, Junker M, Oefner PJ, Bogdahn U, Wischhusen J et al. (2010). Transcriptional profiles of CD133+ and CD133- glioblastoma-derived cancer stem cell lines suggest different cells of origin. Cancer Res 70, 2030-2040.
[208] Piccirillo SG, Reynolds BA, Zanetti N, Lamorte G, Binda E, Broggi G, Brem H, Olivi A, Dimeco F and Vescovi AL (2006). Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 444, 761-765.
[209] Quinlan KG, Nardini M, Verger A, Francescato P, Yaswen P, Corda D, Bolognesi M and Crossley M (2006). Specific recognition of ZNF217 and other zinc finger proteins at a surface groove of C-terminal binding proteins. Mol Cell Biol 26, 8159-8172.
[210] Shi YJ, Matson C, Lan F, Iwase S, Baba T and Shi Y (2005). Regulation of LSD1 histone demethylase activity by its associated factors. Mol Cell 19, 857-864.
[211] Chinnadurai G (2007). Transcriptional regulation by C-terminal binding proteins. Int J Biochem Cell Biol 39, 1593-1607.
[212] Banck MS, Li S, Nishio H, Wang C, Beutler AS and Walsh MJ (2009). The ZNF217 oncogene is a candidate organizer of repressive histone modifiers. Epigenetics 4, 100-106.
[213] Huang G, Krig S, Kowbel D, Xu H, Hyun B, Volik S, Feuerstein B, Mills GB, Stokoe D,Yaswen P et al. (2005). ZNF217 suppresses cell death associated with chemotherapy and telomere dysfunction. Hum Mol Genet 14, 3219-3225.
[214] Wong DJ, Segal E and Chang HY (2008). Stemness, cancer and cancer stem cells. Cell Cycle 7, 3622-3624.
[215] Ben-Porath I, Thomson MW, Carey VJ, Ge R, Bell GW, Regev A and Weinberg RA (2008). An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet 40, 499-507.
[216] Park IH, Zhao R, West JA, Yabuuchi A, Huo H, Ince TA, Lerou PH, Lensch MW and Daley GQ (2008). Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451, 141-146.
[217] Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R et al. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917-1920.
[218] Takahashi K and Yamanaka S (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663-676.
[219] Kim J, Woo AJ, Chu J, Snow JW, Fujiwara Y, Kim CG, Cantor AB and Orkin SH (2010). A Myc network accounts for similarities between embryonic stem and cancer cell transcription programs. Cell 143, 313-324.
[220] Viswanathan SR, Powers JT, Einhorn W, Hoshida Y, Ng TL, Toffanin S, O'Sullivan M, Lu J, Phillips LA, Lockhart VL et al. (2009). Lin28 promotes transformation and is associated with advanced human malignancies. Nat Genet 41, 843-848.
[221] Peng S, Maihle NJ and Huang Y (2010). Pluripotency factors Lin28 and Oct4 identify a sub-population of stem cell-like cells in ovarian cancer. Oncogene,
[222] West JA, Viswanathan SR, Yabuuchi A, Cunniff K, Takeuchi A, Park IH, Sero JE, Zhu H, Perez-Atayde A, Frazier AL et al. (2009). A role for Lin28 in primordial germ-cell development and germ-cell malignancy. Nature 460, 909-913.
[223] Roush S and Slack FJ (2008). The let-7 family of microRNAs. Trends Cell Biol 18, 505-516.
[224] Viswanathan SR, Daley GQ and Gregory RI (2008). Selective blockade of microRNA processing by Lin28. Science 320, 97-100.
[225] Viswanathan SR and Daley GQ (2010). Lin28: A microRNA regulator with a macro role. Cell 140, 445-449.
[226] Miller FD and Gauthier AS (2007). Timing is everything: making neurons versus glia in the developing cortex. Neuron 54, 357-369.
[227] Okano H and Temple S (2009). Cell types to order: temporal specification of CNS stem cells. Curr Opin Neurobiol 19, 112-119.
[228] Namihira M, Kohyama J, Semi K, Sanosaka T, Deneen B, Taga T and Nakashima K (2009). Committed neuronal precursors confer astrocytic potential on residual neural precursor cells. Dev Cell 16, 245-255.
[229] Balzer E, Heine C, Jiang Q, Lee VM and Moss EG (2010). LIN28 alters cell fatesuccession and acts independently of the let-7 microRNA during neurogliogenesis in vitro. Development 137, 891-900.
[230] Nishino J, Kim I, Chada K and Morrison SJ (2008). Hmga2 promotes neural stem cell self-renewal in young but not old mice by reducing p16Ink4a and p19Arf Expression. Cell 135, 227-239.
[231] Braig M and Schmitt CA (2006). Oncogene-induced senescence: putting the brakes on tumor development. Cancer Res 66, 2881-2884.
[232] Baker SJ, Markowitz S, Fearon ER, Willson JK and Vogelstein B (1990). Suppression of human colorectal carcinoma cell growth by wild-type p53. Science 249, 912-915.
[233] Khosravi-Far R, White MA, Westwick JK, Solski PA, Chrzanowska-Wodnicka M, Van Aelst L, Wigler MH and Der CJ (1996). Oncogenic Ras activation of Raf/mitogen-activated protein kinase-independent pathways is sufficient to cause tumorigenic transformation. Mol Cell Biol 16, 3923-3933.
[234] Salmon P, Oberholzer J, Occhiodoro T, Morel P, Lou J and Trono D (2000). Reversible immortalization of human primary cells by lentivector-mediated transfer of specific genes. Mol Ther 2, 404-414.
[235] Sarbassov DD, Guertin DA, Ali SM and Sabatini DM (2005). Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307, 1098-1101.
[236] Moffat J, Grueneberg DA, Yang X, Kim SY, Kloepfer AM, Hinkle G, Piqani B, Eisenhaure TM, Luo B, Grenier JK et al. (2006). A lentiviral RNAi library for human and mouse genes applied to an arrayed viral high-content screen. Cell 124, 1283-1298.
[237] Raabe EH, Laudenslager M, Winter C, Wasserman N, Cole K, LaQuaglia M, Maris DJ, Mosse YP and Maris JM (2008). Prevalence and functional consequence of PHOX2B mutations in neuroblastoma. Oncogene 27, 469-476.
[238] Zheng K, Wu X, Kaestner KH and Wang PJ (2009). The pluripotency factor LIN28 marks undifferentiated spermatogonia in mouse. BMC Dev Biol 9, 38.
[239] Lee ST, Chu K, Oh HJ, Im WS, Lim JY, Kim SK, Park CK, Jung KH, Lee SK, Kim M et al. (2011). Let-7 microRNA inhibits the proliferation of human glioblastoma cells. J Neurooncol 102, 19-24.
[240] Wu J, Liu Z, Shao C, Gong Y, Hernando E, Lee P, Narita M, Muller W, Liu J and Wei JJ (2011). HMGA2 overexpression-induced ovarian surface epithelial transformation is mediated through regulation of EMT genes. Cancer Res 71, 349-359.
[241] Watanabe S, Ueda Y, Akaboshi S, Hino Y, Sekita Y and Nakao M (2009). HMGA2 maintains oncogenic RAS-induced epithelial-mesenchymal transition in human pancreatic cancer cells. Am J Pathol 174, 854-868.
[242] Jin J, Jing W, Lei XX, Feng C, Peng S, Boris-Lawrie K and Huang Y (2011). Evidence that Lin28 stimulates translation by recruiting RNA helicase A to polysomes. Nucleic Acids Res,
[243] Peng S, Chen LL, Lei XX, Yang L, Lin H, Carmichael GG and Huang Y (2011). Genome-wide Studies Reveal that Lin28 Enhances the Translation of Genes Importantfor Growth and Survival of Human Embryonic Stem Cells. Stem Cells,
[244] Qiu C, Ma Y, Wang J, Peng S and Huang Y (2010). Lin28-mediated post-transcriptional regulation of Oct4 expression in human embryonic stem cells. Nucleic Acids Res 38, 1240-1248.
