修回日期: 2010-11-10
接受日期: 2010-11-17
在线出版日期: 2010-12-28
干细胞是存在于胚胎和成体中的一类具有自我更新能力和多向分化潜能的特殊细胞. 有研究显示, 干细胞对肿瘤组织具有较为特异的趋向性. 干细胞与肝癌之间关系错综复杂, 直接影响着肝癌发生及转归. 既往研究表明, 干细胞可参与肝癌细胞生长分化调控, 是原发性肝癌发生的关键因素. 近年来, 亦有研究证实干细胞可能对肝癌细胞的生长具有抑制作用. 阐明干细胞在肝癌发生转归中的具体作用, 可为揭示肝癌的发病机制及制定新型治疗策略提供新线索.
引文著录: 许蜜蝶, 李维卿, 余宏宇. 干细胞与肝癌相关性的研究进展. 世界华人消化杂志 2010; 18(36): 3881-3885
Revised: November 10, 2010
Accepted: November 17, 2010
Published online: December 28, 2010
Stem cells are a class of special embryonic or adult cells that are able to self-renew and undergo multi-directional differentiation. Studies have shown that stem cells have selective tropism toward tumor tissue. Previous studies have shown that hepatic stem cells play an important role in hepatocarcinogenesis by participating in regulation of cell growth and differentiation. However, some other studies demonstrated that stem cells could inhibit cell growth in hepatocellular carcinoma. Elucidation of relationship between stem cells and hepatocellular carcinoma could provide new clues to the pathogenesis of hepatocellular carcinoma and help develop new therapeutic strategies for the disease.
- Citation: Xu MD, Li WQ, Yu HY. Stem cells and hepatocellular carcinoma. Shijie Huaren Xiaohua Zazhi 2010; 18(36): 3881-3885
- URL: https://www.wjgnet.com/1009-3079/full/v18/i36/3881.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v18.i36.3881
干细胞具有自我更新、多向分化、无限增殖潜能三大特征. 存在于或可定向迁移至肝脏内发挥作用的干细胞有: 卵圆细胞、小肝细胞等内源性肝干细胞和间充质干细胞等骨髓源性干细胞和胰腺上皮细胞等外源性肝干细胞. 大部分肝干细胞具有向肝细胞和胆管细胞双向分化的能力. 干细胞对肝癌原发及转移灶具有靶向性, 一些干细胞经基因修饰可在肿瘤局部稳定表达治疗因子而保持自身干细胞特性不变, 利用此特性可将其作为细胞载体参与肿瘤生物靶向治疗; 同时, 一些干细胞到达肝癌后, 作为该环境组分还参与肝癌组织的构建和调控新生血管的形成, 从而对肝癌生长产生促进或抑制效应. 本文就相关研究作一综述.
将绿色荧光蛋白(green fluorescent protein, EGFP)标记的可持续表达c-Kit抗体的肝卵圆样细胞WB-F344通过尾静脉注射入患有CBRH7919大鼠肝癌细胞原位种植肝癌的Wistar大鼠体内, 在不同的时间点取大鼠肝、肾、脾和肺组织荧光显微镜下观察其在大鼠体内的分布情况. 与对照组和其他脏器相比发现, 干预4 d后即可观察到大量这种c-Kit+WB-EGFP细胞位于正常肝组织与肿瘤的交界位置, 而在肿瘤内部只有少许WB-EGFP细胞. 8 d后, 在肿瘤中心地带观察到大量这种WB-EGFP细胞侵袭[1]. 这说明肝卵圆细胞对可向肝内特异性定向迁移、靶向性地集中在肿瘤病灶周围, 具追踪肿瘤细胞特性. 但肝干细胞的这种肿瘤趋向性并不代表其本身具有自然的恶变倾向, 作为唯一有机会获得致瘤过程必须的基因突变的一种自我更新群体, 肝干细胞可经过一系列包括HBV/HCV的感染等特定病理因素或环境刺激下, 经多种癌变途径, 成为肿瘤组织中占支配地位的细胞群体[2]. 这种定向迁移能力是一种瘤变还是聚集后介导免疫反应等发挥抑癌作用尚待证实.
