Chinese Journal of Tissue Engineering Research ›› 2013, Vol. 17 ›› Issue (36): 6521-6526.doi: 10.3969/j.issn.2095-4344.2013.36.022
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Zheng Peng-xiang, Zhou Huan, Tan Jian-ming
Received:
2013-01-13
Revised:
2013-03-02
Online:
2013-09-03
Published:
2013-09-03
Contact:
Tan Jian-ming, M.D., Professor, Chief physician, Doctoral supervisor, Department of Urinary Surgery, Fuzhou General Hospital of Nanjing Military Area Command of PLA, Fuzhou General Clinical Medical College of Fujian Medical University, Fuzhou 350025, Fujian Province, China
tanjm156@yahoo.com.cn
About author:
Zheng Peng-xiang★, Studying for master’s degree, Department of Urinary Surgery, Fuzhou General Hospital of Nanjing Military Area Command of PLA, Fuzhou General Clinical Medical College of Fujian Medical University, Fuzhou 350025, Fujian Province, China
zpx365@163.com
CLC Number:
Zheng Peng-xiang, Zhou Huan, Tan Jian-ming. Impact of mesenchymal stem cells on the proliferation, invasion and biological behaviors of hepatocellular carcinoma cells[J]. Chinese Journal of Tissue Engineering Research, 2013, 17(36): 6521-6526.
2.1 间充质干细胞与肿瘤相关的生物学特征 2.1.1 间充质干细胞与肿瘤相关的生物学特征 一直以来人们对肿瘤发病机制的研究主要集中于肿瘤细胞本身基因及遗传表观的改变,而忽视了肿瘤基质的作用[4]。近些年来,研究者们开始意识到肿瘤基质细胞不仅起到支持肿瘤的作用,还能与肿瘤细胞实现通讯,发生相互作用,从而影响肿瘤的演变[5]。 首先,间充质干细胞对肿瘤细胞具有很强的亲和力,和其向损伤组织归巢一样,可归巢至肿瘤组织,并且被基础及临床实验中均证实为肿瘤基质的组成部分[6],影响肿瘤细胞的增殖、侵袭和转移,促进血管及结缔组织的形成[7-8]。肿瘤组织可产生许多对间充质干细胞具有趋化作用的因子,如血管内皮生长因子、成纤维细胞生长因子、血小板衍生因子、胰岛素样生长因子及补体C3a、C5a等[9-10]。Banas等[11]和Groth等[12]的研究均证实间充质干细胞在肝细胞生长因子和表皮细胞生长因子的作用下可形成肝细胞样细胞,参与肝脏损伤的修复。