Umbilical cord blood mesenchymal stem cells for treatment of tongue squamous cell carcinoma

doi:10.3969/j.issn.2095-4344.1829

Abstract

Abstract:

BACKGROUND: Tongue squamous cell carcinoma is one of the most common oral malignant tumors with strong local invasion, high lymphatic metastasis rate and poor prognosis. Umbilical cord blood mesenchymal stem cells have multidirectional differentiation potential. Recent studies have confirmed that they can inhibit malignant biological behaviors of lung cancer, liver cancer and other tumors. However, the role and specific mechanism of umbilical cord blood mesenchymal stem cells in tongue cancer remain unclear.
OBJECTIVE: To review the research progress of umbilical cord blood mesenchymal stem cells in the treatment of tongue squamous cell carcinoma.
METHODS: PubMed, WanFang and CNKI databases were retrieved for literatures about umbilical cord blood mesenchymal stem cells. The search terms were “umbilical cord blood mesenchymal stem cells, cancer cells,” “umbilical cord blood mesenchymal stem cells, tongue squamous cell carcinoma cells,” and “umbilical cord blood mesenchymal stem cells, migration, invasion” in Chinese and English, respectively. In total 33 articles were induced for result analysis.
RESULTS AND CONCLUSION: Preliminary studies have shown that umbilical cord blood mesenchymal stem cells can inhibit the migration and invasion of tongue squamous cell carcinoma cells. Increasing evidence has confirmed that umbilical cord blood mesenchymal stem cells can migrate to the tumor site due to their tumor chemotaxis, and exert their effects by releasing various signal molecules, chemical factors, and cytokines. Therefore, umbilical cord blood mesenchymal stem cells are expected to provide a new treatment for tongue squamous cell carcinoma.

Key words: umbilical cord blood mesenchymal stem cells, tongue squamous cell carcinoma, proliferation, migration, invasion

CLC Number:

Zhang Xinyu, Wang Zhuhui, Xu Zhuqing, Zheng Jianjin. Umbilical cord blood mesenchymal stem cells for treatment of tongue squamous cell carcinoma[J]. Chinese Journal of Tissue Engineering Research, 2019, 23(33): 5392-5395.