[245] Polesskaya A, Cuvellier S, Naguibneva I, Duquet A, Moss EG and Harel-Bellan A (2007). Lin-28 binds IGF-2 mRNA and participates in skeletal myogenesis by increasing translation efficiency. Genes Dev 21, 1125-1138.
[246] Beck S, Jin X, Sohn YW, Kim JK, Kim SH, Yin J, Pian X, Kim SC, Nam DH, Choi YJ et al. (2010). Telomerase activity-independent function of TERT allows glioma cells to attain cancer stem cell characteristics by inducing EGFR expression. Mol Cells,
[2] DeAngelis LM (2001). Brain tumors. N Engl J Med 344, 114-123.
[3] Fortin D, Cairncross GJ and Hammond RR (1999). Oligodendroglioma: an appraisal of recent data pertaining to diagnosis and treatment. Neurosurgery 45, 1279-1291; discussion 1191.
[4] Ohgaki H and Kleihues P (2007). Genetic pathways to primary and secondary glioblastoma. Am J Pathol 170, 1445-1453.
[5] Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U et al. (2005). Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352, 987-996.
[6] TCGA (2008). Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061-1068.
[7] Dai C, Celestino JC, Okada Y, Louis DN, Fuller GN and Holland EC (2001). PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo. Genes Dev 15, 1913-1925.
[8] Bachoo RM, Maher EA, Ligon KL, Sharpless NE, Chan SS, You MJ, Tang Y, DeFrances J, Stover E, Weissleder R et al. (2002). Epidermal growth factor receptor and Ink4a/Arf: convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. Cancer Cell 1, 269-277.
[9] Holland EC, Celestino J, Dai C, Schaefer L, Sawaya RE and Fuller GN (2000). Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat Genet 25, 55-57.
[10] Marumoto T, Tashiro A, Friedmann-Morvinski D, Scadeng M, Soda Y, Gage FH and Verma IM (2009). Development of a novel mouse glioma model using lentiviral vectors. Nat Med 15, 110-116.
[11] Reilly KM, Loisel DA, Bronson RT, McLaughlin ME and Jacks T (2000). Nf1;Trp53 mutant mice develop glioblastoma with evidence of strain-specific effects. Nat Genet 26, 109-113.
[12] Zhu Y, Guignard F, Zhao D, Liu L, Burns DK, Mason RP, Messing A and Parada LF (2005). Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. Cancer Cell 8, 119-130.
[13] Zheng H, Ying H, Yan H, Kimmelman AC, Hiller DJ, Chen AJ, Perry SR, Tonon G, ChuGC, Ding Z et al. (2008). p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation. Nature 455, 1129-1133.
[14] Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP et al. (2010). Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17, 98-110.
[15] Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD, Misra A, Nigro JM, Colman H, Soroceanu L et al. (2006). Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 9, 157-173.
[16] Carro MS, Lim WK, Alvarez MJ, Bollo RJ, Zhao X, Snyder EY, Sulman EP, Anne SL, Doetsch F, Colman H et al. (2010). The transcriptional network for mesenchymal transformation of brain tumours. Nature 463, 318-325.
[17] Doetsch F (2003). The glial identity of neural stem cells. Nat Neurosci 6, 1127-1134.
[18] Capela A and Temple S (2002). LeX/ssea-1 is expressed by adult mouse CNS stem cells, identifying them as nonependymal. Neuron 35, 865-875.
[19] Doetsch F, Petreanu L, Caille I, Garcia-Verdugo JM and Alvarez-Buylla A (2002). EGF converts transit-amplifying neurogenic precursors in the adult brain into multipotent stem cells. Neuron 36, 1021-1034.
[20] Alvarez-Buylla A, Seri B and Doetsch F (2002). Identification of neural stem cells in the adult vertebrate brain. Brain Res Bull 57, 751-758.
[21] Temple S (2001). The development of neural stem cells. Nature 414, 112-117.
[22] Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM and Alvarez-Buylla A (1999). Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97, 703-716.
[23] Alvarez-Buylla A, Garcia-Verdugo JM and Tramontin AD (2001). A unified hypothesis on the lineage of neural stem cells. Nat Rev Neurosci 2, 287-293.
[24] Barnabe-Heider F, Goritz C, Sabelstrom H, Takebayashi H, Pfrieger FW, Meletis K and Frisen J (2010). Origin of new glial cells in intact and injured adult spinal cord. Cell Stem Cell 7, 470-482.
[25] Reynolds BA and Weiss S (1992). Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255, 1707-1710.
[26] Reynolds BA and Rietze RL (2005). Neural stem cells and neurospheres--re-evaluating the relationship. Nat Methods 2, 333-336.
[27] Ming GL and Song H (2005). Adult neurogenesis in the mammalian central nervous system. Annu Rev Neurosci 28, 223-250.
[28] Sanai N, Berger MS, Garcia-Verdugo JM and Alvarez-Buylla A (2007). Comment on "Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension". Science 318, 393; author reply 393.
[29] Sanai N, Tramontin AD, Quinones-Hinojosa A, Barbaro NM, Gupta N, Kunwar S,Lawton MT, McDermott MW, Parsa AT, Manuel-Garcia Verdugo J et al. (2004). Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature 427, 740-744.
[30] Curtis MA, Kam M, Nannmark U, Anderson MF, Axell MZ, Wikkelso C, Holtas S, van Roon-Mom WM, Bjork-Eriksson T, Nordborg C et al. (2007). Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension. Science 315, 1243-1249.
[31] Shen Q, Wang Y, Kokovay E, Lin G, Chuang SM, Goderie SK, Roysam B and Temple S (2008). Adult SVZ stem cells lie in a vascular niche: a quantitative analysis of niche cell-cell interactions. Cell Stem Cell 3, 289-300.
[32] Tavazoie M, Van der Veken L, Silva-Vargas V, Louissaint M, Colonna L, Zaidi B, Garcia-Verdugo JM and Doetsch F (2008). A specialized vascular niche for adult neural stem cells. Cell Stem Cell 3, 279-288.
[33] Hansen DV, Lui JH, Parker PR and Kriegstein AR (2010). Neurogenic radial glia in the outer subventricular zone of human neocortex. Nature 464, 554-561.
[34] Aguirre A, Rubio ME and Gallo V (2010). Notch and EGFR pathway interaction regulates neural stem cell number and self-renewal. Nature 467, 323-327.
[35] Mizutani K, Yoon K, Dang L, Tokunaga A and Gaiano N (2007). Differential Notch signalling distinguishes neural stem cells from intermediate progenitors. Nature 449, 351-355.
[36] Androutsellis-Theotokis A, Leker RR, Soldner F, Hoeppner DJ, Ravin R, Poser SW, Rueger MA, Bae SK, Kittappa R and McKay RD (2006). Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 442, 823-826.
[37] Mazumdar J, O'Brien WT, Johnson RS, Lamanna JC, Chavez JC, Klein PS and Simon MC (2010). O(2) regulates stem cells through Wnt/beta-catenin signalling. Nat Cell Biol 12, 1007-1013.
[38] Zheng H, Ying H, Wiedemeyer R, Yan H, Quayle SN, Ivanova EV, Paik JH, Zhang H, Xiao Y, Perry SR et al. (2010). PLAGL2 regulates Wnt signaling to impede differentiation in neural stem cells and gliomas. Cancer Cell 17, 497-509.
[39] Kalani MY, Cheshier SH, Cord BJ, Bababeygy SR, Vogel H, Weissman IL, Palmer TD and Nusse R (2008). Wnt-mediated self-renewal of neural stem/progenitor cells. Proc Natl Acad Sci U S A 105, 16970-16975.
