Chinese Journal of Tissue Engineering Research ›› 2016, Vol. 20 ›› Issue (41): 6225-6232.doi: 10.3969/j.issn.2095-4344.2016.41.022
Du Hua, Shi Ying-xu
Revised:
2016-08-10
Online:
2016-10-07
Published:
2016-10-07
Contact:
Shi Ying-xu, M.D., Assistant researcher, Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, Inner Mongolia Autonomous Region, China
About author:
Du Hua, Master, Lecturer, Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, Inner Mongolia Autonomous Region, China
Supported by:
Chunhui Plan of the Ministry of Education in China, No. jyb13ch06
CLC Number:
Du Hua, Shi Ying-xu. Recent advances in surface markers of gastric cancer stem cells[J]. Chinese Journal of Tissue Engineering Research, 2016, 20(41): 6225-6232.
2.1 传统的胃癌干细胞表面标志物 最初在研究乳腺癌时,Cluster of differentiation 44(CD44)第一个被发现并证实是实体瘤干细胞表面标志分子[6]。随后证实脑癌、胰腺癌、黑色素瘤、结肠癌、肝癌等实体瘤中的肿瘤干细胞都有CD44表达[17-22]。CD44是Ⅰ类跨膜糖蛋白,作为细胞膜受体参与细胞的多种生物进程,如存活、增殖、分化[23-25]。例如,CD44可以作为透明质酸的受体将信号传导入胞内激活下游信号通路Wnt/β-catenin。CD44是一种独特的黏附分子,介导肿瘤细胞的迁移并黏附于细胞微环境中的基质上,从而强化肿瘤细胞的侵袭能力,促进肿瘤的增殖。干扰实验显示抑制CD44的表达,可显著降低肿瘤细胞形成克隆以及形成肿瘤的能力[26]。胃腺癌高表达CD44,Takaishi等[27]通过研究多个人胃癌细胞系(NCI-N87,AGS,MKN-28,MKN-45,MKN-74),发现CD44在胃癌细胞中表达,并将其作为胃癌干细胞的表面标记物。进一步分离并经无血清与非贴壁培养这些胃癌细胞系中的CD44+细胞,可以得到肿瘤干细胞球,移植免疫缺陷小鼠的胃与皮下后可形成肿瘤。Zhang等[28]从5例胃癌患者的癌组织中分离出CD44+、CD24+细胞,通过比较不同表型肿瘤细胞的自我更新、分化、成瘤性等发现CD44+/CD24+能够做为胃癌干细胞的标记物。但最近Chen等[29]从人胃癌组织中分离出癌细胞,通过给小鼠移植3倍数量CD44+CD45+细胞的CD44-CD54+或CD44+CD54-细胞也具有在体内外形成肿瘤的能力,提示CD44+/-细胞或CD54+/-细胞可能并不是标记胃癌干细胞所必须的,但有必要指出的是CD44+CD54+细胞中的确含有胃癌干细胞[30]。因此,虽然众多肿瘤细胞表达CD44,但胃癌干细胞是否可用CD44来富集,仍需要进一步的探讨研究。 CD133/Prominin 1(Prom1)也是一类跨膜糖蛋白,CD133在鼠中的同源基因是Prominin 1。CD133+常用于标记和分离大肠肿瘤干细胞、肝肿瘤干细胞、前列腺肿瘤干细胞、脑肿瘤干细胞等。在人胃癌样本中约一半标本的癌细胞表达CD133阳性,并且与肿瘤的发展密切相关[30-31]。在人胃癌细胞中CD133并不与Lgr5共表达[32],CD133高表达会降低患者的生存期[33]。利用胃癌细胞系研究发现并不是所有的胃上皮细胞系都表达CD133,可能是由于分化程度不同的原因,分化实验显示CD133+细胞可分化为CD133+和CD133-细胞而CD133-细胞只能分化为CD133-细胞[34],表明CD133+细胞中具有干细胞或祖细胞。