中国实验诊断学2021年2月第25卷第2期269文章编号：1007 — 4287(2021)02 —0269 — 03
张钓，刘特，严捃，侯雪佳，姜金兰*
(吉林大学中日联谊医院科学研究中心，吉林长春130033)
肝癌是最常见的癌症类型，死亡率非常高。由于间充质干细胞对肿瘤具有强烈的嗜性，可以向肿 瘤部位迁移。因此，间充质干细胞在肿瘤发生，进展 和转移中起到重要作用。已经有大量的证据表明，间充质干细胞具有靶向性，能够迁移和植人到肿瘤部位，刺激癌细胞生长，侵袭和转移。然而，其他研 究表明，它们可以抑制肿瘤的生长，间充质干细胞是 否抑制或促进肿瘤的发展仍存在争议。了解间充质 干细胞促进肿瘤生长和转移的机制及条件，能够促 进我们对肿瘤间质在肿瘤发生中的作用，对于安全 发展间充质干细胞是至关重要的。在本篇综述 中，我们主要分析了过去几年来间充质干细胞用于肿瘤的影响和相关机制，以及用于癌症的新的替代方法。
1间充质干细胞与肿瘤微环境
肿瘤细胞并不单独起作用，肿瘤是一种动态环境，包括多种细胞类型[1]。这些细胞能够产生肿瘤基质的非细胞成分。癌症起始、生长和进展离不开肿瘤基质。这些细胞微环境和非细胞微环境构成了 肿瘤微环
境[2]。肿瘤微环境是癌症的主要标志之—[3]。间充质千细胞（MSCs)的招募离不开细胞与其微环境之间的相互作用w。癌相关间充质干细胞 是肿瘤微环境内重要的基质祖细胞，在调节肿瘤进展中起关键作用。癌相关间充质干细胞能够促进肿 瘤细胞生长，增加肿瘤的“干细胞性”和化疗耐药性[5]。从直肠癌组织中分离出来的M SCs参与了肿 瘤微环境的形成[6]。从新鲜的人类神经胶质瘤手术 标本中分离了神经胶质瘤相关的人类MSCs，可驱 动神经胶质瘤的侵袭性[7]。
2间充质干细胞与肿瘤干细胞
肿瘤干细胞（CSCs)是癌细胞的一个子集，具 有自我更新能力[8]»C SC s是各种恶性肿瘤转移复
基金项目：国家自然科学基金（81903273)；吉林省科技发展计划项目 (20200201429JC, 20190103078JH, 20190304030Y Y,
20190902007TC and 20190901007JC)
*通讯作者发以及对化疗放疗耐药的重要原因[9]。C S C s是肿 瘤生物学研究的热点，已经成为抗癌非常重要的靶点[1°]。近年来，已在多种实体瘤中鉴定出CSCs[11]。Xu P等人[12]从大肠癌细胞株HCT-116 中分离出了大肠癌干细胞。恶性肝癌细胞的发生与 干性标志物的表达有关，因此表明肝细胞癌的发生与癌症干细胞的存在有关[1<K131<]。肝癌干细胞被认为是肝癌生长、转移和复发的原因。他
们对常规化疗或放射有抗药性，这是肿瘤的主要障碍[1517]。因此，根除C S C s是提高效果的关键[18]。肝癌干细胞的鉴定和功能表征有助于肝细胞癌的诊断和预后，对开发新的策略具有重要意义[11]。M S C s对C S C s有一定的促进作用U9]。M SC s本身释放多种因子，诱导肿瘤的干细胞性和耐药性，并且维持C S C s的表型[2°]。一项类似的研究表明，M SC s产生的IL-6通过激活JA K2-STA T3 途径，导致大肠癌细胞中C S C s的比例增加[21]。
3间充质干细胞对肝癌的促进及转移作用
