Relationships between mesenchymal stem cells and tumor

doi:10.3969/j.issn.2095-4344.2013.06.029

Abstract

Abstract:

BACKGROUND: Mesenchymal stem cells have tumor-targeting properties, and can be isolated easily and expand to the numbers required for application, and they can be genetically manipulated with viral vectors, which suggest the potential of mesenchymal stem cells in the clinical cancer gene therapy.
OBJECTIVE: To review the characteristics of mesenchymal stem cells, the tropism of tumor, the relationships between unmodified mesenchymal stem cells and tumor, and the treatment effect of genetically modified mesenchymal stem cells on tumor.
METHODS: A computer-based online search of literatures published between January 2002 to March 2012 related to mesenchymal stem cells and tumor was performed in PubMed database by the first author. The key words were “mesenchymal stem cells, tropism, genetically modified, tumor, therapy”. The repetitive and unrelated researches were excluded, and finally, 50 articles were included according to inclusion criteria.
RESULTS AND CONCLUSION: Mesenchymal stem cells can specifically migrate to multiple kinds of tumors and their metastases. Some studies have shown that mesenchymal stem cells can promote the growth of tumor and some other studies have shown that they also inhibit the growth of tumor. The mode to modify the mesenchymal stem cells and perform the tumor gene therapy is mainly to carry the suicide gene, apoptosis genes, anti-angiogenic gene, immune-stimulating genes or oncolytic viral vectors. In vitro and in vivo experiments have confirmed the effect of this method on tumor treatment.

Key words: stem cells, stem cell review, mesenchymal stem cells, tropism, genetically modified, tumor, therapy

CLC Number:

R318

Dong Hui-yue, Wang Jin, Huang Liang-hu, Tan Jian-ming. Relationships between mesenchymal stem cells and tumor[J]. Chinese Journal of Tissue Engineering Research, 2013, 17(6): 1122-1128.