[40] Lie DC, Colamarino SA, Song HJ, Desire L, Mira H, Consiglio A, Lein ES, Jessberger S, Lansford H, Dearie AR et al. (2005). Wnt signalling regulates adult hippocampal neurogenesis. Nature 437, 1370-1375.
[41] Ille F and Sommer L (2005). Wnt signaling: multiple functions in neural development. Cell Mol Life Sci 62, 1100-1108.
[42] Wexler EM, Paucer A, Kornblum HI, Plamer TD and Geschwind DH (2009). Endogenous Wnt signaling maintains neural progenitor cell potency. Stem Cells 27, 1130-1141.
[43] Fasano CA, Phoenix TN, Kokovay E, Lowry N, Elkabetz Y, Dimos JT, Lemischka IR,Studer L and Temple S (2009). Bmi-1 cooperates with Foxg1 to maintain neural stem cell self-renewal in the forebrain. Genes Dev 23, 561-574.
[44] Molofsky AV, Pardal R, Iwashita T, Park IK, Clarke MF and Morrison SJ (2003). Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425, 962-967.
[45] He S, Iwashita T, Buchstaller J, Molofsky AV, Thomas D and Morrison SJ (2009). Bmi-1 over-expression in neural stem/progenitor cells increases proliferation and neurogenesis in culture but has little effect on these functions in vivo. Dev Biol 328, 257-272.
[46] Armesilla-Diaz A, Bragado P, Del Valle I, Cuevas E, Lazaro I, Martin C, Cigudosa JC and Silva A (2009). p53 regulates the self-renewal and differentiation of neural precursors. Neuroscience 158, 1378-1389.
[47] Groszer M, Erickson R, Scripture-Adams DD, Lesche R, Trumpp A, Zack JA, Kornblum HI, Liu X and Wu H (2001). Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo. Science 294, 2186-2189.
[48] Abdouh M, Facchino S, Chatoo W, Balasingam V, Ferreira J and Bernier G (2009). BMI1 sustains human glioblastoma multiforme stem cell renewal. J Neurosci 29, 8884-8896.
[49] Fan X, Khaki L, Zhu TS, Soules ME, Talsma CE, Gul N, Koh C, Zhang J, Li YM, Maciaczyk J et al. (2010). Notch Pathway Blockade Depletes CD133-Positive Glioblastoma Cells and Inhibits Growth of Tumor Neurospheres and Xenografts. Stem Cells 28, 5-16.
[50] Charles N, Ozawa T, Squatrito M, Bleau AM, Brennan CW, Hambardzumyan D and Holland EC (2010). Perivascular Nitric Oxide Activates Notch Signaling and Promotes Stem-like Character in PDGF-Induced Glioma Cells. Cell Stem Cell 6, 141-152.
[51] Hoeck JD, Jandke A, Blake SM, Nye E, Spencer-Dene B, Brandner S and Behrens A (2010). Fbw7 controls neural stem cell differentiation and progenitor apoptosis via Notch and c-Jun. Nat Neurosci 13, 1365-1372.
[52] Fan X, Matsui W, Khaki L, Stearns D, Chun J, Li YM and Eberhart CG (2006). Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res 66, 7445-7452.
[53] Sareddy GR, Panigrahi M, Challa S, Mahadevan A and Babu PP (2009). Activation of Wnt/beta-catenin/Tcf signaling pathway in human astrocytomas. Neurochem Int 55, 307-317.
[54] Yu JM, Jun ES, Jung JS, Suh SY, Han JY, Kim JY and Kim KW (2007). Role of Wnt5a in the proliferation of human glioblastoma cells. Cancer Lett 257, 172-181.
[55] Facchino S, Abdouh M, Chatoo W and Bernier G (2010). BMI1 confers radioresistance to normal and cancerous neural stem cells through recruitment of the DNA damage response machinery. J Neurosci 30, 10096-10111.
[56] Bruggeman SW, Hulsman D, Tanger E, Buckle T, Blom M, Zevenhoven J, van Tellingen O and van Lohuizen M (2007). Bmi1 controls tumor development in anInk4a/Arf-independent manner in a mouse model for glioma. Cancer Cell 12, 328-341.
[57] Globus J and Kuhlenbeck H (1942). Tumors of the striato thalamic and related regions: their probable source of origin and more common forms. Arch Pathol 24, 674-734.
[58] Tohyama T, Lee VM, Rorke LB, Marvin M, McKay RD and Trojanowski JQ (1992). Nestin expression in embryonic human neuroepithelium and in human neuroepithelial tumor cells. Lab Invest 66, 303-313.
[59] Hopewell JW (1975). The subependymal plate and the genesis of gliomas. J Pathol 117, 101-103.
[60] Lantos PL and Cox DJ (1976). The origin of experimental brain tumours: a sequential study. Experientia 32, 1467-1468.
[61] Lim DA, Cha S, Mayo MC, Chen MH, Keles E, VandenBerg S and Berger MS (2007). Relationship of glioblastoma multiforme to neural stem cell regions predicts invasive and multifocal tumor phenotype. Neuro Oncol 9, 424-429.
[62] Persson AI, Petritsch C, Swartling FJ, Itsara M, Sim FJ, Auvergne R, Goldenberg DD, Vandenberg SR, Nguyen KN, Yakovenko S et al. (2010). Non-stem cell origin for oligodendroglioma. Cancer Cell 18, 669-682.
[63] Alcantara Llaguno S, Chen J, Kwon CH, Jackson EL, Li Y, Burns DK, Alvarez-Buylla A and Parada LF (2009). Malignant astrocytomas originate from neural stem/progenitor cells in a somatic tumor suppressor mouse model. Cancer Cell 15, 45-56.
[64] Wang Y, Yang J, Zheng H, Tomasek GJ, Zhang P, McKeever PE, Lee EY and Zhu Y (2009). Expression of mutant p53 proteins implicates a lineage relationship between neural stem cells and malignant astrocytic glioma in a murine model. Cancer Cell 15, 514-526.
[65] Bonnet D (2005). Cancer stem cells: lessons from leukaemia. Cell Prolif 38, 357-361.
[66] Bonnet D and Dick JE (1997). Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3, 730-737.
[67] Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, Paterson B, Caligiuri MA and Dick JE (1994). A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367, 645-648.
[68] Ignatova TN, Kukekov VG, Laywell ED, Suslov ON, Vrionis FD and Steindler DA (2002). Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia 39, 193-206.
[69] Hemmati HD, Nakano I, Lazareff JA, Masterman-Smith M, Geschwind DH, Bronner-Fraser M and Kornblum HI (2003). Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci U S A 100, 15178-15183.
[70] Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J and Dirks PB (2003). Identification of a cancer stem cell in human brain tumors. Cancer Res 63, 5821-5828.
[71] Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD and Dirks PB (2004). Identification of human brain tumour initiating cells. Nature 432, 396-401.
[72] Singh SK, Clarke ID, Hide T and Dirks PB (2004). Cancer stem cells in nervous system tumors. Oncogene 23, 7267-7273.
[73]邓永文,方加胜,李茗初,陈风华,刘劲芳,伍军,周向阳,方芳,卢明,陈成et al. (2005).胶质瘤中肿瘤干细胞的分离、培养及鉴定.中国现代医学杂志15, 2449-2452.
[74]李茗初,邓永文,伍军,陈风华,刘劲芳and方加胜(2006).髓母细胞瘤中脑肿瘤干细胞的分离培养及鉴定.癌症25, 241-246.
[75]方加胜,邓永文,李茗初,陈风华,王延金,卢明,方芳,伍军,杨转移,周向阳et al. (2007).神经上皮来源脑肿瘤中肿瘤干细胞的分离培养与鉴定.中华医学杂志87, 298-303.