M SC s能促进多种癌症的进展，例如大肠癌、胰 腺癌、卵巢癌等[2225]。骨髓间充质干细胞（BMSCs)能够影响4T1细胞的生长和转移，4T1乳腺癌细胞诱导了骨髓间充质干细胞的恶性分化[26]。L iG C 等人[27]发现，骨髓间充质干细胞通过转化生长因子(31蛋白（TGF-p l)促进了肝癌的血管生成。Chang L iu等人[28]研究了人脐带间充质干细胞（hUCM-SCs)对三维培养肝癌细胞的作用，hU C M SC s通过 TGF-p i诱导的肝癌细胞的上皮间充质转换能显著增强肿瘤细胞的转移。hU C M SC s与H epG-2肝癌 细胞条件培养液孵育后，转分化为癌相关间充质干细胞。将H epG-2细胞与hU C M S C共培养后，H ep02细胞的增殖和迁移明显增加[29]。脂肪间充 质干细胞的可溶性因子促进了犬肝癌细胞的增殖和侵袭[3°]。由于B M SC s分泌白细胞介素-6(IL-6)，BM SCs培养基提高了人肝癌细胞Bel-7404的侵袭 率，刺激了 IL-6/S T A T 3通路的信号转导[31]。
4 M SCs 对肝癌的抑制作用枢怎么读
270Chin J Lab Diagn，February，2021，Vol 25，No. 2
在再生医学中使用M SCs对患者可行且安 全[32]。MSCs能够抑制结肠癌[33]。人胎儿MSCs衍 生的条件培养基表达高水平的胰岛素生长因子结合蛋白，并能隔离游离胰岛素样生长因子以抑制肝癌细 胞的增殖。胰岛素生长因子结合蛋白抑制IGF-1R和PI3K/A k t的表达，影响肝癌的增殖，对胰岛素样生长 因子(IGF)信号转导有明显的抑制作用[
为了提高效果，已将多种药物联合间充质干细胞应用于肝癌的中。索拉非尼与骨髓间充 质干细胞联合应用对异种移植瘤的生长有较强的抑制作用。联合明显的抑制了肝癌细胞增殖，不 仅降低了肿瘤血管生成，诱导细胞凋亡，而且维持M SC s的抗肿瘤相关抗炎作用。很大程度上提高了索拉非尼单药的效果[35]。在M SC s前几天施应用褪黑素，增加了肝癌大鼠肝脏中的MSCs 存活和潜力[36]。
5 间充质干细胞外泌体对肝癌的抑制作用
M SCs衍生的外泌体与M SC s功能相似，然而，外泌体更稳定、更易保存，可为多种疾病提供替代治 疗L37]。Virginea de Araujo Farias 等人[38]认为，M SC s分泌的外泌体可能与后的肿瘤生长延迟和转移控制有关。研究表明，M SC s分泌的外泌体能够抑制乳腺癌细胞，具有抗肿瘤作用.其机制是通 过抑制乳腺癌细胞的血管生成[39]。脂肪源性间充质干细胞衍生的外显子促进大鼠N K T细胞的抗肿 瘤
反应，从而抑制肝癌的生长[4°]。
Lou G等人[41]通过miR-199a慢病毒感染和脓毒霉素筛选，构建miR-199a修饰的脂肪间充质干细 胞（AMSC-199a)。再从AMSC-199a上清液中分离 出miR-199a修饰的外显子通过耙向m T()R途径，有效地提高肝癌对化疗药物的敏感性。Li H等 人[42]修饰了骨髓间充质干细胞以表达外泌体siG-RP78，与索拉菲尼联合应用能有效地靶向肝癌细胞葡萄糖调节蛋白78(GRP 78)，抑制癌细胞的体外生长和侵袭。此外，与索拉非尼组合的siGRP78修 饰的外泌体在体内也能够抑制癌细胞的生长和转移。
6小结
M SCs具有明显的肿瘤靶向性，一些研究表明，M SC s具有抑癌作用，另一些研究报告了其潜在的肿瘤支持作用。这取决于特定的癌症类型和所应用 的动物模型[13]。因此，M SC s在癌症中的临床应用仍然具有挑战性。本文综述了 M SC s对肝癌的 支持或抑制作用，提示应合理利用间充质干细胞，为临床转化提供参考。
参考文献：
[1]Ridge SM, Sullivan F J, Glynn SA, Mesenchymal stem cells： key
players in cancer progression[J]. Mol C an cer,2017,16( 1) ：31.
