修回日期: 2015-11-02
接受日期: 2015-11-09
在线出版日期: 2015-12-18
全球范围内结肠癌肿瘤发病位列第3位. 随着分子生物学研究不断进步, 人们发现肿瘤细胞中存在着一小部分特殊的细胞亚群, 即肿瘤干细胞. 肿瘤干细胞通过不断自我更新和分化使肿瘤具有持续生长、远处转移和复发的能力. 研究表明, 传统的放化疗无法彻底消除肿瘤干细胞, 通过特异性细胞表面标志精确地将肿瘤干细胞从大量肿瘤细胞和正常健康细胞中分离, 为精确靶向治疗提供了基础. 充分认识和利用结肠癌干细胞的自我更新和分化机制, 应用分子生物技术阻断其稳态调控, 将成为靶向治疗结肠癌的新契机.
核心提示: 充分了解和认识结肠癌干细胞表面标志物、特性及致病机制, 深入研究结肠癌干细胞生物学特性, 形成有效摧毁肿瘤干细胞的治疗方法, 是临床提高结肠癌治疗的迫切需要.
引文著录: 高莹, 安啸海, 杨晓玲, 杨柏霖. 结肠癌干细胞表面标志物、特性及致病机制的研究概况. 世界华人消化杂志 2015; 23(35): 5662-5669
Revised: November 2, 2015
Accepted: November 9, 2015
Published online: December 18, 2015
Colorectal cancer (CRC) is the third leading cause of cancer death worldwide. With the development of molecular biology, it is found that there is a small group of special cells, named cancer stem cells (CSCs), in tumor cells. CSCs are capable of continuous self-renewal and differentiation and are closely related to tumor growth, distant metastasis and recurrence. Specific recognition of CSCs from the tumor mass and normal healthy cells could be achieved by targeting specific cell surface markers, thus providing a foundation for CSC targeted therapies. CSCs are also responsible for tumor relapse, because conventional drugs fail to eliminate the CSC reservoir. Therefore, the design of CSC-targeted interventions is a rational strategy, which will enhance responsiveness to traditional therapeutic strategies and reduce local recurrence and metastasis. Understanding the mechanism of self-renewal and differentiation of CSCs and blocking their homeostasis will provide a new opportunity for the targeted treatment of colon cancer.
- Citation: Gao Y, An XH, Yang XL, Yang BL. Colon cancer stem cells: Markers, characteristics and pathogenic roles. Shijie Huaren Xiaohua Zazhi 2015; 23(35): 5662-5669
- URL: https://www.wjgnet.com/1009-3079/full/v23/i35/5662.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v23.i35.5662
结直肠癌居全球癌症死亡率的第3位, 尽管近来诊断及治疗水平有所提高, 但其五年生存率仍仅为65%[1]. 肿瘤复发和转移是影响结直肠肿瘤的两个重要生存因素. 肿瘤是由多种不同等级细胞组成的类器官样组织, 其中存在一部分被称为"肿瘤干细胞"的细胞亚群. 他们拥有致瘤潜能, 同时具有自我更新和分化的特性, 对传统抗肿瘤治疗具有更强的耐受性. 肿瘤干细胞理论的提出为进一步治疗结肠癌开拓了新方向.
1994年, Lapidot等[2]应用特异性细胞表面标志, 第一次成功分离出了人急性粒细胞白血病干细胞, 从而证明了肿瘤干细胞的存在. 2007年, Ricci-Vitiani等[3]和O'Brien等[4]同时报道发现了CD133+表型的结肠癌干细胞亚群, 并将其种植到NOD/SCID小鼠后成功鉴定了CD133+干细胞亚群的致瘤能力, 从而开启了结肠癌干细胞研究的序幕. 截至目前, 人们已经发现了许多结肠癌干细胞表面标志物, 如CD133、CD44、CD166、富含亮氨酸重复单位的G蛋白偶联受体5(leucine-rich repeat containing G protein-coupled receptor 5, Lgr5)和乙酸脱氢酶(aldehyde dehydrogenase, ALDH)等, 根据这些表面标志物可以把结肠癌干细胞分成不同的亚组, 但就哪种标志物最能标记结肠癌干细胞目前仍没有定论.