[76] Collins AT, Berry PA, Hyde C, Stower MJ and Maitland NJ (2005). Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 65, 10946-10951.
[77] Seigel GM, Campbell LM, Narayan M and Gonzalez-Fernandez F (2005). Cancer stem cell characteristics in retinoblastoma. Mol Vis 11, 729-737.
[78] Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M, Haegebarth A, Korving J, Begthel H, Peters PJ et al. (2007). Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003-1007.
[79] Dou J, Pan M, Wen P, Li Y, Tang Q, Chu L, Zhao F, Jiang C, Hu W, Hu K et al. (2007). Isolation and identification of cancer stem-like cells from murine melanoma cell lines. Cell Mol Immunol 4, 467-472.
[80] Ma S, Chan KW, Hu L, Lee TK, Wo JY, Ng IO, Zheng BJ and Guan XY (2007). Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology 132, 2542-2556.
[81] Monzani E, Facchetti F, Galmozzi E, Corsini E, Benetti A, Cavazzin C, Gritti A, Piccinini A, Porro D, Santinami M et al. (2007). Melanoma contains CD133 and ABCG2 positive cells with enhanced tumourigenic potential. Eur J Cancer 43, 935-946.
[82] Olempska M, Eisenach PA, Ammerpohl O, Ungefroren H, Fandrich F and Kalthoff H (2007). Detection of tumor stem cell markers in pancreatic carcinoma cell lines. Hepatobiliary Pancreat Dis Int 6, 92-97.
[83] Yin S, Li J, Hu C, Chen X, Yao M, Yan M, Jiang G, Ge C, Xie H, Wan D et al. (2007). CD133 positive hepatocellular carcinoma cells possess high capacity for tumorigenicity. Int J Cancer 120, 1444-1450.
[84] O'Brien CA, Pollett A, Gallinger S and Dick JE (2007). A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445, 106-110.
[85] Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C and De Maria R (2007). Identification and expansion of human colon-cancer-initiating cells. Nature 445, 111-115.
[86] Sakariassen PO, Immervoll H and Chekenya M (2007). Cancer stem cells as mediators of treatment resistance in brain tumors: status and controversies. Neoplasia 9, 882-892.
[87] Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, Jacquemier J,Viens P, Kleer CG, Liu S et al. (2007). ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1, 555-567.
[88] Wright MH, Calcagno AM, Salcido CD, Carlson MD, Ambudkar SV and Varticovski L (2008). Brca1 breast tumors contain distinct CD44+/CD24- and CD133+ cells with cancer stem cell characteristics. Breast Cancer Res 10, R10.
[89] Wong DJ, Liu H, Ridky TW, Cassarino D, Segal E and Chang HY (2008). Module map of stem cell genes guides creation of epithelial cancer stem cells. Cell Stem Cell 2, 333-344.
[90] Fan X and Eberhart CG (2008). Medulloblastoma stem cells. J Clin Oncol 26, 2821-2827.
[91] Bertolini G, Roz L, Perego P, Tortoreto M, Fontanella E, Gatti L, Pratesi G, Fabbri A, Andriani F, Tinelli S et al. (2009). Highly tumorigenic lung cancer CD133+ cells display stem-like features and are spared by cisplatin treatment. Proc Natl Acad Sci U S A 106, 16281-16286.
[92] Zhang Q, Shi S, Yen Y, Brown J, Ta JQ and Le AD (2009). A subpopulation of CD133(+) cancer stem-like cells characterized in human oral squamous cell carcinoma confer resistance to chemotherapy. Cancer Lett,
[93] Zhu Z, Hao X, Yan M, Yao M, Ge C, Gu J and Li J (2009). Cancer stem/progenitor cells are highly enriched in CD133(+)CD44(+) population in hepatocellular carcinoma. Int J Cancer,
[94] Rutella S, Bonanno G, Procoli A, Mariotti A, Corallo M, Prisco MG, Eramo A, Napoletano C, Gallo D, Perillo A et al. (2009). Cells with characteristics of cancer stem/progenitor cells express the CD133 antigen in human endometrial tumors. Clin Cancer Res 15, 4299-4311.
[95] Friedman S, Lu M, Schultz A, Thomas D and Lin RY (2009). CD133+ anaplastic thyroid cancer cells initiate tumors in immunodeficient mice and are regulated by thyrotropin. PLoS One 4, e5395.
[96] Suva ML, Riggi N, Stehle JC, Baumer K, Tercier S, Joseph JM, Suva D, Clement V, Provero P, Cironi L et al. (2009). Identification of cancer stem cells in Ewing's sarcoma. Cancer Res 69, 1776-1781.
[97] Kelly PN, Dakic A, Adams JM, Nutt SL and Strasser A (2007). Tumor growth need not be driven by rare cancer stem cells. Science 317, 337.
[98] Quintana E, Shackleton M, Sabel MS, Fullen DR, Johnson TM and Morrison SJ (2008). Efficient tumour formation by single human melanoma cells. Nature 456, 593-598.
[99] Richardson GD, Robson CN, Lang SH, Neal DE, Maitland NJ and Collins AT (2004). CD133, a novel marker for human prostatic epithelial stem cells. J Cell Sci 117, 3539-3545.
[100] Vander Griend DJ, Karthaus WL, Dalrymple S, Meeker A, DeMarzo AM and Isaacs JT (2008). The role of CD133 in normal human prostate stem cells and malignantcancer-initiating cells. Cancer Res 68, 9703-9711.
[101] Coskun V, Wu H, Blanchi B, Tsao S, Kim K, Zhao J, Biancotti JC, Hutnick L, Krueger RC, Jr., Fan G et al. (2008). CD133+ neural stem cells in the ependyma of mammalian postnatal forebrain. Proc Natl Acad Sci U S A 105, 1026-1031.
[102] Cheng JX, Liu BL and Zhang X (2009). How powerful is CD133 as a cancer stem cell marker in brain tumors? Cancer Treat Rev 35, 403-408.
[103] Clement V, Dutoit V, Marino D, Dietrich PY and Radovanovic I (2009). Limits of CD133 as a marker of glioma self-renewing cells. Int J Cancer 125, 244-248.
[104] Snippert HJ, van Es JH, van den Born M, Begthel H, Stange DE, Barker N and Clevers H (2009). Prominin-1/CD133 marks stem cells and early progenitors in mouse small intestine. Gastroenterology 136, 2187-2194 e2181.
[105] Zhu L, Gibson P, Currle DS, Tong Y, Richardson RJ, Bayazitov IT, Poppleton H, Zakharenko S, Ellison DW and Gilbertson RJ (2009). Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation. Nature 457, 603-607.
[106] Bakondi B, Shimada IS, Perry A, Munoz JR, Ylostalo J, Howard AB, Gregory CA and Spees JL (2009). CD133 identifies a human bone marrow stem/progenitor cell sub-population with a repertoire of secreted factors that protect against stroke. Mol Ther 17, 1938-1947.
[107] Tsuchiya A, Kamimura H, Takamura M, Yamagiwa S, Matsuda Y, Sato Y, Nomoto M, Ichida T and Aoyagi Y (2009). Clinicopathological analysis of CD133 and NCAM human hepatic stem/progenitor cells in damaged livers and hepatocellular carcinomas. Hepatol Res 39, 1080-1090.
[108] Curley MD, Therrien VA, Cummings CL, Sergent PA, Koulouris CR, Friel AM, Roberts DJ, Seiden MV, Scadden DT, Rueda BR et al. (2009). CD133 Expression Defines a Tumor Initiating Cell Population in Primary Human Ovarian Cancer. Stem Cells 27, 2875-2883.
[109] Ding W, Mouzaki M, You H, Laird JC, Mato J, Lu SC and Rountree CB (2009). CD133+ liver cancer stem cells from methionine adenosyl transferase 1A-deficient mice demonstrate resistance to transforming growth factor (TGF)-beta-induced apoptosis. Hepatology 49, 1277-1286.