刘特[2] P ark S A, Surh YJ. M odulation of tum or microenvironment by
chem opreventive natural p ro d u cts[J]. Ann N Y Acad Sci,2017, 1401(1)：65.
匸3]Noman M Z.H asm im M,L equeux A,e t al. Improving Cancer Im- m unotherapy by T argeting the Hypoxic T um or M icroenvironm en t： New O pportunities and C h allen g es[J]. Cells, 2019,8 ( 9)：1083.
[4]Roorda BD, ter E lst A, K am ps W A，et al. Bone marrow-derived
cell.s and tum or g ro w th：contribution of bone marrow-derived cells to tum or m icro-environm ents w ith special focus on mesenchymal stem cells[J]. Crit Rev Oncol H em ato l,2009,69(3) ： 187. [5]Coffman LG, Pearson A T,F risb ie L G,et al. Ovarian Carcinoma-
Associated Mesenchymal Stem Cells Arise from Tissue-Specific Norm al S tro m a[J]. Stem C e lls,2019,37(2) ：257.
[6]Zhang X,H u F,L i G,e t al. Hum an colorectal cancer-derived m es
坐台照enchymal stem cells prom ote colorectal cancer progression through IL-6/JA K2/S T A T3signaling[J]. Cell Death D is,2018,9
(2)：25.
Q7]Hossain A,G um in J.G ao F,e t al. Mesenchymal stem cells isolated from human gliomas increase proliferation and maintain sternness of glioma stem cells through the IL-6/g p l30/S T A T3path- w ayCJl- Stem C e lls,2015,33(8) ：2400.
[8] Ye T, Li J，Sun Z，et al. Nr5a2 prom otes cancer stem cell proper
ties and tum origenesis in nonsm all cell lung cancer by regulating N an o g[J]. Cancer M ed, 2019,8( 3) ： 1232.
[9]Saha S K，Kim K，Yang G M，et al. (K R T19) Cytokeratin 19 has a
Role in the Reprogram m ing of Cancer Stem Cell-Like Cells to Less Aggressive and More Drug-Sensitive C ells[J]. Int J Mol Sci, 2018,19(5)：1423.
[l〇]C hang H L,C h en H A,B am odu O A.e t al. Ovatodiolide suppresses yes-associated protein 1-m odulated cancer stem cell pheno
types in highly m alignant hepatocellular carcinoma and sensiti-
zes cancer cells to chem otherapy in v itro[J]. Toxicol In V itro,
2018,51：74.
[11] Ji JF,W an g XW. Clinical Im plications of Cancer Stem Cell Biol
ogy in H epatocellular Carcinoma [J ]. Semin O ncol, 2012, 39 ：461.
[12]Xu P,W an g J,S u n B,e t al. Com prehensive analysis of miRNAs
expression profiles revealed potential key m iR N A/m R N A s reg
ulating colorectal cancer stem cell self-renew al[J]. G ene, 2018,
656：30.
[13]Kawai T，Yasuchika K’Ishii T，et al. K eratin 19,a Cancer Stem
Cell M arker in Hum an H epatocellular C arcinom a[J]. Clin Cane-
er R e s,2015,21(13)：3081.