但是通过体内、体外实验发现组织中分离获得的胃癌干细胞其成瘤能力与CD133无关[12]。因此,CD133在临床中的应用仍需进一步的探究。 Lgr5也被称为Gpr49,主要用于标记胃上皮祖细胞,最初是作为体内大肠癌细胞和小肠腺窝细胞中Wnt的靶基因被发现[35-36]。Lgr5是一类G蛋白受体,具有一个巨大的N末端胞外结构域,此结构域由多个富含leucine的重复序列组成[37]。Lgr5属于一类受体超家族,此家族包括Lgr4,Lgr6,Lgr7,Lgr8,TSH受体,FSH受体以及LH受体。经研究发现,Lgr5像CD44一样在小肠腺窝基质的柱状细胞上表达,这些柱状细胞很可能是位于腺窝底部的干细胞,而且随着胃癌的进程Lgr5的表达量逐步增加[31,38]。Barker等[35]研究发现表达Lgr5的小肠干细胞可分化为各种类型的小肠上皮细胞,说明表达Lgr5的细胞的确具有干细胞特性。 侧群细胞(Side population,SP)曾被用于标记胃癌干细胞[39-40],研究发现在许多人胃癌细胞系中SP细胞占0.3%-2.2%[40],而且这类细胞具有自我更新的能力[41]。但一些研究发现SP阳性细胞并不等同于肿瘤干细胞,例如胃癌细胞MKN28表达SP但是用此种细胞来构建肿瘤模型不会有肿瘤产生[42-43]。而神经胶质瘤细胞虽然不表达SP细胞特有的ABCG2与ATP-binding cassette half-transporter却可用于构建肿瘤模型[44]。此外,大肠癌细胞中无论是SP细胞还是non-SP细胞都可以用于异种移植产生肿瘤,而且这两种细胞具有相同的多向分化能力[45],以上研究都表明侧群细胞可能不是一个很有效的标记癌干细胞的标记物,推测它可能适合标记肿瘤干细胞的某一状态或者处于细胞周期时的某一阶段[46]。 具有Villin启动子的干细胞(Villin-promoter marked stem cells,Villin-promoter):Villin高表达于小肠细胞,大多数胃上皮细胞不表达。但是有些文献利用细胞的系列实验证实鼠的胃上皮细胞或峡部底端的细胞中存在处于静息状态的Villin-promoter细胞[47]。这些静息的细胞能够生成各类胃组织细胞,例如腺窝表面的细胞、内分泌细胞、侧壁细胞。内源Villin蛋白却不在胃上皮细胞中表达,推测可能是由于Villin基因结构被破坏所导致。因此,无法确立Villin基因活性与处于静息状态的干细胞之间是否有联系。采用IFN-γ刺激来模拟炎症过程发现大量具有Villin-promoter的细胞增殖,增殖细胞几乎遍布于胃峡部,实验说明炎症不仅可以促进Villin-promoter细胞增殖还可以促进其迁移。类似于Lgr5,具有Villin-promoter的干细胞也不存在于胃的体部,表明在胃的峡部底端存在着不同类型的胃干细胞[47]。此外,在16.5日龄鼠胚的胃窦中会低表达内源Villin,但随后这一区域的Villin表达就被沉默了[48]。Qiao等[47]利用β-galactosidase标记的Villin cDNA研究发现Villin在成体小鼠的胃部表达,并只在少数的细胞亚群中表达。Villin表达只能够反映villin mRNA的表达与否。有些胃祖细胞会表达Villin promotor,但内源villin蛋白在这些细胞中不表达[47],因此限制了其研究只能局限在RNA水平。 三叶样因子2(Trefol factor 2,Tff2)主要用于标记胃上皮祖细胞。Tff2是一种小肽,构成小肽的基序能够组成三叶样的结构。在胃峡部的下部区域可以发现有Tff2蛋白表达,但是Tff2 mRNA转录本却在体部的黏膜层中表达。这一位置的表达差异说明具有Tff2 mRNA转录表达的细胞(TTE)可能是祖细胞,并且Tff2 mRNA转录本就是其标志物[49]。通过系列分析发现泌酸细胞膜Tff2 mRNA标记的细胞能够迁移至腺体的底部增殖成为壁细胞、黏液细胞甚至胃实体细胞,但是不能够分化成为肠嗜铬样细胞,而且TTE的分化细胞无法存活超过200 d。TTE并不向胃窦区迁移,说明TTE细胞只定位于胃体部[49]。Tff2可调控胃黏膜的修复过程[50]。利用转基因鼠研究发现Tff2 mRNA可标记胃祖细胞,而不是干细胞,这些被标记细胞不能够分化为所有类型的体部细胞,而且不能长期存活[49]。