胶质瘤细胞上皮-间质转化及靶向抑制策略的研究进展

doi:10.13481/j.1671-587x.20170539

摘要/Abstract

摘要： 上皮-间质转化（EMT）在促进肿瘤的侵袭、转移、复发和治疗抵抗中起重要作用。胶质瘤细胞能够发生EMT，但有一定特殊性。EMT与胶质瘤干细胞（GSCs）之间有密切联系，EMT能使胶质瘤细胞获得干细胞特性。EMT、CSCs和耐药构成肿瘤致命性"三组合"。靶向干预EMT可能阻止肿瘤细胞侵袭和转移、清除CSCs并克服耐药性，已成为备受重视的胶质瘤治疗新策略。本文重点介绍胶质瘤细胞发生EMT的证据和特殊性、EMT与GSCs之间的关系以及靶向抑制EMT的策略，为治疗脑胶质瘤提供了新的思路。

关键词: 肿瘤干细胞, 胶质瘤细胞, 胶质瘤干细胞, 上皮-间质转化

中图分类号:

R739.4

宋扬, 赵丽艳, 李蕴潜, 陈勇. 胶质瘤细胞上皮-间质转化及靶向抑制策略的研究进展[J]. 吉林大学学报(医学版), 2017, 43(05): 1064-1068.