[14]Jang JW,S o n g Y,K im S H,e t al. CD133 confers cancer stem-like
cell properties by stabilizing E G FR-A K T signaling in hepatocel
lular carcinom a[J]. Cancer L e tt,2017»389： 1.
qq自动回复在哪设置[153Sun J H, Luo Q, Liu L L，et al. Liver cancer stem cell m arkers:
中国实验诊断学2021年2月第25卷第2期271
progression and therapeutic im plications[J]. W orld J G astroen
te ro l,2016,22：3547.
[16] Flores-Tellez T N, V illa-Trevino S, Pina-Vazquez C. Road to
sternness in hepatocellular carcinoma [J].W orld J G astroen
te ro l,2017,23:6750.
[17]Muenzner JK,K u n ze P, Lindner P,e t al. Generation and charac
terization of hepatocellular carcinoma cell lines with enhanced cancer stem cell potential [J ]. J Cell Mol M ed, 2018,22 ( 12)：6238.
[18] Zhu C P，W ang A Q，Zhang H H，et al. Research progress and
prospects of m arkers for liver cancer stem cells [J].W orld J
G astroenterol，2015，21 (42): 12190.
[19] Federica Papaccio, Francesca Paino, T arik Regad. Concise R e
马来西亚地震view： Cancer C ells, Cancer Stem C ells, and Mesenchymal Stem
C ells：Influence in Cancer Development [J].Stem Cells T ransl
Med. 2017 D ec；6( 12) ：2115.
[20] Papaccio F，Paino F，Regad T，et al. Concise R eview：C a ncer
C ells，Cancer Stem C ells，and Mesenchymal Stem C ells：Influ
ence in Cancer D evelopm ent[J]. Stem Cells T ransl Med 2017,6
(12),2115.
[21] K.S. T sa i，S. H. Y ang, Y. P. L ei，et al. Mesenchymal stem cells
prom ote form ation of colorectal tum ors in m ice[J]. G astro en ter
ology, 141 (2011) ：1046.
[22] Rhee K J, Lee J I, Eom YW. Mesenchymal stem cell-mediated
effects of tum or support or suppression[J]. Int J Mol Sci，2015,
16:30015.
[23]Zhou H S.S u X F,F u X L,et al. Mesenchymal stem cells prom ote
pancreatic adenocarcinoma cells invasion by transform ing grow th factor-^1 induced epithelial-mesenchym al tra n sitio n[J].
O n cotarget,2016,7 ：41294.
[24] Li W, Xu H, Qian C. c-K it-Positive Adipose Tissue-Derived
Mesenchymal Stem Cells Prom ote the G row th and Angiogenesis of Breast C an cer[J]. Biomed Res I n t,2017,2017:7407168.
[25] Chu Y, T ang H, Guo Y, et al. Adipose-derived mesenchymal
stem cells prom ote cell proliferation and invasion of epithelial 〇- varian cancer[J]. Exp Cell R e s,2015 »337( 1) ： 16.
[26]Nie X,T an g J,L iu Y,e t al. Fullerenol inhibits th e cross-talk be
tween bone m arrow-derived mesenchym al stem cells and tum or cells by regulating M A PK signaling[J]. N anom edicine,2017,13
(6)：1879.
[27]Li G C,Z hang H W,Z hao Q C,e t al. Mesenchymal stem cells pro
mote tum or angiogenesis via the action of transform ing grow th factor p l[J]. Oncol L e t t,2016,11 (2) ： 1089.
[28]Liu C，Liu Y，Xu X X，et al. M esenchymal stem cells enhance the
m etastasis of 3D-cultured hepatocellular carcinoma cells [J].
BMC C a n cer,2016,16：566.
[29] Yang J,M ia o Y, Chang Y, et al. Condition medium of HepG-2
cells induces the transdifferentiation of human umbilical cord mesenchymal stem cells into cancerous mesenchymal stem cells [J]. Am J T ransl R e s,2016,8(8) ：3429.