CD133+亚群在许多实体瘤的癌细胞中都存在, 其中包括眼癌[5,6]、畸胎瘤[6]、脑癌[7,8]、肾癌[9]、前列腺肿瘤[10]、肝癌[11]和结肠癌[3,4]. CD133是最早发现的结肠癌干细胞表面标志物. 2007年, O'Brien等[4]应用流式细胞术分选原发性结肠癌和转移性结肠癌的肿瘤细胞, 结果发现在肿瘤细胞中CD133+细胞占3.2%-24.5%, 而正常组织中CD133+细胞仅占0.4%-2.1%. 体外悬浮球实验结果显示CD133+肿瘤球中包含了CD133+和CD133-的亚细胞组, 但仅有CD133+具有致瘤性. 其后, 人们开始运用CD133作为鉴定和分选结肠癌干细胞的标志. 但随着研究深入, 人们发现CD133作为结肠癌干细胞的标志有其局限和不足. Shmelkov等[12]证明, 在转移性结肠癌中CD133+和CD133-两组细胞皆可以使NOD/SCID小鼠成瘤, 且CD133阴性的肿瘤细胞更具有侵袭性, 形成肿瘤速度更快. 由此说明, 转移性结肠癌细胞无论是否表达CD133都具有成瘤能力. 因此, 对于CD133而言, 其作为结肠癌干细胞表面标志尚有争议.
CD44同样是多点结构层次和多功能的细胞表面黏附分子, 通过β-蛋白和Wnt信号通路激活CD44基因转录, 进而参与细胞与细胞、细胞与基质间的联系, 促进干细胞分化和肿瘤的进展[13,14]. Dalerba等[15]应用流式细胞技术以上皮细胞黏附分子(epithelial cell adhesion molecule, EpCAM)和CD44作为标志物从结肠癌组织中分离出CD44+/EpCAMHIGH和CD44-/EpCAMLOW两组细胞, 分别注射到NOD/SCID小鼠皮下, 发现仅200-500个CD44+/EpCAMHIGH肿瘤细胞即可长出与原代肿瘤具有相同的表型、异质性和形态学特征的肿瘤, 而104个CD44-/EpCAMLOW细胞仍无法形成肿瘤. 同时, 有研究[16]表明, 在大鼠移植结肠癌肿瘤模型中, 仅极低的CD44, 而非CD133, 即可表现出极强的抑制肿瘤增殖和致癌性作用. 因此认为CD44是一个更易筛选的肿瘤干细胞特异性标志物.
近来, Lgr5+被认为是结肠癌干细胞的特异性标记[17-21]. Lgr5是Wnt途径的一个转录因子, 是第一个被定义为正常肠道干细胞的标志物[22]. Lgr5是在筛检T细胞因子4(T-cell factor 4, TCF4)下游蛋白过程中被发现的. 有报道显示Lgr5+细胞通过删除腺瘤样息肉蛋白(adenomatous polyposis coli, APC)形成腺瘤, 同时Lgr5也在结肠癌细胞轴中表达[17]. Lgr5+细胞具有强烈的Wnt信号通路活动性, 因此被认为功能上等同结肠癌干细胞. 但尚需进一步的研究来明确Lgr5作为特殊的干细胞标志物能否反映结肠癌干细胞的异质性.
肿瘤干细胞具有无限自我更新和分化成肿瘤细胞并最终形成肿瘤的能力. 了解结肠癌干细胞特性有助于了解其致癌机制, 并为进一步治疗提供新的方向.
干细胞具有形成一个完全相同的新干细胞能力, 新生的干细胞具有完全相同的增殖、扩散及分化能力, 并维持干细胞池. 自我更新机制使肿瘤干细胞始终维持原始致癌途径, 经典的信号通路包括Wnt/β蛋白和Notch信号通路等. 另有一个在胚胎形成时就存在的自我更新调节机制即Hh(sonic hedgehog)信号通路, 但目前对于这种信号通路在成熟干细胞和肿瘤干细胞中的作用知之甚少[30]. 2007年Li等[31]首次报道了在胰腺癌的异种移植模型中肿瘤干细胞的Hh信号通路优先表达, 有证据显示Hh信号通路在实体肿瘤中异常活跃, 包括结肠癌[32]. 最后, 肝细胞生长因子(hepatocyte growth factor, HGF)被认为可以维持结肠癌干细胞处于干细胞状态, 阻碍分化[33].
干细胞具有发育成为各种形态及功能细胞的能力, 依照分级程序逐步多样化、专业化, 不断地将组织中短暂的、成熟的要素细胞填满[34]. 近来有报道将结肠癌作为独立的肿瘤, 因为对比其他分化较高的肿瘤, 结肠癌在组织病理学中是相对未分化的, 包含了更高的肿瘤干细胞比例, 这就意味着更差的临床预后[35,36].