[110] Wei XD, Zhou L, Cheng L, Tian J, Jiang JJ and Maccallum J (2009). In vivo investigation of CD133 as a putative marker of cancer stem cells in Hep-2 cell line. Head Neck 31, 94-101.
[111] Quintana E, Shackleton M, Foster HR, Fullen DR, Sabel MS, Johnson TM and Morrison SJ (2010). Phenotypic heterogeneity among tumorigenic melanoma cells from patients that is reversible and not hierarchically organized. Cancer Cell 18, 510-523.
[112] Yeung J, Esposito MT, Gandillet A, Zeisig BB, Griessinger E, Bonnet D and So CW (2010). beta-Catenin mediates the establishment and drug resistance of MLL leukemic stem cells. Cancer Cell 18, 606-618.
[113] Goardon N, Marchi E, Atzberger A, Quek L, Schuh A, Soneji S, Woll P, Mead A, AlfordKA, Rout R et al. (2011). Coexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia. Cancer Cell 19, 138-152.
[114] Majeti R and Weissman IL (2011). Human acute myelogenous leukemia stem cells revisited: there's more than meets the eye. Cancer Cell 19, 9-10.
[115] Yuan X, Curtin J, Xiong Y, Liu G, Waschsmann-Hogiu S, Farkas DL, Black KL and Yu JS (2004). Isolation of cancer stem cells from adult glioblastoma multiforme. Oncogene 23, 9392-9400.
[116] Wang J, Sakariassen PO, Tsinkalovsky O, Immervoll H, Boe SO, Svendsen A, Prestegarden L, Rosland G, Thorsen F, Stuhr L et al. (2008). CD133 negative glioma cells form tumors in nude rats and give rise to CD133 positive cells. Int J Cancer 122, 761-768.
[117] Sun Y, Kong W, Falk A, Hu J, Zhou L, Pollard S and Smith A (2009). CD133 (Prominin) negative human neural stem cells are clonogenic and tripotent. PLoS One 4, e5498.
[118] Beier D, Hau P, Proescholdt M, Lohmeier A, Wischhusen J, Oefner PJ, Aigner L, Brawanski A, Bogdahn U and Beier CP (2007). CD133(+) and CD133(-) glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res 67, 4010-4015.
[119] Ogden AT, Waziri AE, Lochhead RA, Fusco D, Lopez K, Ellis JA, Kang J, Assanah M, McKhann GM, Sisti MB et al. (2008). Identification of A2B5+CD133- tumor-initiating cells in adult human gliomas. Neurosurgery 62, 505-514; discussion 514-505.
[120] Son MJ, Woolard K, Nam DH, Lee J and Fine HA (2009). SSEA-1 is an enrichment marker for tumor-initiating cells in human glioblastoma. Cell Stem Cell 4, 440-452.
[121] Ward RJ, Lee L, Graham K, Satkunendran T, Yoshikawa K, Ling E, Harper L, Austin R, Nieuwenhuis E, Clarke ID et al. (2009). Multipotent CD15+ cancer stem cells in patched-1-deficient mouse medulloblastoma. Cancer Res 69, 4682-4690.
[122] Read TA, Fogarty MP, Markant SL, McLendon RE, Wei Z, Ellison DW, Febbo PG and Wechsler-Reya RJ (2009). Identification of CD15 as a marker for tumor-propagating cells in a mouse model of medulloblastoma. Cancer Cell 15, 135-147.
[123] Mao XG, Zhang X, Xue XY, Guo G, Wang P, Zhang W, Fei Z, Zhen HN, You SW and Yang H (2009). Brain Tumor Stem-Like Cells Identified by Neural Stem Cell Marker CD15. Transl Oncol 2, 247-257.
[124] Chen R, Nishimura MC, Bumbaca SM, Kharbanda S, Forrest WF, Kasman IM, Greve JM, Soriano RH, Gilmour LL, Rivers CS et al. (2010). A hierarchy of self-renewing tumor-initiating cell types in glioblastoma. Cancer Cell 17, 362-375.
[125] Capela A and Temple S (2006). LeX is expressed by principle progenitor cells in the embryonic nervous system, is secreted into their environment and binds Wnt-1. Dev Biol 291, 300-313.
[126] Harris MA, Yang H, Low BE, Mukherjee J, Guha A, Bronson RT, Shultz LD, Israel MA and Yun K (2008). Cancer stem cells are enriched in the side population cells in a mouse model of glioma. Cancer Res 68, 10051-10059.
[127] Bleau AM, Huse JT and Holland EC (2009). The ABCG2 resistance network of glioblastoma. Cell Cycle 8, 2936-2944.
[128] Hirschmann-Jax C, Foster AE, Wulf GG, Nuchtern JG, Jax TW, Gobel U, Goodell MA and Brenner MK (2004). A distinct "side population" of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci U S A 101, 14228-14233.
[129] Bleau AM, Hambardzumyan D, Ozawa T, Fomchenko EI, Huse JT, Brennan CW and Holland EC (2009). PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells. Cell Stem Cell 4, 226-235.
[130] Broadley KW, Hunn MK, Farrand KJ, Price KM, Grasso C, Miller RJ, Hermans IF and McConnell MJ (2010). Side Population is not Necessary or Sufficient for a Cancer Stem Cell Phenotype in Glioblastoma Multiforme. Stem Cells,
[131] Christensen K, Schroder HD and Kristensen BW (2008). CD133 identifies perivascular niches in grade II-IV astrocytomas. J Neurooncol 90, 157-170.
[132] Calabrese C, Poppleton H, Kocak M, Hogg TL, Fuller C, Hamner B, Oh EY, Gaber MW, Finklestein D, Allen M et al. (2007). A perivascular niche for brain tumor stem cells. Cancer Cell 11, 69-82.
[133] Mirzadeh Z, Merkle FT, Soriano-Navarro M, Garcia-Verdugo JM and Alvarez-Buylla A (2008). Neural stem cells confer unique pinwheel architecture to the ventricular surface in neurogenic regions of the adult brain. Cell Stem Cell 3, 265-278.
[134] Wang R, Chadalavada K, Wilshire J, Kowalik U, Hovinga KE, Geber A, Fligelman B, Leversha M, Brennan C and Tabar V (2010). Glioblastoma stem-like cells give rise to tumour endothelium. Nature 468, 829-833.
[135] Ricci-Vitiani L, Pallini R, Biffoni M, Todaro M, Invernici G, Cenci T, Maira G, Parati EA, Stassi G, Larocca LM et al. (2010). Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 468, 824-828.
[136] Rodrigues CA, Diogo MM, da Silva CL and Cabral JM (2009). Hypoxia enhances proliferation of mouse embryonic stem cell-derived neural stem cells. Biotechnol Bioeng,
[137] Chen X, Tian Y, Yao L, Zhang J and Liu Y (2009). Hypoxia stimulates proliferation of rat neural stem cells with influence on the expression of cyclin D1 and c-Jun N-terminal protein kinase signaling pathway in vitro. Neuroscience,
[138] Li Z, Bao S, Wu Q, Wang H, Eyler C, Sathornsumetee S, Shi Q, Cao Y, Lathia J, McLendon RE et al. (2009). Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell 15, 501-513.
[139] Bertout JA, Patel SA and Simon MC (2008). The impact of O2 availability on human cancer. Nat Rev Cancer 8, 967-975.
[140] Chen HL, Pistollato F, Hoeppner DJ, Ni HT, McKay RD and Panchision DM (2007). Oxygen tension regulates survival and fate of mouse central nervous system precursors at multiple levels. Stem Cells 25, 2291-2301.