间充质干细胞(mesenchymal stem cells, MSC)是存在于骨髓微环境中的具有多分化潜能的干细胞, 正常情况下的MSC可向体内多种组织器官定向移动, 但主要存在于骨髓内. 生长中的肿瘤可分泌多种细胞因子, 如表皮生长因子(epidermal growth factor, EGF)、成纤维细胞生长因子(fibroblast growth factor, FGF)、IL-8、IL-6、肝细胞生长因子(hepatocyte growth factor, HGF)、基质金属蛋白酶-l(matrix metalloproteinase-1, MMP-1)等, MSC可通过表面相应受体与这些细胞因子作用向肿瘤靶向性迁移而不影响自身干细胞特性[3,4]. 不过MSC在对肿瘤原发和继发灶靶向迁移的同时, 亦可向脾、肺、肾等无瘤荷器官迁移.
肝癌的发生发展及侵袭转移是建立在肝癌细胞与周围微环境及机体内环境之间的相互作用之上的复杂过程. 干细胞微环境改变与肿瘤发生机制、肿瘤分期及肿瘤预后密切相关. 针对干细胞与肝癌的发生发展及预后的具体相关性研究有助于阐明干细胞在肝癌中所扮演的具体角色.
既往对肝脏组织不典型增生结节癌变机制的研究表明肝癌起源于成熟肝细胞的去分化[5]. 然而近年来, 随着对卵圆细胞等肝干细胞的研究的深入及肝癌干细胞这一概念的提出, 有学者开始倾向于认为肝癌细胞是肝干细胞成熟终止的产物, 随后实验证实, 肝癌是一种干细胞疾病, 肝癌可由多种不同阶段的肝干细胞分化而来[6].
卵圆细胞在肝内可转化为肝癌细胞[7-10], 且为原发性肝癌发生的关键因素: (1)向卵圆细胞转染致癌基因或将细胞内抑癌基因敲除可导致肝癌的发生[11,12]; (2)卵圆细胞瘤变过程中可检测到c-myc原癌基因的过表达, 而Myc蛋白失活的卵圆细胞则可分化成为肝细胞或胆管细胞[13,14]. 参与细胞生长分化调控的Wnt、SHH、Notch等信号传导途径亦参与肿瘤细胞的生长调控, 这些调节机制异常可能是肿瘤发生的重要原因[15].
由于在肝卵圆细胞中表达的c-Kit, CD34和Thy-1等分子标记亦可在骨髓干细胞中表达[16-21], 故有学者提出卵圆细胞由骨髓干细胞分化而来, 且当成熟干细胞的增殖受阻时这种分化作用更趋明显[22-26], 持续、严重的肝损伤释放某种信号分子, 诱使骨髓干细胞移行至肝脏, 肝内局部微环境刺激其向卵圆细胞方向分化, 进而分化为肝细胞或胆管上皮细胞, 以修复损伤肝脏, 参与组织构建[27]. 由此可否推断肝癌可由骨髓干细胞转分化而来? 有研究表明MSC癌变为肝癌的可能性很小[28], Wu等[29]则提出低分化肝癌起源于骨髓干细胞和卵圆细胞, 而分化良好肝癌源于成熟的肝细胞.
但目前尚未成功分离任何肝癌干细胞, 也无明确的肝癌干细胞分子标志物提出, 因此, 肝癌的细胞起源仍需要更为深入的研究.
肝切除治疗后肝癌复发患者体内包括CK-19、ABCG2、CD133、Nestin、CD44、VEGF和PD-ECGF等在内的许多肝干细胞或肿瘤血管发生相关分子标志物过表达, 并且对患者的生存率和存活率有统计学相关意义, 其中肝癌组织中VEGF和MVD高表达的患者的生存率和无复发率明显要低于低表达患者. 说明肝干细胞分子标志物的高表达与肝癌血管发生和肝癌的预后不良显著相关[30], 利用这一现象可有利于将肝癌患者按切除术后复发风险进行分类, 进而帮助临床选择治疗方案.