研究证明存在于肠隐窝中的肠上皮分化细胞分别是富含亮氨酸重复序列的Lgr5和B细胞淋巴瘤Mo-MLV插入同源区1(B lymphoma Mo-MLV insertion region 1 homolog, Bmi-1)两种类型的干细胞, 他们具有维持组织稳态环境下的再生能力[37]. Lgr5表达的细胞是更活跃干细胞类型, 维持组织稳态环境下的再生能力更强. 此外, Lgr5表达的细胞增殖活跃, 他对Rspol调节下的Wnt激活和Dkk1调节下的Wnt抑制高度敏感. 相反, Bmi-1表达的细胞通常是不活跃的, 较少受环境压力的影响(即对Wnt调控不敏感), 只有在特殊的时机下, 他们通过无性繁殖子细胞重新注入多个相邻的隐窝绒毛轴, 维持肠再生过程[38]. 与其他肿瘤干细胞相似, Wnt 蛋白和Notch信号通路对于维持结肠癌干细胞的稳态调控非常重要, 具有维持肿瘤干细胞显型的作用[39].
肿瘤干细胞的更新、分化提示了其对肿瘤形成的作用. 肿瘤干细胞的耐药性则提示其对肿瘤侵袭和转移的影响. 目前研究[40]发现, ATP-blinding cassette家族在人类中至少存在7个家族(从A到G)49个基因群, 这些基因所表达的蛋白具有各种各样的功能, 其中至少有16种与肿瘤耐药相关. 许多研究已证实ABC转运蛋白对肿瘤干细胞有抵抗作用. 他们结合三磷酸腺苷(adenosine triphosphate, ATP), 借助其能量来驱动跨膜运输的各种分子, 使抗癌药物从细胞排出, 从而形成机体对化疗药物的耐药性[41]. 在结肠癌干细胞研究中, Cisternino等[42]证实姜黄素通过下调乳腺癌耐药蛋白(breast cancer resistance protein, BCRP或ABCG2)的敏感性增加CD44+CD166+结肠癌干细胞对5氟尿嘧啶和奥沙利铂的耐药性. Chen等[43]经实验发现BEZ235通过阻碍P13K/Akt/mTOR信号通路, 减少结肠癌干细胞的增殖, 同时能够抑制CD133和Lgr5表达减少细胞干性. 由此认为P13K/Akt/mTOR信号通路与维持结肠癌干细胞干性及耐药性相关.
结肠癌起源于胃肠道上皮细胞, 其特定的基因序列中发生突变, 从而破坏正常的增殖和自我更新机制[44]. 目前许多机制研究都围绕结肠癌干细胞自身基因突变及其微环境变化展开.
通过研究具有遗传特性的结肠癌, 如家族性腺瘤样息肉病(familial adenomatous polyposis, FAP)、幼年性息肉样综合征(juvenile polyposis syndrome, JPS)以及遗传性非息肉病性结肠癌(hereditary nonpolyposis colorectal cancer, HNPCC), 可以帮助理解基因突变导致"腺瘤-癌"序列的结直肠癌发展过程[45]. Fearon等[45]首先提出通过一系列可识别的形态变化可发现结肠癌的发展: 局部扩散的结肠上皮细胞形成小腺瘤, 并逐步不典型增生, 最终进展为浸润性癌. 大多数结肠癌以Wnt/β-连环蛋白(β-catenin)通路失调为特征[46]. 大约80%的FAP患者存在参与调节β-连环蛋白稳定性的腺瘤样息肉蛋白(adenomatous polyposis coli, APC)基因编码的缺失或突变. 由于Wnt配体的缺乏, β-catenin易被蛋白酶体磷酸化和降解. 当APC发生突变, 胞浆内的β-catenin水平达到稳定后, 蛋白开始在核内聚集, 作为Tcf家族转录因子的激活因子使得特定的目标基因过表达, 包括一些金属蛋白酶、黏连蛋白和原癌基因c-myc和D1[47]. 在这过程中, 少数未分化的肿瘤干细胞通过分泌可溶性因子调控细胞增生, 维护和传播肿瘤独特的生物学特性[48].
结肠癌的发生发展与微环境的复杂变化密切相关[49,50]. 肿瘤微环境被认为是肿瘤发生、发展的温床, 他包括很多成分, 如基质细胞、稳定基质的细胞因子, 以及各种类型的免疫细胞, 与肿瘤的侵袭和转移密切相关[51]. 炎症反应和肿瘤进程中微环境的协同作用被认为是癌症发生的重要特征[50]. 来源于肠隐窝的结肠癌干细胞团表现出同生理性干细胞相似的特性, 对肿瘤的进程有很大的影响[52,53]. 研究[51,54]认为肿瘤干细胞是一种特别的细胞类型, 通过维持微环境的稳定, 进一步增加肿瘤转移和侵袭的能力. 结肠癌干细胞可以直接或间接地与肿瘤微环境中的某些免疫细胞相互作用, 进而显著影响肿瘤进程. Buhrmann等[55]实验证明结肠癌肿瘤干细胞同单层肿瘤微环境共培养可以增强肿瘤细胞和纤维原细胞交联, 导致转移性活性黏附分子(β1-integrin, ICAM-1)、转化生长因子信号分子(TGF-β3, p-Smad2)、增殖相关蛋白(cyclin D1, Ki-67)和上皮间质转化因子(Vimentin)表达增高, 这些分子都与肿瘤侵袭和转移密切相关. Vermeulen等[56]通过实验发现微环境中的成纤维细胞因子、肝细胞生长因子可以激活β-catenin的转录, 进而形成结肠癌干细胞集合, 成纤维细胞因子将已分化的肿瘤细胞恢复为肿瘤干细胞, 进一步证实微环境可以影响结肠癌细胞干性特征.
肿瘤干细胞处于相对静止状态, 使他们容易逃避针对活跃循环细胞的传统化疗方案; 同时, 多药耐药家族基因在肿瘤干细胞内高表达, 使他们能更高效地代谢化疗药物和/或具有先天性多药耐药能力. 尽管化疗能够导致大部分肿瘤细胞死亡, 缩小肿瘤体积, 但由于肿瘤干细胞未能消除, 残余肿瘤中的肿瘤干细胞富集, 从而保留了肿瘤迅速再生的能力, 复发或转移不可避免. 研究证实奥沙利铂能够缩小结肠癌异种移植瘤体积, 但增加CD133+的百分比[59]. 应用吉西他滨治疗胰腺癌时也证实了上述结果[60,61]. 随着肿瘤干细胞分离鉴定技术的成熟, 针对肿瘤干细胞耐药的特性, 开发靶向消灭肿瘤干细胞的药物, 从根本上清除恶性肿瘤已成为肿瘤治疗的新思路[62]. 利用小分子物质阻止Wnt通路、γ-分泌酶抑制Notch通路目前被认为可能是治疗结肠癌的新方法. 通过抗IL-4抗体或IL-4感受器α拮抗剂抑制结直肠肿瘤IL-4信号通路传递, 下调抗凋亡蛋白, 如cFLIP、Bcl-xL和PED从而抑制肿瘤干细胞, 进而达到化学治疗的目的[59]. Todaro等[63]发现, 唑来膦酸酯可以激活引起γδT细胞对结肠癌干细胞应答, 进而增加机体抗癌活动. 随着研究的不断深入, 靶向抑制结肠癌干细胞的药物不断涌现, 针对性抑制结肠癌干细胞的治疗方案或将成为治疗主流.
深入了解结肠癌干细胞生物学特性、形成有效摧毁肿瘤干细胞的治疗策略, 是临床提高结肠癌治疗的迫切需要. 临床前的体外结肠癌干细胞靶向治疗实验已经显示了很大的希望. 然而, 尽管通过特异性表面标记靶向治疗肿瘤干细胞是相对合理的途径, 但是在实际操作中仍有诸多阻碍, 寻求多靶向治疗策略, 如肿瘤干细胞特异性信号通路, 转录因子或肿瘤干细胞微环境相互作用可能是结肠癌治疗的发展方向.
从1994年Lapidot等发现人急性粒细胞白血病干细胞开始, 人类进入了肿瘤干细胞时代. 越来越多的研究证实, 结直肠癌中的肿瘤干细胞是肿瘤发生、发展、侵袭和转移的终极原因.
邓安梅, 教授, 主任医师, 第二军医大学长海医院实验诊断科
目前对结肠癌干细胞的研究主要集中在表面标志物和发病机制. 通过研究分离并纯化结肠癌干细胞表面标志物, 深入了解其诱导肿瘤耐药的机制, 探寻靶向杀灭肿瘤干细胞的手段是彻底治愈结肠癌的研究热点.
Ong等总结了目前为止有关结肠癌干细胞表面标志、信号通路、致瘤理论的研究情况, 同时对比了结肠癌干细胞与正常消化道干细胞不同之处, 为进一步细化研究提供理论基础; Chen等通过实验发现BEZ235通过阻碍P13K/Akt/mTOR信号通路, 减少结肠癌干细胞的增殖, 为药物作用结肠癌干细胞的信号通路研究开拓了新方向.
本文将目前结肠癌干细胞研究内容集中归纳, 从特异性标志物、干细胞特性及其相关的致病机制逐层深入, 系统阐述了目前结肠癌干细胞基础与临床研究内容.
本文总结概括了目前关于结肠癌干细胞的相关研究进展, 特别是其机制研究, 为基础和临床研究靶向治疗结肠癌提供了新思路.
结直肠干细胞的研究目前存在很多争议, 本文综述了结直肠癌干细胞研究的现状, 具有一定的基础和临床意义.
编辑:郭鹏 电编:都珍珍
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