[141] Keith B and Simon MC (2007). Hypoxia-inducible factors, stem cells, and cancer. Cell 129, 465-472.
[142] Semenza GL (2007). Life with oxygen. Science 318, 62-64.
[143] Seidel S, Garvalov BK, Wirta V, von Stechow L, Schanzer A, Meletis K, Wolter M, Sommerlad D, Henze AT, Nister M et al. (2010). A hypoxic niche regulates glioblastoma stem cells through hypoxia inducible factor 2 alpha. Brain 133, 983-995.
[144] Heddleston JM, Li Z, McLendon RE, Hjelmeland AB and Rich JN (2009). The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype. Cell Cycle 8, 3274-3284.
[145] Bar EE, Lin A, Mahairaki V, Matsui W and Eberhart CG (2010). Hypoxia increases the expression of stem-cell markers and promotes clonogenicity in glioblastoma neurospheres. Am J Pathol 177, 1491-1502.
[146] Soeda A, Park M, Lee D, Mintz A, Androutsellis-Theotokis A, McKay RD, Engh J, Iwama T, Kunisada T, Kassam AB et al. (2009). Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1alpha. Oncogene 28, 3949-3959.
[147] McCord AM, Jamal M, Shankavaram UT, Lang FF, Camphausen K and Tofilon PJ (2009). Physiologic oxygen concentration enhances the stem-like properties of CD133+ human glioblastoma cells in vitro. Mol Cancer Res 7, 489-497.
[148] Mole DR, Blancher C, Copley RR, Pollard PJ, Gleadle JM, Ragoussis J and Ratcliffe PJ (2009). Genome-wide association of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha DNA binding with expression profiling of hypoxia-inducible transcripts. J Biol Chem 284, 16767-16775.
[149] Mao XG, Zhang X and Zhen HN (2009). Progress on potential strategies to target brain tumor stem cells. Cell Mol Neurobiol 29, 141-155.
[150]毛星刚and章翔(2009).脑肿瘤干细胞研究进展.中华神经外科疾病研究杂志8, 84-86.
[151]章翔and毛星刚(2008).靶向消除脑肿瘤干细胞的潜在治疗策略.中华神经外科疾病研究杂志7, 481-484.
[152] Lee J, Kotliarova S, Kotliarov Y, Li A, Su Q, Donin NM, Pastorino S, Purow BW, Christopher N, Zhang W et al. (2006). Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 9, 391-403.
[153] Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD and Rich JN (2006). Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444, 756-760.
[154] Lu C and Shervington A (2008). Chemoresistance in gliomas. Mol Cell Biochem 312, 71-80.
[155] Kang MK and Kang SK (2007). Tumorigenesis of chemotherapeutic drug-resistant cancer stem-like cells in brain glioma. Stem Cells Dev 16, 837-847.
[156] Eramo A, Ricci-Vitiani L, Zeuner A, Pallini R, Lotti F, Sette G, Pilozzi E, Larocca LM, Peschle C and De Maria R (2006). Chemotherapy resistance of glioblastoma stem cells.Cell Death Differ 13, 1238-1241.
[157] Bar EE, Chaudhry A, Lin A, Fan X, Schreck K, Matsui W, Piccirillo S, Vescovi AL, DiMeco F, Olivi A et al. (2007). Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma. Stem Cells 25, 2524-2533.
[158] Frank RT, Najbauer J and Aboody KS (2010). Concise review: stem cells as an emerging platform for antibody therapy of cancer. Stem Cells 28, 2084-2087.
[159] Frank RT, Edmiston M, Kendall SE, Najbauer J, Cheung CW, Kassa T, Metz MZ, Kim SU, Glackin CA, Wu AM et al. (2009). Neural stem cells as a novel platform for tumor-specific delivery of therapeutic antibodies. PLoS One 4, e8314.
[160] Aboody KS, Najbauer J and Danks MK (2008). Stem and progenitor cell-mediated tumor selective gene therapy. Gene Ther 15, 739-752.
[161] Aboody KS, Brown A, Rainov NG, Bower KA, Liu S, Yang W, Small JE, Herrlinger U, Ourednik V, Black PM et al. (2000). Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc Natl Acad Sci U S A 97, 12846-12851.
[162] Mapara KY, Stevenson CB, Thompson RC and Ehtesham M (2007). Stem cells as vehicles for the treatment of brain cancer. Neurosurg Clin N Am 18, 71-80, ix.
[163] Kabos P, Ehtesham M, Black KL and Yu JS (2003). Neural stem cells as delivery vehicles. Expert Opin Biol Ther 3, 759-770.
[164] Dickson PV, Hamner JB, Burger RA, Garcia E, Ouma AA, Kim SU, Ng CY, Gray JT, Aboody KS, Danks MK et al. (2007). Intravascular administration of tumor tropic neural progenitor cells permits targeted delivery of interferon-beta and restricts tumor growth in a murine model of disseminated neuroblastoma. J Pediatr Surg 42, 48-53.
[165] Benedetti S, Pirola B, Pollo B, Magrassi L, Bruzzone MG, Rigamonti D, Galli R, Selleri S, Di Meco F, De Fraja C et al. (2000). Gene therapy of experimental brain tumors using neural progenitor cells. Nat Med 6, 447-450.
[166] Ehtesham M, Kabos P, Kabosova A, Neuman T, Black KL and Yu JS (2002). The use of interleukin 12-secreting neural stem cells for the treatment of intracranial glioma. Cancer Res 62, 5657-5663.
[167] Schmidt NO, Przylecki W, Yang W, Ziu M, Teng Y, Kim SU, Black PM, Aboody KS and Carroll RS (2005). Brain tumor tropism of transplanted human neural stem cells is induced by vascular endothelial growth factor. Neoplasia 7, 623-629.
[168] Ehtesham M, Yuan X, Kabos P, Chung NH, Liu G, Akasaki Y, Black KL and Yu JS (2004). Glioma tropic neural stem cells consist of astrocytic precursors and their migratory capacity is mediated by CXCR4. Neoplasia 6, 287-293.
[169] Ziu M, Schmidt NO, Cargioli TG, Aboody KS, Black PM and Carroll RS (2006). Glioma-produced extracellular matrix influences brain tumor tropism of human neural stem cells. J Neurooncol 79, 125-133.
[170] Zhao D, Najbauer J, Garcia E, Metz MZ, Gutova M, Glackin CA, Kim SU and Aboody KS (2008). Neural stem cell tropism to glioma: critical role of tumor hypoxia. MolCancer Res 6, 1819-1829.
[171] Nakamizo A, Marini F, Amano T, Khan A, Studeny M, Gumin J, Chen J, Hentschel S, Vecil G, Dembinski J et al. (2005). Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas. Cancer Res 65, 3307-3318.
[172] Ferrari N, Glod J, Lee J, Kobiler D and Fine HA (2003). Bone marrow-derived, endothelial progenitor-like cells as angiogenesis-selective gene-targeting vectors. Gene Ther 10, 647-656.
[173] Tabatabai G, Hasenbach K, Herrmann C, Maurer G, Mohle R, Marini P, Grez M, Wick W and Weller M (2010). Glioma tropism of lentivirally transduced hematopoietic progenitor cells. Int J Oncol 36, 1409-1417.
[174] Tabatabai G, Herrmann C, von Kurthy G, Mittelbronn M, Grau S, Frank B, Mohle R, Weller M and Wick W (2008). VEGF-dependent induction of CD62E on endothelial cells mediates glioma tropism of adult haematopoietic progenitor cells. Brain 131, 2579-2595.
[175] Vescovi AL, Galli R and Reynolds BA (2006). Brain tumour stem cells. Nat Rev Cancer 6, 425-436.
[176] Liu G, Yuan X, Zeng Z, Tunici P, Ng H, Abdulkadir IR, Lu L, Irvin D, Black KL and Yu JS (2006). Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer 5, 67.