间充质干细胞因其表面大量存在炎症因子受体,具有炎症趋化能力已被证实,最新的观点认为把肿瘤看成是一种“不可逆的损伤”,从而解释了间充质干细胞对肿瘤的趋向性[13-14]。Kidd等[15]应用小动物成像系统,在无损伤的条件下,观察经发光物标记的间充质干细胞在活体动物中分布情况,为干细胞的趋肿瘤性及趋损伤性提供了直接证据。 其次,间充质干细胞是肿瘤基质的组成成分来源。实体肿瘤的基质中含有多种间质细胞类型,如内皮细胞、淋巴细胞、巨噬细胞、嗜中性粒细胞和肿瘤相关的成纤维细胞[16-18]。进展期的肿瘤可动员多种类型的细胞,从而干扰肿瘤的形成[19]。无论是肿瘤细胞本身还是受肿瘤影响的邻近组织都可以分泌化学物质的方式动员各种类型细胞,形成肿瘤基质的微环境,从而进行一系列复杂的相互作用[20-21]。间充质干细胞对肿瘤细胞也有直接的作用。间充质干细胞可产生多种分子,如趋化因子、细胞因子和生长因子等,它们以旁分泌的形式作用于癌症细胞的表面上相应受体,从而调节肿瘤的生长和进展。间充质干细胞来源的趋化因子,如CXCL1、CXCL2及CXCL12/SDF-1可以通过作用于肿瘤细胞表面的CXCR2和CXCR4受体,促进多种肿瘤细胞的增殖[22-23]。同样,间充质干细胞分泌的细胞因子白细胞介素6和白细胞介素8,已被证明可增强乳腺癌和结肠癌的恶性度[24]。 第三,间充质干细胞具有调节肿瘤免疫的作用。其可以调节先天免疫和后天免疫的双重作用。骨髓间充质干细胞对免疫调节主要通过对T淋巴细胞及B淋巴细胞增殖的影响,它可以明显抑制二者的增殖,从而达到免疫抑制的效果。同时间充质干细胞还能调整T细胞的表型[25],抑制抗肿瘤免疫应答反应。 第四,肿瘤相关间充质干细胞参与肿瘤血管的形成。新生血管的生成对于肿瘤的营养十分重要。间充质干细胞可分泌血管生成因子促进血管生成。间充质干细胞在一定微环境刺激下还可分化为内皮细胞、平滑肌细胞等,也可能是肿瘤血管生成的重要因素[26]。 总之,间充质干细胞以上这些多方面的作用是通过与肿瘤细胞与之相互影响,而后肿瘤微环境发生改变,最终肿瘤与其间质组织共同发生改变来完成的,二者之间相互促进,互为因果。 2.1.2 间充质干细胞的致瘤性 间充质干细胞除了能对肿瘤细胞产生抑制或促进的作用外,在一定条件下,还可能是某些肿瘤的“元凶”。由于间充质干细胞具有非常强的自我更新和无限增殖能力,在体外多次传代培养后可产生基因突变,变成致瘤细胞。目前的报道主要以间充质干细胞向多种类型的人类肉瘤转化为主,其中以尤文肉瘤为典型代表[27],FLI-1基因产物与EWS的结合位点的融合,可导致间充质干细胞向尤文肉瘤转化。突变基因修复后的尤文肉瘤细胞可重新被诱导分化成骨细胞和脂肪细胞,这一点符合间充质干细胞的特性,也为尤文肉瘤可能源于间充质干细胞提供了可靠的依据。Houghton等[28]研究发现间充质干细胞也可能直接发展为上皮癌,其发现在幽门螺杆菌感染的情况下,移植间充质干细胞后,可胃黏膜细胞的融合等现象。 2.2 间充质干细胞对肝癌的抑制作用 2.2.1 肿瘤坏死因子相关凋亡诱导配体途径的抑制作用 肿瘤坏死因子相关凋亡诱导配体是肿瘤坏死因子家族中的成员,能通过与肿瘤细胞表面的DR4 (肿瘤坏死因子相关凋亡诱导配体-R1)或DR5 (肿瘤坏死因子相关凋亡诱导配体-R2)结合,诱导多种肿瘤细胞凋亡。目前,以肿瘤坏死因子相关凋亡诱导配体为靶点的抗肿瘤研究越来越受到人们的关注,可能成为治疗肿瘤新的突破点[29]。 Sun等[30]的研究显示,通过直接与间接共培养的方法,间充质干细胞上的肿瘤坏死因子相关凋亡诱导配体均能够激活HepG2的DR5,从而促进HepG2细胞的凋亡,其凋亡的数量与间充质干细胞上的肿瘤坏死因子相关凋亡诱导配体的表达量存在正相关。