关于TTE细胞的功能仍需进一步的研究。 Musashi-1是helix-loop-helix家族的一种转录因子,调控细胞分化的最后阶段以及精细调节产酶细胞的顶体结构[51],主要在胃腺体基底层以及颈部与基底层间的细胞表达[52]。通过系列追踪实验观察表达Mist1的细胞在急性与慢性泌酸小鼠模型中的分化情况,发现Mist1细胞可以分化成为所有的表达解痉多肽的化生组织SPEM细胞。SPEM细胞可以形成相对于肠化生的胃黏膜化生。SPEM细胞表达TFF2,也可称为假性幽门化生、黏液性化生或体部胃窦化生[53]。胃壁细胞的缺失可诱导体细胞转分化为SPEM细胞,并且这一化生过程在急性或慢性炎症的刺激下被激发。但是至今仍不清楚胃癌是不是由化生发展而来,关于SPEM细胞与胃癌发展的关系需进一步的研究。 2.2 新的胃癌干细胞表面标志物 CD90(Thy-1)是一种细胞表面糖蛋白,在内皮细胞、平滑肌细胞、成纤维细胞以及多种干细胞中表达[54-56]。最近研究发现CD90在胃癌原发性肿瘤中也有表达[54],分离并经无血清肿瘤球培养法培养可获得肿瘤球。CD90细胞可在小鼠体内成瘤,并且单细胞移植裸鼠后形成各阶段的肿瘤细胞[54]。基因表达分析肿瘤球中肿瘤细胞,显示与干细胞干性相关因子如CD90、Oct4、Sox2、Notch1、ALDH1、Oct4、Sox2均高表达,其中Notch1与ALDH1在正常与肿瘤干祖细胞中均高表达,但CD133却不高表达[54]。ERBB2过表达可以激活干/祖细胞的增殖,研究发现ERBB2的RNA表达水平与CD90密切相关,通过阻断ERBB2的信号通路可以明显抑制胃癌的发生,并可在化疗过程中抑制肿瘤的增长[54]。这些研究表明CD90可能是胃肿瘤干细胞的标记物并可用于监测胃癌的治疗情况。 CD166属于细胞表面免疫球蛋白超家族,定位于人染色体的3q13[57]。CD166通常表达于增殖或trafficking细胞,例如被激活的淋巴细胞、胚胎造血细胞、内皮细胞等[58]。研究发现CD166的表达与肿瘤的增殖、淋巴结转移以及浸润脉管系统密切相关,且肿瘤细胞的侵袭与转移能力与CD166的表达相一致。拮抗实验显示肿瘤细胞的增殖能力被明显减弱甚至逆转[59]。细胞膜表达的CD166与淋巴结转移相关,且会导致术后不良[60]。Yang等[61]研究发现黏膜被浸润的程度及部位与CD166的表达密切相关,表明CD166在胃癌的发生过程中起重要作用,而且CD166的基因表达变化要早于组织学改变。如需进行预防性治疗,可特异性的针对黏膜上CD166高表达的被浸润部位,而且此靶向治疗可减缓或逆转癌细胞的浸润过程[61]。因此,CD166可能是一个新的抗肿瘤靶向位点。 CD24是一种细胞表面重链糖基化蛋白,表达于人的某些肿瘤细胞,在肿瘤扩散过程中作为P-选择素的配体起作用[62],且在具有侵袭能力和预后不良的弥散式胃癌细胞的胞质中表达[63]。Duckworth等[64]研究发现正常状况下CD24在胃肠道细胞中作为抗凋亡蛋白起作用,此外γ射线照射损伤后CD24的表达也会增高,表明CD24可通过抵抗辐射诱导的凋亡作用来维护组织的内环境稳定。CD24-胃癌细胞经长周期培养后相对于CD24+胃癌细胞无法保持其干性,且CD24的表达有助于提升胃癌细胞的黏附、侵袭、迁移能力[65]。因此,有些研究将CD24作为胃癌细胞靶向治疗的靶点[66]。 研究发现从人胃癌组织中分离出的具有胃癌干细胞特性的细胞表面会表达CD54。Xu等[67]研究证实CD44及CD54共表达的细胞会大量出现在胃癌复发早期患者的体内而不是晚期,说明表达CD44及CD54的肿瘤细胞是导致胃癌发生以及复发的重要原因。虽然CD54的研究报道较少,但通过上述研究可以看出表达CD54的胃癌细胞的确是胃癌干细胞的一个重要标志物。 EpCAM属于Ⅰ型跨膜糖蛋白,含有314个氨基酸,胞内区包含26个氨基酸,胞外区域含有2个生长因子样的结构[68]。多数正常上皮细胞的基底侧会低表达EpCAM,且在上皮起源的多种肿瘤细胞中表达增多,被认为是肿瘤细胞的标志物。最近的研究发现EpCAM不仅参与黏附作用,还与细胞信号传导过程、转移、增殖及分化密切相关。"
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