[177] Griguer CE, Oliva CR, Gobin E, Marcorelles P, Benos DJ, Lancaster JR, Jr. and Gillespie GY (2008). CD133 is a marker of bioenergetic stress in human glioma. PLoS One 3, e3655.
[178] Weiss S, Dunne C, Hewson J, Wohl C, Wheatley M, Peterson AC and Reynolds BA (1996). Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuroaxis. J Neurosci 16, 7599-7609.
[179] Sanai N, Alvarez-Buylla A and Berger MS (2005). Neural stem cells and the origin of gliomas. N Engl J Med 353, 811-822.
[180] Moore KA and Lemischka IR (2006). Stem cells and their niches. Science 311, 1880-1885.
[181] Clark PA, Treisman DM, Ebben J and Kuo JS (2007). Developmental signaling pathways in brain tumor-derived stem-like cells. Dev Dyn 236, 3297-3308.
[182] Reifenberger G, Sieth P, Niederhaus M and Wechsler W (1992). Expression of CD15 in tumours of the nervous system. Histochem J 24, 890-901.
[183] Martin K, Akinwunmi J, Rooprai HK, Kennedy AJ, Linke A, Ognjenovic N and Pilkington GJ (1995). Nonexpression of CD15 by neoplastic glia: a barrier to metastasis? Anticancer Res 15, 1159-1166.
[184] Gocht A, Struckhoff G and Lhler J (1996). CD15-containing glycoconjugates in the central nervous system. Histol Histopathol 11, 1007-1028.
[185] Budka H and Majdic O (1985). Shared antigenic determinants between human hemopoietic cells and nervous tissues and tumors. Acta Neuropathol 67, 58-66.
[186] Tropepe V, Sibilia M, Ciruna BG, Rossant J, Wagner EF and van der Kooy D (1999). Distinct neural stem cells proliferate in response to EGF and FGF in the developing mouse telencephalon. Dev Biol 208, 166-188.
[187] Yi L, Zhou ZH, Ping YF, Chen JH, Yao XH, Feng H, Lu JY, Wang JM and Bian XW (2007). Isolation and characterization of stem cell-like precursor cells from primary human anaplastic oligoastrocytoma. Mod Pathol 20, 1061-1068.
[188] Zheng X, Shen G, Yang X and Liu W (2007). Most C6 cells are cancer stem cells: evidence from clonal and population analyses. Cancer Res 67, 3691-3697.
[189] Joo KM, Kim SY, Jin X, Song SY, Kong DS, Lee JI, Jeon JW, Kim MH, Kang BG, Jung Y et al. (2008). Clinical and biological implications of CD133-positive and CD133-negative cells in glioblastomas. Lab Invest 88, 808-815.
[190] Stiles CD and Rowitch DH (2008). Glioma stem cells: a midterm exam. Neuron 58, 832-846.
[191] Pfenninger CV, Roschupkina T, Hertwig F, Kottwitz D, Englund E, Bengzon J, Jacobsen SE and Nuber UA (2007). CD133 is not present on neurogenic astrocytes in the adult subventricular zone, but on embryonic neural stem cells, ependymal cells, and glioblastoma cells. Cancer Res 67, 5727-5736.
[192] Platet N, Liu SY, Atifi ME, Oliver L, Vallette FM, Berger F and Wion D (2007). Influence of oxygen tension on CD133 phenotype in human glioma cell cultures. Cancer Lett 258, 286-290.
[193] Zeppernick F, Ahmadi R, Campos B, Dictus C, Helmke BM, Becker N, Lichter P, Unterberg A, Radlwimmer B and Herold-Mende CC (2008). Stem cell marker CD133 affects clinical outcome in glioma patients. Clin Cancer Res 14, 123-129.
[194] Pouyssegur J, Dayan F and Mazure NM (2006). Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 441, 437-443.
[195] Kaelin WG, Jr. and Ratcliffe PJ (2008). Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell 30, 393-402.
[196] Mendez O, Zavadil J, Esencay M, Lukyanov Y, Santovasi D, Wang SC, Newcomb EW and Zagzag D (2010). Knock down of HIF-1alpha in glioma cells reduces migration in vitro and invasion in vivo and impairs their ability to form tumor spheres. Mol Cancer 9, 133.
[197] Krig SR, Miller JK, Frietze S, Beckett LA, Neve RM, Farnham PJ, Yaswen PI and Sweeney CA (2010). ZNF217, a candidate breast cancer oncogene amplified at 20q13, regulates expression of the ErbB3 receptor tyrosine kinase in breast cancer cells. Oncogene 29, 5500-5510.
[198] Sun G, Zhou J, Yin A, Ding Y and Zhong M (2008). Silencing of ZNF217 gene influences the biological behavior of a human ovarian cancer cell line. Int J Oncol 32, 1065-1071.
[199] Quinlan KG, Verger A, Yaswen P and Crossley M (2007). Amplification of zinc finger gene 217 (ZNF217) and cancer: when good fingers go bad. Biochim Biophys Acta 1775,333-340.
[200] Li P, Maines-Bandiera S, Kuo WL, Guan Y, Sun Y, Hills M, Huang G, Collins CC, Leung PC, Gray JW et al. (2007). Multiple roles of the candidate oncogene ZNF217 in ovarian epithelial neoplastic progression. Int J Cancer 120, 1863-1873.
[201] Nonet GH, Stampfer MR, Chin K, Gray JW, Collins CC and Yaswen P (2001). The ZNF217 gene amplified in breast cancers promotes immortalization of human mammary epithelial cells. Cancer Res 61, 1250-1254.
[202] Collins C, Rommens JM, Kowbel D, Godfrey T, Tanner M, Hwang SI, Polikoff D, Nonet G, Cochran J, Myambo K et al. (1998). Positional cloning of ZNF217 and NABC1: genes amplified at 20q13.2 and overexpressed in breast carcinoma. Proc Natl Acad Sci U S A 95, 8703-8708.
[203] Krig SR, Jin VX, Bieda MC, O'Geen H, Yaswen P, Green R and Farnham PJ (2007). Identification of genes directly regulated by the oncogene ZNF217 using chromatin immunoprecipitation (ChIP)-chip assays. J Biol Chem 282, 9703-9712.
[204] Cowger JJ, Zhao Q, Isovic M and Torchia J (2007). Biochemical characterization of the zinc-finger protein 217 transcriptional repressor complex: identification of a ZNF217 consensus recognition sequence. Oncogene 26, 3378-3386.
[205] Mao XG, Guo G, Wang P, Zhang X, Xue XY, Zhang W, Fei Z, Jiang XF and Yan M (2010). Maintenance of critical properties of brain tumor stem like cells after cryopreservation. Cell Mol Neurobiol 30, 775-786.
[206] Jordan CT (2009). Cancer stem cells: controversial or just misunderstood? Cell Stem Cell 4, 203-205.
[207] Lottaz C, Beier D, Meyer K, Kumar P, Hermann A, Schwarz J, Junker M, Oefner PJ, Bogdahn U, Wischhusen J et al. (2010). Transcriptional profiles of CD133+ and CD133- glioblastoma-derived cancer stem cell lines suggest different cells of origin. Cancer Res 70, 2030-2040.
[208] Piccirillo SG, Reynolds BA, Zanetti N, Lamorte G, Binda E, Broggi G, Brem H, Olivi A, Dimeco F and Vescovi AL (2006). Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 444, 761-765.
[209] Quinlan KG, Nardini M, Verger A, Francescato P, Yaswen P, Corda D, Bolognesi M and Crossley M (2006). Specific recognition of ZNF217 and other zinc finger proteins at a surface groove of C-terminal binding proteins. Mol Cell Biol 26, 8159-8172.