但其尚缺乏体内试验证据,无法证明间充质干细胞在体内能否表达肿瘤坏死因子相关凋亡诱导配体并激活肿瘤细胞表面的DR。同时还缺乏肿瘤坏死因子相关凋亡诱导配体在体内的表达量及表达条件的研究。 Liu等[31]的研究弥补了表达条件不确定这一不足,其成功构建了以强力霉素为控制开关的重组腺病毒载体Ad-Tet-TRE-肿瘤坏死因子相关凋亡诱导配体,并感染间充质干细胞,在体外与人肝癌细胞系SMMC-7402共培养结果显示:改造后的间充质干细胞上的肿瘤坏死因子相关凋亡诱导配体实现了可控性表达,其表达的肿瘤坏死因子相关凋亡诱导配体仍然可以达到诱导肝癌细胞凋亡的活性。这一研究使得肿瘤坏死因子相关凋亡诱导配体介导间充质干细胞在肿瘤治疗中具有了人工控制性,但其同样缺乏体内试验的证据,未评估经改造的间充质干细胞在体内能否达到同样的可控性,同时也没有评价其在体内的安全性及其对机体的影响。 2.2.2 Wnt途径的抑制作用 近年来Wnt 通路成为研究的热点。干细胞与多种肿瘤细胞都存在相同的信号传导通路,包括Wnt、Notch、BMP通路等。Wnt通路在干细胞自我更新和分化中有重要作用,Wnt信号通路的异常活化与肿瘤的形成有关[32-33]。Wnt家族相关的分泌蛋白能促进细胞增殖和转化,当突变或过度表达,可导致肿瘤形成。Wnt信号可同时调节所涉及的基因,达到调节细胞代谢、增殖、细胞周期和细胞凋亡的效应。增殖细胞核抗原和c-myc基因、survivin和bcl-2基因都是Wnt信号的靶点[32,34]。 Qiao等[35]应用间充质干细胞与2种人肝癌细胞株H7402和HepG2分别在体内、体外进行试验。在SCID鼠移植瘤模型中,等量的间充质干细胞与H7402细胞混合注射至皮下,肿瘤形成的潜伏时间延长,肿瘤体积较对照组小。体外实验中,Z3人间充质干细胞与H7402及HepG2细胞共培养,结果显示2种肝癌细胞增殖减少,凋亡增加,Bcl-2、c-myc,增殖细胞核抗原和survivin的表达均下调。同时也出现集落形成能力下降和增殖能力下降。最终结果说明间充质干细胞能抑制恶性表型的H7402和HepG2人肝癌细胞系,其中包括增殖,克隆形成能力和体外、体内的癌基因的表达。此外,也说明Wnt信号途径是人间充质干细胞的介导的抑制肿瘤细胞的途径。同样,Abdel等[36]采用化学诱导的方法建立鼠肝癌模型,输注间充质干细胞后,发现增殖细胞核抗原、β-catenin、cyclin D、survivin的表达下调了,从而证实间充质干细胞抑制肝癌的生长与Wnt途径有关。 2.2.3 其他途径的抑制作用 间充质干细胞还存在其他方式对肝癌细胞产生抑制效应。间充质干细胞可与肝癌细胞发生融合,从而抑制肝癌的肺转移。Li等[37]的研究通过采用生物发光基因分别标记间充质干细胞和肝癌细胞用于观察间充质干细胞在体内的分布情况。其研究结果显示,间充质干细胞参与了肝癌基质的形成,并且发生了肝癌细胞与间充质干细胞的融合现象,这可能是间充质干细胞抑制肝癌细胞转移的重要原因。 间充质干细胞在代谢水平上对肝癌产生抑制作用。Qiao等[38]采用体外共培养方法发现,人间充质干细胞对肝癌细胞 H7402具有明显的抑制作用,核转录因子κB表达的下调可能是是其原因,表明代谢水平的调控可能是干细胞抑制肿瘤细胞恶性增殖的重要因素之一。但其未做进一步的研究阐明核转录因子κB的下调抑制肝癌细胞增殖的机制。除了静脉输注间充质干细胞外,陈双庆等[39]采用肝内注射Walker-256瘤株建立SD大鼠荷瘤模型,经脾植入超顺磁性氧化铁粒子标记的间充质干细胞,采用无创的MRI检查技术动态检测肿瘤的生长情况,发现间充质干细胞对原位肝癌有抑制作用,并可延长生存期。 