将CBRH-7919大鼠肝癌细胞与WB-F344肝卵圆样干细胞按照不同比例共培养, 随着培养基中WB-F344肝卵圆样干细胞的增多, CBRH-7919大鼠肝癌细胞凋亡率明显升高. 同时在肝癌细胞内可检测到TGF-β/Smad信号通路及其通路成员Smad4和TGF-βRⅡ上调, 提示肝卵圆细胞可通过上调肝癌细胞内TGF-β/Smad信号通路从而促进肝癌细胞的凋亡[31].
Qiao等[32]应用胎儿真皮来源的Z3 MSC和胎儿骨髓来源的BMMS-03 MSC的条件培养液分别作用于肝癌H7402/HepG2细胞, 结果显示肝癌细胞的增殖受到明显抑制. Wnt信号转导途径是调节细胞自我更新和分化并可决定细胞的分化发展命运的重要通路, 对肿瘤细胞在MSC条件培养液作用后Wnt/β-catenin信号转导途径进行观察发现, 在应用MSC条件培养液作用后H7402和HepG2细胞中β-catenin和其下游靶蛋白如c-myc、survivin、PCNA和Bcl-2的表达水平发生明显下调; H7402细胞胞质和胞核内β-catenin的含量明显减少, 说明MSC可能通过抑制肿瘤细胞Wnt/β-catenin信号转导途径从而抑制肿瘤细胞恶性表型, 削弱其增殖能力. NF-κB是重要的转录调控因子, 他与肿瘤的发生发展、浸润转移以及耐药性有密切的关系. 其异常表达可影响肿瘤细胞的增殖、分化、细胞周期和凋亡．对干预后H7402肝癌细胞进行基因芯片检测发现, 肝癌细胞中NF-κB的表达受到明显抑制[33].
值得一提的是MSC亦可通过抑制Wnt通路对乳腺癌细胞发挥抑瘤作用[34], 相对的也有实验表明MSC可促进一些肿瘤的增殖[35]. 此外, 应用共培养系统将具高肺转移潜能的MHCC97-H肝癌细胞与MSC共培养并建立荷瘤小鼠进行体外观察, 其结果显示MSC可促进肝癌细胞的增殖, 同时也可抑制癌灶的侵袭和转移, 该作用可能与MSC TGF-β1表达下调具一定联系[36]. 干细胞对肿瘤细胞的作用可能与干细胞数量及所处肿瘤微环境相关, 两种显著差异的原因有待于进一步探查. 目前对于MSC抑瘤效率尚无量化标准, 其可能导致的不良反应也无明确评价.
上述研究表明干细胞具有抑制肝癌细胞增殖的作用, 且此作用为一个多基因多因子参与的过程. 虽然在各研究中使用的细胞起源不同, 干细胞和肿瘤细胞调节自我更新、分化和凋亡的信号通路却相似, 如Wnt/β- catenin信号通路参与调节干细胞和祖细胞的扩增[15,37-39], 诱导哺乳动物祖细胞转化[40,41]; Notch BMP信号通路在干细胞自我更新和分化中扮演重要角色[15,37,42]; 以及TGF-κ/Smad通路参与胚胎肝细胞扩增和肿瘤细胞形成[43-45]. 这些通路可能决定了肿瘤细胞的分化能力和发展方向, 也随之决定肿瘤细胞的恶性程度, 但相对于不同细胞的调控机制尚待进一步研究.
目前治疗肝癌最有效的方法是肿瘤切除和原位肝移植, 但术后高复发率和肝源的缺乏严重制约了患者的治愈率. 近年来对肝干细胞的研究提供了诸如利用干细胞的体内定向分化增殖能力在癌灶切除术前或术后向患者体内注射干细胞以提高远期存活率[46]等新型的治疗方式.
因MSC不表达MHC-Ⅱ类抗原等, 免疫原性低, 而肝干细胞不仅可以通过患者自体血液收集, 且不具有抗原性, 不会引起免疫抑制, 因此有学者设想将MSC和肝干细胞作为理想的载体携带治疗基因靶向治疗肝癌. 这一途径可以解决基因治疗中目的基因的高效转移、表达高度组织特异性和精确表达调控等问题, 有望达到"载体携带足够的效应剂到达肿瘤部位并持续发挥作用而对正常组织无不良反应"的理想治疗目标[47]. 例如, HGF为多种组织细胞内分裂素, 若使用肝干细胞为载体靶向导入受损肝脏, HGF可望在损伤的肝脏中大量聚集, 从而修复受损组织细胞. 向二甲基亚硝胺诱导的肝硬化大鼠模型骨骼肌转染HGF, 将构建载有HGF的肝干细胞对病肝进行干预, 结果表明硬变的肝脏中很多病理标志物的明显减少[48,49], 绝大多数肝癌由硬变肝中肝瘤再生发展而来, 临床肝硬变缓解率的提高有助于降低肝癌发病率. Chen等[50]将编码IL-l2的腺病毒或逆转录病毒载人MSC后予小鼠行腹腔注射, 1 wk后皮下注射肝癌细胞, 结果肿瘤细胞的生长明显受抑, 这证实IL-12-MSC可有效作用于临床前期肿瘤, 抑制肿瘤再发和复发.
如前文所述, 干细胞不仅可以靶向性地集中在肿瘤病灶的周围, 对肿瘤细胞进行直接杀伤; 而且可能在分子(基因)水平上恢复致癌基因与抑癌基因的平衡状态, 有效地防止肿瘤的侵袭和转移. 此外, 有研究表明MSC还可通过旁分泌VEGF、HGF及IGF-1等细胞因子并上调Bcl-2蛋白表达修复肿瘤术后放化疗对正常组织造成的损伤, 重建造血的功能, 恢复机体的免疫监视和抗肿瘤能力[51]. 但干细胞增殖过程中也容易受外来因素的影响, 引起肿瘤的发生. 若将干细胞在肝癌微环境中发挥促瘤作用还是抑瘤作用的先决条件阐明并善加利用, 干细胞治疗将不仅仅是针对肝脏慢性疾病的治疗方法[52], 更将发展为作为临床治疗肝癌的重要途径.
干细胞的肿瘤趋向性及促瘤抑瘤双向性的发现为肝癌发病机制和治疗策略的调整提供了新思路. 深入研究干细胞、肝癌细胞特征和关系可望开展针对肝癌的靶向治疗策略, 解决肿瘤多药耐药、肿瘤复发转移等诸多棘手问题. 但怎样分离、特异性鉴定及筛选高纯度的干细胞这些问题成为限制肝干细胞应用的瓶颈. 而干细胞与对肝癌组织抑制具体机制的阐明, 更是有待研究的重点问题, 可为认识和治疗肝癌提供新的治疗靶点, 开发新的治疗措施. 上述问题的圆满解决将为干细胞在肝癌治疗中应用提供切实的理论基础.
干细胞与肝癌之间的关系错综复杂, 他既是肝癌发生的关键因素又可对肝癌产生抑制作用, 其对肝癌发生转归的影响可能是多因素的.
单云峰, 副主任医师, 温州医学院附属第一医院肝胆外科
干细胞因其不可替代的多种优势而被认为是最具肿瘤治疗潜力的细胞. 而干细胞对肝癌的促瘤之外尚存抑瘤作用. 这一发现成为肝癌治疗又一新突破点. 但其作用机制尚不完全清楚, 需深入研究和探讨.
Li等应用共培养系统将具高肺转移潜能的MHCC97-H肝癌细胞与MSC共培养, 并建立荷瘤小鼠进行体外观察,发现MSC可促进肝癌细胞的增殖,同时也可抑制癌灶的侵袭和转移, 为干细胞并可能应用于临床HCC治疗提供理论基础.
近年来, 干细胞在肝癌中的研究日益增多, 但大多致力于癌变机制探讨或移植治疗效果观察和评价, 本文则首次对干细胞促瘤之外抑瘤作用的可能机制作了较全面的归纳和系统的阐述.
本文为从事干细胞治疗肝癌的研究者提供了借鉴和指导. 如能深入研究并阐明具体的作用机制, 并针对性的采取一些措施来提高干细胞治疗肝癌的有效性和安全性, 将为肝癌治疗提供新视角.
本文选题新颖, 具有一定的学术价值.
编辑:曹丽鸥 电编:李薇
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