Figures/Tables 1

2.1 间充质干细胞的作用有研究表明间充质干细胞具有促进创面愈合的作用，可通过旁分泌因子吸引角质细胞、巨噬细胞、内皮细胞等募集至创面，促进创面部位的血管再生，从而促使真皮成纤维细胞生成胶原，减少炎性反应及瘢痕的形成，其中间充质干细胞释放的血管内皮生长因子和低氧诱导因子在促进新生血管形成过程中起到重要作用[11]。骨髓间充质干细胞是一种来源于骨髓的多功能干细胞，在许多临床疾病的治疗中发挥着关键性的作用[12-13]。Kitaori等[14]研究探讨基质细胞衍生因子及其受体CRCX4在骨愈合中的作用，通过实时聚合酶链反应和免疫组织化学方法检测基质细胞衍生因子在小鼠股骨结构骨移植修复过程中的表达，通过体内和体外迁移实验观察基质细胞衍生因子对骨髓间充质干细胞的影响，结果发现在移植骨愈合过程中基质细胞衍生因子的表达有所增加，体内和体外迁移实验研究表明基质细胞衍生因子能够促进骨折部位骨膜募集间充质干细胞，从而将其诱导分化为骨细胞，促进骨折愈合。间充质干细胞具有肿瘤趋向性，肿瘤的生长与伤口愈合及修复过程相似，常常和各种基质细胞产生相互影响。在机体发生组织损伤和慢性炎症时，间充质干细胞可作为首批参与者进行机体修复，这些损伤及炎症部位可释放某些特殊的内分泌信号作用于间充质干细胞，使其向损伤及炎症部位迁移。有学者认为肿瘤可以通过释放血管内皮生长因子等信号和因子来募集间充质干细胞，并形成具有支持作用的间质[15]，但其中的具体机制还需进一步研究。总之，肿瘤微环境中的肿瘤细胞、炎性组织可通过分泌各种可溶性因子促进间充质干细胞迁移至肿瘤微环境。间充质干细胞可作为载体细胞参与肿瘤的基因治疗，间充质干细胞对包括肝癌在内的人类恶性肿瘤的生长和转移的影响尚存争议，其机制尚不清楚，Li等[16]研究探讨间充质干细胞在肝癌进展中的作用。研究过程中发现间充质干细胞对高转移潜能肝癌细胞株的转移具有抑制作用，在体外共培养及裸鼠移植瘤实验中发现间充质干细胞可通过下调转化生长因子β1表达，进而抑制肝癌细胞的转移。还有研究者认为间充质干细胞能够促进肿瘤血管形成[17-18]，肿瘤细胞的快速增长可导致其组织内部缺血缺氧，肿瘤间质细胞成为肿瘤微环境中的支持细胞，能够保护肿瘤细胞；间充质干细胞可诱导产生连接蛋白使微血管的完整性增加，还可以形成平滑肌细胞及内皮细胞等，参与形成肿瘤新生血管[19]。 2.2 脐血间充质干细胞的作用脐血间充质干细胞是一种多潜能干细胞，可诱导分化成胶质细胞、神经元，并分泌脑源性神经营养因子、胶质细胞源性神经营养因子等多种神经营养因子[20-21]。有研究表明在猴子纹状体内移植脐血间充质干细胞可在脑内存活并向黑质迁移，且动物的肢体力量、平衡能力得到增强，机械运动也变得无障碍[22]。脐血间充质干细胞具有很强的生命力，并且在体外一定的诱导条件下可以分化为各种神经元样细胞。许多学者采用不同的诱导方法都成功地获得了神经元样细胞。Yang等[23]采用细胞共培养的方法，通过羊膜上皮细胞分泌的多效生长因子刺激脐血间充质干细胞分化为神经细胞，从而获得多巴胺神经元。Devarajan等[24]将腺病毒作为载体表达Atoh1，从而首次诱导脐血间充质干细胞分化为听毛细胞样细胞。另外，脐血间充质干细胞已经被证实能够抑制αβT细胞、巨噬细胞、NK细胞和树突状细胞的功能[25]。 2.3 脐血间充质干细胞对恶性肿瘤的影响脐血间充质干细胞对不同肿瘤细胞的作用不同，或者促进肿瘤细胞的增殖和侵袭，或者抑制肿瘤细胞的增殖和侵袭，发挥作用的不同可根据肿瘤细胞的种类、细胞处理方式等不同而产生差异。目前已有相关研究证实脐血间充质干细胞对不同癌细胞的疗效。Zhang等[26]将慢性病毒转染至脐血间充质干细胞，构建HUCMSC-LV-IL-21表达载体，并将其转移至SKOV3卵巢癌裸鼠体内，结果显示卵巢癌的生长受到抑制。该实验认为HUCMSC-LV-IL-21通过调节典型的Wnt信号通路发挥抗肿瘤作用，与β-catenin和cyclin-D1在肿瘤组织中的表达下调有关。Jing等[27]研究发现脐血间充质干细胞产生的白细胞介素15能够抑制胰腺癌细胞的生长，小鼠体内肿瘤生长受到抑制，且小鼠的生存时间得到延长，这与NK细胞和T细胞的聚集有关，为胰腺肿瘤提供了新的治疗策略。张娜等[28]研究证明脐血间充质干细胞能够抑制胃癌MGC80-3细胞的迁移，实验组中基质金属蛋白酶7的分子表达水平随条件培养液浓度的增加而降低，蛋白表达水平低于空白对照组，而基质金属蛋白酶抑制剂1的分子表达水平随条件培养液浓度增加而增加，蛋白表达水平高于空白对照组，上述结果表明脐血间充质干细胞可以通过下调基质金属蛋白酶7、上调基质金属蛋白酶抑制剂1而抑制胃癌MGC80-3细胞的迁移。Akimoto等[29]实验发现脐血间充质干细胞对原发性多形性胶质母细胞瘤的生长起抑制作用，并促使肿瘤细胞的凋亡。实验中将脐血间充质干细胞与原代多形性胶质母细胞瘤)细胞共培养，分析其对多形性胶质母细胞瘤生长的抑制作用，结果发现脐血间充质干细胞能抑制多形性胶质母细胞瘤的生长并诱导细胞凋亡。研究表明，脐血间充质干细胞与食管癌细胞的人工融合导致细胞生长下降，凋亡增加，致瘤性降低，其发生的可能机制为增加DUSP6/MKP3在MAPK通路中的表达，从而抑制肿瘤细胞的生长[30]。有关脐血间充质干细胞在体内及体外对不同肿瘤细胞的作用机制还需要继续深入研究，以便为达到相关的治疗目的。 2.4 脐血间充质干细胞对舌鳞癌细胞生长的作用脐血间充质干细胞是有吸引力的癌症靶向治疗工具，具有迁移到肿瘤的能力，它可作为肿瘤治疗的靶向载体[31-32]。有报道表明脐血间充质干细胞能够抑制舌鳞癌细胞的增殖[33]，其中凋亡相关蛋白PARP-1的表达明显上调，抗凋亡标志蛋白Bcl-2的表达明显受抑制。 2.5 脐血间充质干细胞对舌鳞癌侵袭和迁移的作用将脐血间充质干细胞与Cal27细胞共培养，见图1，通过Transwell体系观察发现共培养后细胞迁移和侵袭数目减少。Real-time PCR检测实验组细胞中Ahoa、Emp1、MMP2、MMP9的mRNA的表达量与对照组相比显著降低，从基因水平上说明脐血间充质干细胞能抑制Cal27细胞的迁移和侵袭。用Western blot进一步从蛋白水平对这一结果进行验证，发现实验组中MMP2和MMP9蛋白的相对表达量与对照组相比显著降低，表明脐血间充质干细胞能抑制Cal27细胞的迁移和侵袭。"

References

[1]蒋芳艳,王瑜,陈吉荣,等. 转录因子XBP1在口腔鳞状细胞癌中的表达[J].口腔医学研究,2016, 32(2):139-142.

[2]Jensen DH, Dabelsteen E, Specht L, et al. Molecular profiling of tumour budding implicates TGFβ-mediated epithelial-mesenchymal transition as a therapeutic target in oral squamous cell carcinoma. J Pathol. 2015;236(4):505-516.

[3]Noguti J, De Moura CF, De Jesus GP, et al. Metastasis from oral cancer: an overview. Cancer Genomics Proteomics. 2012;9(5): 329-335.

[4]Patel SG, Amit M, Yen TC, et al. Lymph node density in oral cavity cancer: results of the International Consortium for Outcomes Research. Br J Cancer. 2013;109(8):2087-2095.

[5]郑鹏翔.人脐带间充质干细胞对肝癌细胞生长的影响[D]. 福州:福建医科大学, 2013.

[6]张文宇,巴特,刘玲英.人脐带间充质干细胞研究进展及应用[J].中华损伤与修复杂志(电子版), 2014,9(2):203-205.

[7]Mehrabani D, Nazarabadi RB, Kasraeian M, et al. Growth Kinetics, Characterization, and Plasticity of Human Menstrual Blood Stem Cells. Iran J Med Sci. 2016;41(2):132-139.

[8]Ramdasi S, Sarang S, Viswanathan C. Potential of Mesenchymal Stem Cell based application in Cancer. Int J Hematol Oncol Stem Cell Res. 2015;9(2):95-103.

[9]邵俊峰,陈余清.间充质干细胞与肿瘤关系的研究进展[J].蚌埠医学院学报, 2019,44(1):134-137.

[10]Patel SA, Meyer JR, Greco SJ, et al. Mesenchymal stem cells protect breast cancer cells through regulatory T cells: role of mesenchymal stem cell-derived TGF-beta. J Immunol. 2010;184(10):5885-5894.

[11]Ribeiro J, Pereira T, Amorim I, et al. Cell therapy with human MSCs isolated from the umbilical cord Wharton jelly associated to a PVA membrane in the treatment of chronic skin wounds. Int J Med Sci. 2014;11(10):979-987.

[12]贺继刚,李贝贝,韩金秀,等.过表达IDO大鼠骨髓间充质干细胞改善异位移植心脏存活[J].中国免疫学杂志, 2017,33(10):1447-1452.

[13]余云湖,付晓红,杨开华,等. BMSCs联合硫酸软骨素酶ABC移植修复大鼠脊髓损伤的研究[J].中国医学创新,2017,14(11):31-33.

[14]Kitaori T, Ito H, Schwarz EM, et al. Stromal cell-derived factor 1/CXCR4 signaling is critical for the recruitment of mesenchymal stem cells to the fracture site during skeletal repair in a mouse model. Arthritis Rheum. 2009;60(3):813-823.

[15]Yan XL, Fu CJ, Chen L, et al. Mesenchymal stem cells from primary breast cancer tissue promote cancer proliferation and enhance mammosphere formation partially via EGF/EGFR/ Akt pathway. Breast Cancer Res Treat. 2012;132(1):153-164.

[16]Li GC, Ye QH, Xue YH, et al. Human mesenchymal stem cells inhibit metastasis of a hepatocellular carcinoma model using the MHCC97-H cell line. Cancer Sci. 2010;101(12): 2546-2553.

[17]Wu Y, Chen L, Scott PG, et al. Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis. Stem Cells. 2007;25(10):2648-2659.

[18]Potapova IA, Gaudette GR, Brink PR, et al. Mesenchymal stem cells support migration, extracellular matrix invasion, proliferation, and survival of endothelial cells in vitro. Stem Cells. 2007;25(7):1761-1768.

[19]王嗣予,王福生.间充质干细胞作为免疫调节剂用于临床肝移植治疗研究进展[J].细胞与分子免疫学杂志, 2010, 26(2):200-201.

[20]Chung HJ, Chung WH, Lee JH, et al. Expression of neurotrophic factors in injured spinal cord after transplantation of human-umbilical cord blood stem cells in rats. J Vet Sci. 2016;17(1):97-102.

[21]Lee S, Choi E, Cha MJ, et al. Cell adhesion and long-term survival of transplanted mesenchymal stem cells: a prerequisite for cell therapy. Oxid Med Cell Longev. 2015;2015:632902.

[22]Sibov TT, Pavon LF, Miyaki LA, et al. Umbilical cord mesenchymal stem cells labeled with multimodal iron oxide nanoparticles with fluorescent and magnetic properties: application for in vivo cell tracking. Int J Nanomedicine. 2014;9:337-350.

[23]Yang S, Xue DD, Wu B, et al. Pleiotrophin is involved in the amniotic epithelial cell-induced differentiation of human umbilical cord blood-derived mesenchymal stem cells into dopaminergic neuron-like cells. Neurosci Lett. 2013;539:86-91.

[24]Devarajan K, Forrest ML, Detamore MS, et al. Adenovector-mediated gene delivery to human umbilical cord mesenchymal stromal cells induces inner ear cell phenotype. Cell Reprogram. 2013;15(1):43-54.

[25]Marquez-Medina D, Salla-Fortuny J, Salud-Salvia A. Role of gamma-delta T-cells in cancer: another opening door to immunotherapy. Clin Transl Oncol. 2012;14(12):891-895.

[26]Zhang Y, Wang J, Ren M, et al. Gene therapy of ovarian cancer using IL-21-secreting human umbilical cord mesenchymal stem cells in nude mice. J Ovarian Res. 2014;7:8.

[27]Jing W, Chen Y, Lu L, et al. Human umbilical cord blood-derived mesenchymal stem cells producing IL15 eradicate established pancreatic tumor in syngeneic mice. Mol Cancer Ther. 2014;13(8): 2127-2137.

[28]张娜.人脐带血间充质干细胞对人胃癌MGC80-3细胞生物学行为的影响[J].现代肿瘤医学, 2014,22(6):1288-1293.

[29]Akimoto K, Kimura K, Nagano M, et al. Umbilical cord blood-derived mesenchymal stem cells inhibit, but adipose tissue-derived mesenchymal stem cells promote, glioblastoma multiforme proliferation. Stem Cells Dev. 2013;22(9):1370-1386.

[30]Wang Y, Fan H, Zhou B, et al. Fusion of human umbilical cord mesenchymal stem cells with esophageal carcinoma cells inhibits the tumorigenicity of esophageal carcinoma cells. Int J Oncol. 2012;40(2): 370-377.

[31]Ghaedi M, Soleimani M, Taghvaie NM, et al. Mesenchymal stem cells as vehicles for targeted delivery of anti-angiogenic protein to solid tumors. J Gene Med. 2011;13(3):171-180.

[32]Sun B, Yu KR, Bhandari DR, et al. Human umbilical cord blood mesenchymal stem cell-derived extracellular matrix prohibits metastatic cancer cell MDA-MB-231 proliferation. Cancer Lett. 2010; 296(2):178-185.

[33]徐玥.人脐带血间充质干细胞对舌鳞癌细胞系CAL-27生长作用的研究[D].青岛:青岛大学,2018.