[3〇]T eshim a T,M atsu m o to H,K oyam a H. Soluble factors from adipose tissue-derived mesenchym al stem cells prom ote canine hep
atocellular carcinoma cell proliferation and invasion [J ]. PLoS O n e,2018,13(1),e0191539.
[31]Mi F, Gong L. Secretion of interleukin-6 by bone m arrow m es
enchymal stem cells prom otes m etastasis in hepatocellular carci-
n o m a[J]. Biosci R e p,2017,37(4) ： BSR20170181.
[32]Kim G,E o m Y W,B aik S K,e t al. T herapeutic effects of m esen
chymal stem cells for patients w ith chronic liver d iseases： S y s
tem atic review and m eta-analysis[J]. K orean Med. Sci. 2015；30：1405.
[33]T ang R J,S h en SN.Z hao al. M esenchym al stem cells-reg-
ulated T reg cells suppress colitis-associated colorectal cancer [J]. Stem Cell Res T h e r，2015,6 (1):71.
[34]Yulyana Y, Ho IA,S ia K C,et al. Paracrine factors of hum an fe
tal MSCs inhibit liver cancer grow th through reduced activation of IG F-1R/P I3K/A k t signaling [J].Mol T h e r, 2015,23( 4 )：746.
[35]Seyhoun I, H ajighasem lou S, M uham madnejad S,e t al. C om bina
tion therapy of sorafenib w ith m esenchym al stem cells as a novel cancer treatm ent regimen in xenograft models of hepatocellular carcinom a[J3. J Cell P h y sio l,2019,234(6) ：9495.
[36]E1-Magd M A.M oham ed Y,E1-Shetry E S,e t al. M elatonin m axi
mizes the therapeutic potential of non-preconditioned MSCs in a DEN-induced rat model of HCC [J ]• Biomed Pharm acot h er,
2019,114:108732.
[37] Bo Y u, Xiaomin Zhang, X iaorong Li. Exosom es derived from
国庆节休假m esenchym al stem cells[J]. Int J Mol Sci，2014，15(3) :4142. [38]de A raujo Farias V,Q V alle F,Serrano-Saenz S,e t al. Exosom es
derived from mesenchym al stem cells enhance radiotherapy-in
duced cell death in tum or and m etastatic tum or foci [J]• Mol
C a n c er,2018,17(1) ：122.
[39]Pakravan K，Babashah S，Sadeghizadeh M，et al. M icroRN A-100
shuttled by m esenchym al stem cell-derived exosom es suppresses in vitro angiogenesis through m odulating the m T O R/H I F-la/ V E G F signaling axis in breast cancer c ells[J]. Cell Oncol (D or- dr) ,2017,40(5) ：457.
[4〇]K o S F,Y ip H K,Z h en Y Y,e t al. Adipose-Derived M esenchym al Stem Cell Exosom es Suppress H epatocellular Carcinom a
G row th in a Rat Model ： A pparent Diffusion C oefficient, N atural
K iller T-Cell R esponses, and H istopathological F eatu res [ J ].
Stem Cells I n t,2015,2015 ：853506.
[41]Lou G,C h en L,X ia C,e t al. MiR-199a-modified exosom es from
adipose tissue-derived m esenchym al stem cells im prove hep ato
cellular carcinoma chem osensitivity through m T O R pathw ay [J]. J Exp Clin Cancer R es»2020,39( 1) ：4.
[42] ]Li H,Y a n g C»Shi Y,Z hao L. Exosom es derived from siR N A a-
gainst GRP78 modified bone-m arrow-derived m esenchym al stem
cells suppress Sorafenib resistance in hepatocellular carcinom a [J]. J N anobiotechnology,2018,16(1)
： 103.
[43]Zong C,Z hang H,Y an g X,e t al. T he distinct roles of m esenchy
mal stem cells in the initial and progressive stage of hepatocarci- n o m a[J]. Cell D eath D is，2018,9(3):345.
(收稿日期：2020—10 —20)
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