Figures/Tables 2

间充质干细胞不仅可以从骨髓中分离获得，还可以从其他组织中获得，例如：脐带、脂肪组织、羊膜液、外周血、胰腺组织等等。一些研究已显示间充质干细胞可以归巢到瘢痕和肿瘤组织的微环境，代替受损细胞的功能并活跃增殖。另外间充质干细胞具有低免疫原性的特点，到目前为止临床大量应用间充质干细胞治疗移植物抗宿主病和自身免疫性疾病。 2.2 间充质干细胞的肿瘤趋向性间充质干细胞能特异性的归巢到各种肿瘤组织，第1次证实间充质干细胞的肿瘤趋向性的研究是大鼠同基因神经胶质瘤的间充质干细胞移植，随后大量研究证实间充质干细胞向肿瘤及转移肿瘤部位的趋向性。间充质干细胞向肿瘤部位迁移的特性在一些前临床体外迁移实验和肿瘤动物模型实验中得到证实，例如：恶性神经胶质瘤[2-4]、乳腺癌[5-7]、卡波西肉瘤、黑色素瘤、结肠癌[8]、卵巢癌和肺癌[9-10]，以及在肿瘤过程中发生的转移[10]。间充质干细胞归巢至肿瘤组织的确切机制尚未明确，其最可能的机制是来自肿瘤的趋化因子和生长因子的释放，包括肿瘤细胞特异性受体和可溶性的肿瘤衍生因子，这些肿瘤细胞的特异性受体和因子可以和间充质干细胞表面受体结合。肿瘤细胞分泌的因子包括基质细胞衍生因子1、肿瘤细胞坏死因子α、白细胞介素类，其他一些经鉴定和未鉴定的炎症递质[11-12]。 CXCR4是牵涉到细胞迁移和归巢的最公认的趋化因子受体，研究发现CXCR4在间充质干细胞中高表达，并且主要在胞内表达。体外三维培养的间充质干细胞增强基质细胞衍生因子1α信号通路，此信号通路增强可以恢复基质细胞衍生因子1α的受体CXCR4的功能和归巢能力，对治疗应用发挥了决定性作用[13]。间充质干细胞归巢的机制也可能与白细胞从脉管系统外渗的机制相似，同样有黏附分子和整合素的参与。间充质干细胞沿血管壁内皮细胞表面滚动的过程中，P-选择素在间充质干细胞与内皮细胞结合上发挥了重要作用，极迟抗原4是黏附分子的一种整合素与其相对应的配体血管细胞黏附分子1构成极迟抗原4/血管细胞黏附分子1轴，在间充质干细胞黏附到内皮细胞上有重要作用，并且它们中的任一个经过抗体处理后均能减少间充质干细胞黏附到内皮细胞。可以推测，间充质干细胞与内皮细胞黏附、结合以及沿着内皮细胞血管壁滚动都涉及间充质干细胞归巢[14]。肿瘤的微环境被认为是慢性炎症部位，这种环境可以通过可溶性因子的释放介导间充质干细胞的迁移。最新研究发现肿瘤微环境中的炎症程度在间充质干细胞的募集能力中发挥了作用，在间充质干细胞-干扰素β介导的胰腺癌治疗研究中发现：抗炎治疗后间充质干细胞向肿瘤植入能力下降，逆转了对肿瘤的抑制作用[15]。间充质干细胞到达肿瘤之后，表现出促肿瘤，发挥免疫抑制作用，抑制肿瘤凋亡[16]，刺激上皮到间质转变，血管生成，增殖，外渗，迁移和转移[17]。另外，在肉瘤、白血病研究中发现间充质干细胞具有抗肿瘤的作用，永生化的间充质干细胞还可以抑制原发肿瘤的生长和集落的形成[18]。 2.3 未修饰的间充质干细胞对体内外肿瘤的作用 2.3.1 促进肿瘤生长许多研究发现间充质干细胞可以促进肿瘤生长。Karnoub等[5]将绿色荧光蛋白标记的人乳腺癌细胞系(MCF/Ras，MDA-MB-231， MDA-MB-435，HMLER)与间充质干细胞以1∶3的比例共同移植到免疫缺陷的小鼠体内时发现：间充质干细胞在MCF/Ras细胞系中加速肿瘤生长，而在其他3株细胞中未影响肿瘤的生长，但是间充质干细胞可以促进四株人乳腺癌细胞系的转移。成人和胚胎来源的间充质干细胞与结肠癌细胞(SW480和F6)共同移植到鼠的异体移植模型中发现：肿瘤的发生率明显提高，成人和胚胎来源的间充质干细胞具有相似的促进肿瘤增长的作用，但是成人来源的间充质干细胞比胚胎来源的间充质干细胞更能促进肿瘤的发生[19]。在没有与间充质干细胞共同移植的情况下，B16黑色素瘤细胞移植到同基因小鼠体内不会形成肿瘤，这也提示了间充质干细胞的免疫抑制的作用。间充质干细胞也对人滤泡型B淋巴细胞瘤的体外存活提供保护作用，并且经过肿瘤坏死因子α和淋巴霉素-α1β2处理的间充质干细胞保护作用增强[20]。脂肪组织富含间充质干细胞，研究显示在同基因的小鼠模型中，脂肪来源的间充质干细胞可以促进肿瘤生长[21]。脂肪来源的间充质干细胞与乳腺癌细胞共同移植，与单独移植乳腺癌细胞相比，肿瘤增大，形成肿瘤速度加快[22]。另研究显示人脂肪来源的间充质干细胞可以促进裸鼠体内肿瘤细胞的生长，将人脂肪来源的间充质干细胞与肺癌细胞(H460)或神经胶质瘤细胞(U87MG)皮下注射到裸鼠体内，在肿瘤的大小和存活的肿瘤细胞数量上均明显增加[23]。 2.3.2 抑制肿瘤生长许多研究报道间充质干细胞可以促进肿瘤生长，但是另外一些研究显示间充质干细胞也可以抑制肿瘤生长。间充质干细胞与结肠癌细胞按1∶1或10∶1的比例共同移植到大鼠里内，间充质干细胞可以抑制大鼠结肠癌的生长。在高炎症性和血管发生的卡波西肉瘤模型中，间充质干细胞可以抑制肿瘤生长[24]。体内外研究发现，胎儿皮肤来源的间充质干细胞可以抑制人肝癌细胞的生长，表现为降低细胞增殖、集落形成和癌基因的表达[25]。另体外研究发现胎儿皮肤来源的间充质干细胞可以抑制乳腺癌细胞MCF-7的生长[19]。间充质干细胞分泌Dickkopf相关蛋白1，干细胞转录因子NANOG调控Dickkopf相关蛋白1，而Dickkopf相关蛋白1介导间充质干细胞的肿瘤抑制作用，研究发现脂肪来源的间充质干细胞通过分泌Dickkopf相关蛋白1抑制白血病细胞的生长[26]。间充质干细胞通过改变细胞周期进展来抑制胰腺肿瘤的生长，体外共培养研究发现，在胰腺肿瘤细胞中间充质干细胞增加G1期细胞比例。脂肪来源的间充质干细胞移植到胰腺肿瘤模型中抑制肿瘤的生长[27]。用升温处理的间充质干细胞的上清液培养卵巢癌细胞SKOV-3，SKOV-3细胞数量减少、活力降低。间充质干细胞分泌的因子在这一过程中发挥了作用，包括血管生成素、胰岛素样生长因子结合蛋白4、神经营养因子3和趋化因子配体18[28]。 2.4 修饰的间充质干细胞对体内外肿瘤的作用未修饰的间充质干细胞既有促肿瘤的作用，也有抗肿瘤的作用。而对间充质干细胞修饰主要是为了抑制肿瘤，达到治疗肿瘤的目的。总体来说，间充质干细胞的肿瘤趋向性及逃避免疫清除的特性在肿瘤特异基因传递的应用上具有广阔研究空间[29-30]。对间充质干细胞进行修饰进行肿瘤基因治疗的方式主要是携带：自杀基因、凋亡基因、抗血管发生基因、免疫刺激基因或者溶瘤病毒载体。间充质干细胞携带这些基因或者载体能够克服直接应用间充质干细胞带来的不利因素：安全性；不完全的肿瘤靶向作用；无效的基因治疗导致的转基因免疫原性；病毒特异性受体对肿瘤细胞作用的局限性。目前主要是通过病毒载体将需携带的基因转染进间充质干细胞，病毒载体包括：腺病毒[31]、慢病毒和其他反转录病毒[32-33]，或者用于治疗和追踪的腺病毒伴随病毒。目前的抗肿瘤治疗主要是对间充质干细胞进行基因修饰，这些基因包括干扰素类、肿瘤坏死因子相关的凋亡诱导配体(TNF-related apoptosis- inducing ligand，TRAIL)、白细胞介素类、趋化因子CX3(CX3CL1)等。在小鼠黑色素瘤肺转移模型中，干扰素α基因修饰的间充质干细胞抑制肿瘤细胞增殖，减缓肺转移灶的生长[34]。体内外研究显示，腺病毒转染的间充质干细胞表达干扰素β可以有效的杀死神经胶质瘤细胞[35]。在黑色素瘤肺转移模型中，表达干扰素β的间充质干细胞抑制肿瘤生长并延长生存期，这种抗肿瘤作用是由于肿瘤部位干扰素β释放，提示间充质干细胞移植对肿瘤靶向治疗的重要性。前列腺癌肺转移模型中，表达干扰素β的间充质干细胞可以延长生存期和降低肿瘤负荷，其可能机制是干扰素β促进肿瘤细胞凋亡、抑制血管新生和增加自然杀伤细胞的活性[36]。在人胰腺癌肿瘤模型中，转染干扰素β的间充质干细胞抑制肿瘤细胞的生长[15]。腺病毒转染的间充质干细胞表达干扰素γ在体外可以抑制白血病细胞增殖并可以引起白血病细胞的凋亡[37]。在肺肿瘤模型中，TRAIL基因修饰的间充质干细胞可以抑制肿瘤生长[38]。在肺转移癌模型中，Loebinger等[32]研究发现携带TRAIL的间充质干细胞可以减少肿瘤生长和复发，并在多数小鼠中抑制肺转移灶的生长。利用间充质干细胞作为细胞工具将分泌型的TRAIL靶向运输到人神经胶质瘤处或在肿瘤部位分泌TRAIL，慢病毒转染人间充质干细胞，使间充质干细胞携带分泌型的TRAIL(S-TRAIL)，体内研究发现间充质干细胞-S-TRAIL显著抑制肿瘤细胞生长并延长小鼠生存期[39]。最新研究显示，神经胶质瘤小鼠模型中，辐照后携带TRAIL的脐带间充质干细胞的肿瘤趋向性增强，间充质干细胞-TRAIL对肿瘤细胞的促凋亡作用增强[40]。在大鼠神经胶质瘤模型中，表达白细胞介素2的间充质干细胞具有明显的抗肿瘤作用[41]。在表达白细胞介素7的间充质干细胞的研究中发现了相似的效果。将白细胞介素12转染到间充质干细胞中，转染后的间充质干细胞具有抗肿瘤功能并且免疫监视的功能得到提高。有学者用转染白细胞介素12的间充质干细胞治疗肾细胞癌，对肿瘤生长起到明显抑制作用[42]。基因修饰的间充质干细胞表达白细胞介素18在大鼠神经胶质瘤移植模型中抑制肿瘤生长，减小肿瘤体积[43]。CX3CL1能激活T细胞和NK细胞，携带CX3CL1的间充质干细胞使结肠癌和黑素瘤静脉转移到肺转移灶的数目减少[44]。erbB2是肿瘤细胞常见的表面标志，Komarova等[9]将间充质干细胞修饰成带有erbB2的人工受体(MSCs-AR)，MSCs-AR静脉注射到卵巢癌模型体内，聚集到肿瘤部位的间充质干细胞明显增多，提高了间充质干细胞的靶向作用，增强间充质干细胞为基础的肿瘤治疗作用。在乳腺癌动物模型中，表达碘化钠(NIS)的间充质干细胞通过静脉内或瘤内注射后，可以长久聚集在肿瘤部位并明显降低肿瘤生长[45]。细胞毒性药物代谢的集中可以通过表达胞嘧啶脱氨酶的间充质干细胞来实现。前体药物的集中转换，5-氟胞嘧啶到5-氟尿嘧啶，可以抑制结直肠癌和黑色素瘤肿瘤的生长[46-47]。将单纯疱疹病毒胸苷激酶(HSV-tk)利用反转录病毒转染到间充质干细胞，利用HSV-tk/gcv自杀基因治疗，体内外研究发现可以杀死神经胶质瘤细胞[48]。间充质干细胞还可作为条件复制性腺病毒的载体，在体内减少肿瘤生长和转移。这些病毒通过复制产生新生病毒释放到肿瘤组织的周围，使肿瘤细胞发生溶解破坏。在鼠的原位肺癌和乳腺癌肿瘤模型中，利用这种治疗可以延长生存期。在肺转移癌模型中也取得了同样的效果[49]。腹膜内注射携带溶瘤腺病毒的间充质干细胞到卵巢癌模型中，发现宿主生存期延长，延缓肿瘤生长[50]。"

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