[210] Shi YJ, Matson C, Lan F, Iwase S, Baba T and Shi Y (2005). Regulation of LSD1 histone demethylase activity by its associated factors. Mol Cell 19, 857-864.
[211] Chinnadurai G (2007). Transcriptional regulation by C-terminal binding proteins. Int J Biochem Cell Biol 39, 1593-1607.
[212] Banck MS, Li S, Nishio H, Wang C, Beutler AS and Walsh MJ (2009). The ZNF217 oncogene is a candidate organizer of repressive histone modifiers. Epigenetics 4, 100-106.
[213] Huang G, Krig S, Kowbel D, Xu H, Hyun B, Volik S, Feuerstein B, Mills GB, Stokoe D,Yaswen P et al. (2005). ZNF217 suppresses cell death associated with chemotherapy and telomere dysfunction. Hum Mol Genet 14, 3219-3225.
[214] Wong DJ, Segal E and Chang HY (2008). Stemness, cancer and cancer stem cells. Cell Cycle 7, 3622-3624.
[215] Ben-Porath I, Thomson MW, Carey VJ, Ge R, Bell GW, Regev A and Weinberg RA (2008). An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet 40, 499-507.
[216] Park IH, Zhao R, West JA, Yabuuchi A, Huo H, Ince TA, Lerou PH, Lensch MW and Daley GQ (2008). Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451, 141-146.
[217] Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R et al. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917-1920.
[218] Takahashi K and Yamanaka S (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663-676.
[219] Kim J, Woo AJ, Chu J, Snow JW, Fujiwara Y, Kim CG, Cantor AB and Orkin SH (2010). A Myc network accounts for similarities between embryonic stem and cancer cell transcription programs. Cell 143, 313-324.
[220] Viswanathan SR, Powers JT, Einhorn W, Hoshida Y, Ng TL, Toffanin S, O'Sullivan M, Lu J, Phillips LA, Lockhart VL et al. (2009). Lin28 promotes transformation and is associated with advanced human malignancies. Nat Genet 41, 843-848.
[221] Peng S, Maihle NJ and Huang Y (2010). Pluripotency factors Lin28 and Oct4 identify a sub-population of stem cell-like cells in ovarian cancer. Oncogene,
[222] West JA, Viswanathan SR, Yabuuchi A, Cunniff K, Takeuchi A, Park IH, Sero JE, Zhu H, Perez-Atayde A, Frazier AL et al. (2009). A role for Lin28 in primordial germ-cell development and germ-cell malignancy. Nature 460, 909-913.
[223] Roush S and Slack FJ (2008). The let-7 family of microRNAs. Trends Cell Biol 18, 505-516.
[224] Viswanathan SR, Daley GQ and Gregory RI (2008). Selective blockade of microRNA processing by Lin28. Science 320, 97-100.
[225] Viswanathan SR and Daley GQ (2010). Lin28: A microRNA regulator with a macro role. Cell 140, 445-449.
[226] Miller FD and Gauthier AS (2007). Timing is everything: making neurons versus glia in the developing cortex. Neuron 54, 357-369.
[227] Okano H and Temple S (2009). Cell types to order: temporal specification of CNS stem cells. Curr Opin Neurobiol 19, 112-119.
[228] Namihira M, Kohyama J, Semi K, Sanosaka T, Deneen B, Taga T and Nakashima K (2009). Committed neuronal precursors confer astrocytic potential on residual neural precursor cells. Dev Cell 16, 245-255.
[229] Balzer E, Heine C, Jiang Q, Lee VM and Moss EG (2010). LIN28 alters cell fatesuccession and acts independently of the let-7 microRNA during neurogliogenesis in vitro. Development 137, 891-900.
[230] Nishino J, Kim I, Chada K and Morrison SJ (2008). Hmga2 promotes neural stem cell self-renewal in young but not old mice by reducing p16Ink4a and p19Arf Expression. Cell 135, 227-239.
[231] Braig M and Schmitt CA (2006). Oncogene-induced senescence: putting the brakes on tumor development. Cancer Res 66, 2881-2884.
[232] Baker SJ, Markowitz S, Fearon ER, Willson JK and Vogelstein B (1990). Suppression of human colorectal carcinoma cell growth by wild-type p53. Science 249, 912-915.
[233] Khosravi-Far R, White MA, Westwick JK, Solski PA, Chrzanowska-Wodnicka M, Van Aelst L, Wigler MH and Der CJ (1996). Oncogenic Ras activation of Raf/mitogen-activated protein kinase-independent pathways is sufficient to cause tumorigenic transformation. Mol Cell Biol 16, 3923-3933.
[234] Salmon P, Oberholzer J, Occhiodoro T, Morel P, Lou J and Trono D (2000). Reversible immortalization of human primary cells by lentivector-mediated transfer of specific genes. Mol Ther 2, 404-414.
[235] Sarbassov DD, Guertin DA, Ali SM and Sabatini DM (2005). Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307, 1098-1101.
[236] Moffat J, Grueneberg DA, Yang X, Kim SY, Kloepfer AM, Hinkle G, Piqani B, Eisenhaure TM, Luo B, Grenier JK et al. (2006). A lentiviral RNAi library for human and mouse genes applied to an arrayed viral high-content screen. Cell 124, 1283-1298.
[237] Raabe EH, Laudenslager M, Winter C, Wasserman N, Cole K, LaQuaglia M, Maris DJ, Mosse YP and Maris JM (2008). Prevalence and functional consequence of PHOX2B mutations in neuroblastoma. Oncogene 27, 469-476.
[238] Zheng K, Wu X, Kaestner KH and Wang PJ (2009). The pluripotency factor LIN28 marks undifferentiated spermatogonia in mouse. BMC Dev Biol 9, 38.
[239] Lee ST, Chu K, Oh HJ, Im WS, Lim JY, Kim SK, Park CK, Jung KH, Lee SK, Kim M et al. (2011). Let-7 microRNA inhibits the proliferation of human glioblastoma cells. J Neurooncol 102, 19-24.
[240] Wu J, Liu Z, Shao C, Gong Y, Hernando E, Lee P, Narita M, Muller W, Liu J and Wei JJ (2011). HMGA2 overexpression-induced ovarian surface epithelial transformation is mediated through regulation of EMT genes. Cancer Res 71, 349-359.
[241] Watanabe S, Ueda Y, Akaboshi S, Hino Y, Sekita Y and Nakao M (2009). HMGA2 maintains oncogenic RAS-induced epithelial-mesenchymal transition in human pancreatic cancer cells. Am J Pathol 174, 854-868.
[242] Jin J, Jing W, Lei XX, Feng C, Peng S, Boris-Lawrie K and Huang Y (2011). Evidence that Lin28 stimulates translation by recruiting RNA helicase A to polysomes. Nucleic Acids Res,
[243] Peng S, Chen LL, Lei XX, Yang L, Lin H, Carmichael GG and Huang Y (2011). Genome-wide Studies Reveal that Lin28 Enhances the Translation of Genes Importantfor Growth and Survival of Human Embryonic Stem Cells. Stem Cells,
[244] Qiu C, Ma Y, Wang J, Peng S and Huang Y (2010). Lin28-mediated post-transcriptional regulation of Oct4 expression in human embryonic stem cells. Nucleic Acids Res 38, 1240-1248.
[245] Polesskaya A, Cuvellier S, Naguibneva I, Duquet A, Moss EG and Harel-Bellan A (2007). Lin-28 binds IGF-2 mRNA and participates in skeletal myogenesis by increasing translation efficiency. Genes Dev 21, 1125-1138.
[246] Beck S, Jin X, Sohn YW, Kim JK, Kim SH, Yin J, Pian X, Kim SC, Nam DH, Choi YJ et al. (2010). Telomerase activity-independent function of TERT allows glioma cells to attain cancer stem cell characteristics by inducing EGFR expression. Mol Cells,
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |