Chinese Journal of Tissue Engineering Research ›› 2013, Vol. 17 ›› Issue (19): 3551-3557.doi: 10.3969/j.issn.2095-4344.2013.19.021
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Jiang Xue-mei1, Li Hua2
Received:
2012-09-12
Revised:
2012-10-01
Online:
2013-05-07
Published:
2013-05-07
About author:
Jiang Xue-mei★, Master, Lecturer, Medical College, China Three Gorges University, Yichang 443002, Hubei Province, China
jxm9981@sina.com
CLC Number:
Jiang Xue-mei, Li Hua. Extrinsic factors regulating apoptosis in cancer stem cells[J]. Chinese Journal of Tissue Engineering Research, 2013, 17(19): 3551-3557.
2.1 细胞微环境中的可溶性因子和凋亡 癌干细胞是指肿瘤组织中存在的极少量具有干细胞性质的癌细胞亚群,其具有多向分化潜能和无限增殖及自我更新能力。重要的是,癌干细胞群与其他细胞亚群通过启动试验动物肿瘤的生长能力被区分,即便是单个癌干细胞。相反,大量移植的非癌干细胞是不能建立肿瘤的,肿瘤细胞亚群表达确定的标志且在活体内启动肿瘤特性已经被归因于干细胞特性,包括播种成球形和有关干细胞基因的表达[1]。营养干细胞且在稳定的组织内使它们能执行生理功能的微环境构成干细胞的生态位(合适的位置)。 癌干细胞的特性具有可塑性且必须通过非癌干细胞群获得,从原发肿瘤播散的癌细胞依赖间质的微环境并且它们遇到的第二个位置的微环境决定它们的命运。干细胞需要生态位维持特性以及转移生态位的部件已显示在骨髓播散肿瘤细胞里诱导或保持与干细胞相关的特性[2],转移生态位也许会促进转移的建立。转移生态位血管周围环境能够启动和保持癌干细胞特性。定位于血管周围的位置使非癌干细胞亚群获得干细胞样特征。血管周围生态位诱导血管内皮生长因子A适应保持皮肤肿瘤的癌干细胞群,血管周围位置保持胶质瘤的癌干细胞且可能识别其他型别肿瘤的癌干细胞。生态位保护干细胞与环境损伤,分化诱导物和细胞凋亡刺激物分开[3]。尽管已经假设肿瘤干细胞可能比正常干细胞更少依赖生态位,生态位路径存在可能是因为肿瘤干细胞以相同的方式确定自我更新的特征,导致内在变异的聚集形成可变非依赖生态位的增殖性质的结果[4-5]。 相对有限的研究已经提出了癌干细胞生态位的存在,特别是白血病干细胞和脑肿瘤干细胞[6]。例如,正常干细胞和白血病干细胞微环境中的骨髓内皮细胞有显示归巢和移植物移入是必需的,并且发现细胞微环境因素促进引起化疗抵抗急性髓系白血病细胞的存活[7-8]。在脑肿瘤里面,CD133+肿瘤干细胞集中和固定在脉管内皮细胞上,小鼠模型脉管内皮细胞刺激肿瘤的形成,它已经作为证据证明脉管生态位存在于脑肿瘤干细胞里[9]。在结肠癌里观察到的β连环蛋白颠倒现象指挥不是全部具有抗原递呈细胞诱导的肿瘤细胞具有相同的信号途径活动[10],这种情况提出一个调控信号激活作用机制问题。由Vermulen等最近的研究表明Wnt信号活动标记结肠癌干细胞并且通过微环境调控。由肌纤维母细胞分泌肝细胞生长因子是针对信号激活的一个重要信号。此研究强调了一个重要的概念就是癌干细胞有可变通特性并且能被特殊的微环境调节[11]。脑肿瘤的研究表明血管周围生态位维持了脑肿瘤干细胞池,然而这个池的破坏协调了脑肿瘤细胞的自我更新的活性,导致随后的生长停滞[12]。 外源性因素如细胞因子、化学增活素和包括细胞黏附的信号通过生态位产生并且伴有发育调控信号分子如Hh,Wnt,Notch和骨形态发生蛋白,它们已经加入干细胞更新和分化的控制中。例如,研究发现Notch信号提高小鼠胚胎状态神经前体/干细胞的存活,Bcl-2和Mcl-1的增量调节介导神经前体/干细胞;抗细胞凋亡基因的RNA干扰沉默阻止了依赖性Notch的存活[13]。最近,通过γ分泌酶抑制剂Notch信号的靶向治疗显示减少GBSCs并阻止了体外提取的神经生长及在异种嫁接的小鼠里通过一种包含Akt存活信号的机制抑制提取神经的生长[14]。Notch信号和肿瘤细胞里的凋亡核心机构之间的更多直接联系也已经被报道了。增加BCL-2、bcl-xl、CIAP-2和cFLIP的表达引起化学和TRAIL抵抗,在Jurkat T淋巴样干细胞里Notch信号活化显示阻断线粒体以及死亡受体介导的凋亡。在恶性黑色素瘤细胞Notch信号的封闭导致前凋亡BCL-2成员NOXA的蓄积,在非依赖P53途径里NOXA刺激凋亡的活化[15]。 Wnt途径抑制凋亡信号并在不成熟的前B细胞株里Wnt信号的激活能阻断TRAIL诱导的凋亡 ,经由一个非完全阐明的机制这种凋亡至少部分包括TRAIL受体下调及ERK1/2和NF-kB信号[16]。在人类结肠癌细胞里,TRAIL抵抗与骨保护素依赖Wnt/B蛋白的表达有关,骨保护素-针对TRAIL可溶性的诱饵受体[17]。近来,抗凋亡BCL-2成员BCL-w被鉴定是与提供线粒体凋亡抑制有联系的Wnt路径的靶基因[18]。 其他的分泌因子也被牵涉到肿瘤干细胞的凋亡抵抗。通过CD133+克隆的肿瘤干细胞自分泌产生的白细胞介素4显示促成保护由化疗和TRAIL诱导的凋亡。使用白细胞介素4中和抗体致敏由CFLIP,PED 和BCL-XL下调引起的凋亡[19]。癌干细胞、非癌干细胞和微环境之间的动态相互作用最近也已经被阐明。乳腺癌研究通过特异的分泌因子揭示了癌干细胞和非癌干细胞之间的动态平衡的维持。癌干细胞分泌的白细胞介素6促进非癌干细胞向癌干细胞的转变。癌干细胞显示了自我更新能力,通过分化不断地产生一些非癌干细胞和通过在肿瘤内分泌白细胞介素6使一些非癌干细胞变回成癌干细胞[20]。 许多种刺激物能够激活NF-κB途径如细胞因子和压力信号,它们能控制许多细胞过程包括炎症、免疫反应,细胞生长和凋亡。存在于细胞微环境的生长因子及细胞因子和含氧量低的条件能够诱导NF-κB,接着NF-κB能引导它们当中的其他反凋亡靶基因转录子的激活。另外,在血液和实体肿瘤细胞里NF-κB经常被组成性激活,在NF-κB或I-κB基因里肿瘤细胞与基因突变有关。后者I-κB基因编码NF-κB特异性抑制剂[21]。在正常干细胞和肿瘤干细胞里NF-κB信号的作用特别是在血液系统里已经有相对少的研究。例如,在白血病干细胞里(AML CD34+),而不是正常的干细胞里(CD34+)NF-κB被发现是组成性激活并且促进存活。治疗蛋白体抑制剂 MG-123和倍半萜(烯)内酯银胶菊内酯在AML CD34+细胞里诱导凋亡,它们损害NF-κB信号。事实就是倍半萜(烯)内酯银胶菊内酯损坏了AML CD34+细胞的潜在的移植物,而不是正常的CD34+细胞,这表明不仅白血病的子代后裔而且白血病干细胞也许能被有效的定向使用这种方法[22]。近来一种新的氨基银胶菊内酯(DMPAT(LC1))通过它在NF-κB的抑制效应上被鉴定为一种新的抗白血病试剂[23]。在白血病干细胞里NF-κB的下游区关键目标介导抗凋亡信号仍需被确定。 2.2 以黏附为基础的凋亡调控 细胞微环境支持干细胞及肿瘤生长。近来,在癌干细胞的调控上通过微环境几个研究已经提供了显著的证据。已经有线索显示癌干细胞性质被特殊的周围微环境影响和诱导[24-25]。除可溶性因子外微环境在肿瘤细胞里和/或正常细胞之间也还有直接的交互作用,而且/或已知细胞外部分/基质促成癌症凋亡抵抗并且也许会妨碍治疗的有效性。 在肿瘤细胞里与黏附介导有关的凋亡抵抗路径显示经常集中在MAPK/ERK和PI3K/Akt路径的激活[26]。MAPK/ERK途径能直接调控凋亡的结构,例如通过磷酸化途径和前凋亡BCL-2家族成员BIM的降解。ERK也影响BCL-2、BCL-XL和MCL-1的表达,BCL-2、BCL-XL和MCL-1在ERK的抑制上引起它们的下调[27]。PI3K/Akt信号能够通过前凋亡BAD和caspase-9的依赖磷酸化抑制,或者间接通过抑制BIM、PUMA和NOXA的转录刺激存活。细胞外基质的结构改变以及其给肿瘤细胞提供酶底物和转移生态位的细胞部件,细胞外基质改造的增加基质的稳定性的重要结果能深深影响肿瘤细胞的性质。转移生态位的形成与新的细胞外基质成分的沉积及细胞外基质组分的重塑有关,例如纤维连接蛋白、黏蛋白、骨膜蛋白以及多功能蛋白被牵涉到转移生态位的形成。