国内外均已有研究者分别对晚期肝癌化疗、肝动脉化疗栓塞、肝癌手术切除后的患者[40-41],配合骨髓间充质干细胞输注作为辅助手段进行治疗,发现配合间充质干细胞输注的患者,治疗有效率及生存率高于对照组患者。这种机制目前还不明确,可能原因是干细胞在肝脏组织微环境中可受原位肝脏组织中的生长促进相关因子的作用,如肝细胞生长因子和表皮细胞生长因子等的作用,分化为类肝细胞,促进了肝脏的修复[12,42]。遗憾的是,这种条件下尚不能说明间充质干细胞是否直接参与了肝癌细胞的抑制,对降低复发率是否起到直接作用。 2.3 间充质干细胞对肝癌的促进作用 间充质干细胞对肝癌细胞起促进作用可能的机制包括:参与肿瘤基质的形成、促进转化生长因子β的表达、促进肿瘤血管生成等。Li等[43]的研究显示:在体外实验中,间充质干细胞与MHCC97-H肝癌细胞共培养后,肝癌细胞的增殖能力增强,侵袭能力减弱。与体外结果一致,其裸鼠体内实验的结果显示:间充质干细胞输注的荷瘤裸鼠瘤体积增长速度快,但肺转移率降低。其指出肿瘤增殖能力增强、侵袭能力下降可能与间充质干细胞参与肿瘤局部基质的形成有关,有利于肿瘤的定植。与Li的结果不一致的是,Yan等[44]的研究表明与肝癌相关的间充质干细胞不仅可以促进肝癌细胞的生长,同时也能促进其转移。Yan等[44]的研究首次在肝癌组织中发现了间充质干细胞的存在。其主要机制可能为与肝癌相关的间充质干细胞可分泌S100A4有关,S100A4的表达可促进miR-155的表达,而miR-155可使细胞信号转导抑制因子SOCS1发生下调,激活STAT3信号,由此促进了基质金属蛋白酶9表达,导致肿瘤侵袭性增高。 周佳美等[45]在体外用不同浓度的间充质干细胞条件培养基处理CBRH-7919肝癌细胞48 h后,发现肝癌细胞增殖率升高,且呈浓度依赖性。有学者直接将间充质干细胞注射至皮下移植瘤体内,发现间充质干细胞可在原发性肝癌Heps荷瘤小鼠肿瘤组织内定植,间充质干细胞接种后的第1周肿瘤增长速度较对照组快,但后期增长速度无差异,接种间充质干细胞的小鼠生存期延长。 2.4 经修饰的间充质干细胞对肝癌的作用 由于间充质干细胞具有向肿瘤组织迁移的能力,很多学者已利用这一特点将间充质干细胞作为荷载抗肿瘤成分的工具,包括各种细胞因子、自杀基因、放射性物质等,以达到治疗肿瘤的目的。 Chen等[46]将导入白细胞介素2的间充质干细胞与肝癌细胞混合后注射至小鼠皮下,发现能够明显抑制肿瘤的形成,几乎不能成瘤。这说明表达白细胞介素2的间充质干细胞可以有效抑制肿瘤形成,但具体机制不详,同时也没有研究间充质干细胞在机体其他部位是否有迁移,因此临床应用价值不大。 有学者将正电子发射断层成像技术引入了对间充质干细胞体内分布的研究中,他将钠碘转运体基因导入后的钠碘转运体-间充质干细胞输注到肝癌模型动物中,再用131I静脉输注对动物进行治疗,结果发现131I具有肿瘤部位特异性的富集,这项研究对体内放射治疗提供了新的思路,转入钠碘转运体的间充质干细胞可以使放射治疗部位局限在肿瘤部位,减少了对其他正常组织的损伤,从而减少并发症,也使得有效的治疗浓度提高。其后他利用间充质干细胞分泌RANTES/CCl5的特性,将钠碘转运体-间充质干细胞注射至Huh7肝癌动物模型中,结果显示间充质干细胞为载体的治疗可明显抑制肿瘤生长速度,提高动物的生存率。 Niess等[47]将单纯疱疹病毒胸苷激酶自杀基因导入间充质干细胞,将此种间充质干细胞注射至肝癌模型C57小鼠体内后,发现此种间充质干细胞可以在肿瘤部位富集,经启动子激活自杀基因后,肿瘤的质量较对照组减轻。遗憾的是,此研究未就其在体内的安全性进行探讨,无从得知自杀基因修饰的间充质干细胞对机体其他部位是否存在负面影响。"
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