研究报道成纤维细胞和成纤维样细胞产生的纤维样结合蛋白的蓄积决定在哪个部位形成转移生态位,原发肿瘤里至少发现一些沉积的纤维连接蛋白,这些纤维蛋白的沉积导致细胞外基质的改造,正如骨膜蛋白作为桥梁与黏蛋白结合同纤维连接蛋白结合Ⅰ型胶原一样[28]。相反细胞外基质蛋白fibulin-5水平的减少是肝和肺转移形成必需的,这可能是因为fibulin-5抑制基质金属蛋白酶9的表达,基质金属蛋白酶9是在转移生态位形成和促进转移生长期间改变细胞外基质的蛋白酶[29]。在另一项研究中,在成胶质细胞瘤细胞株中,细胞外基质-细胞和细胞-细胞间的相互作用抑制必需被要求致敏其中其他的TRAIL和CD95/FASL-诱导的凋亡[30]。在CD133+GBSCs细胞中,包括任何来自患者的标本,RNA介导的干扰下调神经细胞粘连分子L1CAM阻止了核包含体的形成并且诱导凋亡,在异种嫁接的小鼠模型里与减少肿瘤的形成有关。然而潜在的凋亡激活机制没有被进一步研究[31]。针对造血干细胞依赖黏附的凋亡抑制已经被报道过,由血管细胞黏附分子1引起的白血病和脉管细胞的相互作用的破裂被发现诱导线粒体的凋亡[32]。有趣的是,使用AMD3456抑制CXCR4而靶向非白血性白血病的微环境已经显示出增强了针对FLT3抑制剂——氯化钙脲的敏感性,表明在白血病干细胞和骨髓生态位之间SDF1a/CXCR4的相互作用能够促成诱导治疗的凋亡[33]。 2.3 缺氧 最近的研究显示缺氧是一个影响生态位生物学的重要因素。缺氧生态位维持变化的正常干细胞的相同状态[34]。缺氧在原发肿瘤里诱导启动和调节形成转移生态位起很重要的作用。缺氧已经被报道保持癌干细胞的干细胞样特性。转移生态位内的缺氧对促进转移功能也许起一个很重要的作用,缺氧促进炎症环境的形成[35]。转移生态位的缺氧已经表明支持转移生长并通过营养启动转移的癌干细胞群。伴有干细胞生态位的低氧水平(缺氧)在调控分化及正常细胞和癌干细胞的死亡方面也已被鉴定为是一个重要因素;并且在癌症治疗抵抗的方面已经被公认为是一个的主要原因[6,36]。低氧诱导的转录因子家族,最著名的HIF-1α,在细胞适应缺氧方面通过调整过程(如血管的发生、能量代谢和细胞的存活)的范围起了一个关键作用[37]。LOX和LOX样蛋白(LOXL)在生态位的形成期间归因于交联胶原和弹力蛋白的能力并通过HIF-1α的缺氧反应被正调节。原发肿瘤局限在纤维连接蛋白的沉积LOX会产生缺氧有关的反应[38]。与干细胞转录因子有关的一个特殊的路径就是通过缺氧被激活的[39]。氧的利用率在通过可诱导的缺氧因子HIF-1α介导的Wnt/β连环蛋白信号调节胚胎干细胞和成人神经干细胞上有直接的作用,HIF-1α增强β连环蛋白激活作用以及下游区效应器LEF-1和TCF-1的表达[40]。结直肠细胞株衍生的癌干细胞保持了它们干细胞样表型和阻止了肠上皮细胞和杯状细胞在缺氧条件下的分化,并且这个效应被HIF-1α介导[41]。神经胶质瘤里,癌干细胞群保持了未分化表型,显示了在缺氧条件下的自我更新和增殖。针对缺氧癌干细胞的反应包括对应增强CD133+细胞自我更新效能的HIF-1的激活作用,缺氧也诱导了胶质瘤里非干细胞样表型转移成干细胞样表型[42]。 在癌干细胞凋亡的激活方面缺氧的直接效应迄今仍然还没有广泛的研究。在培养的肿瘤细胞模型里癌干细胞里缺氧诱导的凋亡抵抗也许包含了HIF-1α靶向基因的增量调节,靶向基因能调节内在的细胞凋亡途径,包括抗细胞凋亡MCL-1和BCL-XL[43-44]。低氧水平能导致减少细胞内活性氧种类的产生率,自由基清道夫系统也能平衡活性氧种类。造血干细胞,神经干细胞以及最近还有乳房上皮的正常的和恶性的干细胞已经显示比他们更成熟的后代包含更低水平的活性氧[45]。活性氧在癌症中有双重的作用;一个方面它们有致癌效应、这个致癌效应与氧化DNA损害活性有关,另一方面活性氧能调节包括凋亡激活的各种信号级联放大——凋亡激活也许有肿瘤抑制效应。例如,CD95/FASL死亡受体激活被显示来刺激导致增加活性氧水平的NADPH氧化酶并且随后增强caspase-8的活化以及凋亡[46]。被提高水平的活性氧也已经显示通过TRAIL-R2的上调,cFLIP和BCL-2的下调来增强TRAIL诱导的凋亡[47-48]。因此癌干细胞里的低水平活性氧也许对激活凋亡有抑制影响。"
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