参考文献

[1] Kesari S. Understanding glioblastoma tumor biology:The potential to improve current diagnosis and treatments[J].Semin Oncol, 2011, 38(Suppl 4):S2-10.
[2] Joseph JV, Conroy S, Tomar T, et al. TGF-β is an inducer of ZEB1-dependent mesenchymal transdifferentiation in glioblastoma that is associated with tumor invasion[J]. Cell Death Dis, 2014,5:e1443.
[3] Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition[J]. J Clin Invest, 2009, 119(6):1420-1428.
[4] Ajani JA, Song S, Hochster HS, et al. Cancer stem cells:the promise and the potential[J]. Semin Oncol, 2015, 42(Suppl 1):S3-17.
[5] Singh SK, Clarke ID, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors[J]. Cancer Res, 2003, 63(18):5821-5828.
[6] Son H, Moon A. Epithelial-mesenchymal transition and cell invasion[J].Toxicol Res,2010,26(4):245-252.
[7] Cervantes-Arias A, Pang LY, Argyle DJ. Epithelial-mesenchymal transition as a fundamental mechanism underlying the cancer phenotype[J]. Vet Comp Oncol, 2013, 11(3):169-184.
[8] Gheldof A, Berx G. Cadherins and epithelial-to-mesenchymal transition[J]. Prog Mol Biol Transl Sci, 2013, 116:317-336.
[9] Tania M, Khan MA, Fu J. Epithelial to mesenchymal transition inducing transcription factors and metastatic cancer[J]. Tumour Biol, 2014, 35(8):7335-7342.
[10] Iwatsuki M, Mimori K, Yokobori T, et al. Epithelial-mesenchymal transition in cancer development and its clinical significance[J]. Cancer Sci, 2010, 101(2):293-299.
[11] Kahlert UD, Maciaczyk D, Doostkam S, et al. Activation of canonical WNT/β-catenin signaling enhances in vitro motility of glioblastoma cells by activation of ZEB1 and other activators of epithelial-to-mesenchymal transition[J]. Cancer Lett, 2012, 325(1):42-53.
[12] Brabletz T. To differentiate or not-routes towards metastasis[J]. Nat Rev Cancer, 2012, 12(6):425-436.
[13] Lewis-Tuffin LJ, Rodriguez F, Giannini C, et al. Misregulated E-cadherin expression associated with an aggressive brain tumor phenotype[J]. PLoS One, 2010, 5(10):e13665.
[14] Mikheeva SA, Mikheev AM, Petit A, et al. TWIST1 promotes invasion through mesenchymal change in human glioblastoma[J]. Mol Cancer, 2010, 9:194-212.
[15] Carro MS, Lim WK, Alvarez MJ, et al. The transcriptional network for mesenchymal transformation of brain tumours[J]. Nature, 2010, 463(7279):318-325.
[16] Tso CL, Shintaku P, Chen J, et al. Primary glioblastomas express mesenchymal stem-like properties[J]. Mol Cancer Res, 2006, 4(9):607-619.
[17] Péglion F, Etienne-Manneville S. N-cadherin expression level as a critical indicator of invasion in non-epithelial tumors[J]. Cell Adh Migr, 2012, 6(4):327-332.
[18] Camand E, Peglion F, Osmani N, et al. N-cadherin expression level modulates integrin-mediated polarity and strongly impacts on the speed and directionality of glial cell migration[J]. J Cell Sci, 2012, 125(Pt 4):844-857.
[19] Musumeci G, Magro G, Cardile V, et al. Characterization of matrix metalloproteinase-2 and -9, ADAM-10 and N-cadherin expression in human glioblastoma multiforme[J]. Cell Tissue Res, 2015, 362(1):45-60.
[20] Iwadate Y. Epithelial-mesenchymal transition in glioblastoma progression[J]. Oncol Lett, 2016, 11(3):1615-1620.
[21] Kahlert UD, Nikkhah G, Maciaczyk J. Epithelial-to-mesenchymal(-like)transition as a relevant molecular event in malignant gliomas[J]. Cancer Lett, 2013, 331(2):131-138.
[22] Lee JK, Joo KM, Lee J, et al. Targeting the epithelial to mesenchymal transition in glioblastoma:the emerging role of MET signaling[J]. Onco Targets Ther, 2014, 7:1933-1944.
[23] Iser IC, Pereira MB, Lenz G, et al. The Epithelial-to-mesenchymal transition-like process in glioblastoma:an updated systematic review and in silico investigation[J]. Med Res Rev, 2017, 37(2):271-313.
[24] 宋扬, 赵丽艳, 陈勇, 等. TGF-β1对胶质瘤U87细胞上皮-间质转化的诱导作用[J]. 吉林大学学报:医学版, 2016, 42(6):1087-1091.
[25] Mahabir R, Tanino M, Elmansuri A, et al. Sustained elevation of Snail promotes glial-mesenchymal transition after irradiation in malignant glioma[J]. Neuro Oncol, 2014, 16(5):671-685.
[26] Velpula KK, Dasari VR, Tsung AJ, et al. Cord blood stem cells revert glioma stem cell EMT by down regulating transcriptional activation of Sox2 and Twist1[J]. Oncotarget,2011,2(12):1028-1042
[27] Zarkoob H, Taube JH, Singh SK, et al. Investigating the link between molecular subtypes of glioblastoma, epithelial-mesenchymal transition, and CD133 cell surface protein[J]. PLoS One, 2013, 8(5):e64169.
[28] Liu X, Fan D. The epithelial-mesenchymal transition and cancer stem cells:functional and mechanistic links[J]. Curr Pharm Des, 2015, 21(10):1279-1291.
[29] Sato R. Concise review:Stem cells and epithelial-mesenchymal transition in cancer:biological implications and therapeutic targets[J]. Stem Cells, 2016, 34(8):1997-2007.
[30] Mani SA, Guo W, Liao MJ, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells[J]. Cell, 2008, 133(4):704-715.
[31] Gupta PB, Onder TT, Jiang G, et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening[J]. Cell, 2009, 138(4):645-659.
[32] Lee KH, Ahn EJ, Oh SJ, et al. KITENIN promotes glioma invasiveness and progression, associated with the induction of EMT and stemness markers[J]. Oncotarget, 2015, 6(5):3240-3253.
[33] Zhang XH, Qian Y, Li Z, et al. Let-7g-5p inhibits epithelial-mesenchymal transition consistent with reduction of glioma stem cell phenotypes by targeting VSIG4 in glioblastoma[J]. Oncol Rep, 2016, 36(5):2967-2975.
[34] Zhu T, Li X, Luo L, et al. Reversion of malignant phenotypes of human glioblastoma cells by β-elemene through β-catenin-mediated regulation of stemness-, differentiation-and epithelial-to-mesenchymal transition-related molecules[J]. J Transl Med, 2015, 13:356-370.
[35] Siebzehnrubl FA, Silver DJ, Tugertimur B, et al. The ZEB1 pathway links glioblastoma initiation, invasion and chemoresistance[J]. EMBO Mol Med, 2013, 5(8):1196-1212.
[36] Singh A, Settleman J. EMT, cancer stem cells and drug resistance:an emerging axis of evil in the war on cancer[J]. Oncogene, 2010, 29(34):4741-4751.
[37] Mladinich M, Ruan D, Chan CH. Tackling cancer stem cells via Inhibition of EMT transcription factors[J]. Stem Cells Int, 2016:ID5285892.
[38] Du B, Shim JS. Targeting epithelial-mesenchymal transition (EMT) to overcome drug resistance in cancer[J]. Molecules, 2016, 21(8):965.
[39] Marcucci F, Stassi G, De Maria R. Epithelial-mesenchymal transition:a new target in anticancer drug discovery[J]. Nat Rev Drug Discov, 2016, 15(5):311-325.
[40] Malek R, Wang H, Taparra K, et al. Therapeutic targeting of epithelial plasticity programs:Focus on the epithelial-mesenchymal transition[J]. Cells Tissues Organs, 2017, 203(2):114-127.
[41] Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition[J]. Nat Rev Mol Cell Biol, 2014, 15(3):178-196.
[42] Tania M, Khan MA, Fu J. Epithelial to mesenchymal transition inducing transcription factors and metastatic cancer[J]. Tumour Biol, 2014, 35(8):7335-7342.
[43] Hsu HY, Lin TY, Hwang PA, et al. Fucoidan induces changes in the epithelial to mesenchymal transition and decreases metastasis by enhancing ubiquitin-dependent TGFβ receptor degradation in breast cancer[J]. Carcinogenesis, 2012, 34(4):874-884.
[44] Gonzalez DM, Medici D. Signaling mechanisms of the epithelial-mesenchymal transition[J]. Sci Signal, 2014,7(344):re8-27.
[45] Díaz-López A, Moreno-Bueno G, Cano A. Role of microRNA in epithelial to mesenchymal transition and metastasis and clinical perspectives[J]. Cancer Manag Res, 2014, 6:205-216.
[46] Xu Q, Deng F, Qin Y, et al. Long non-coding RNA regulation of epithelial-mesenchymal transition in cancer metastasis[J]. Cell Death Dis,2016,7(6):e2254-2263.
[47] Zhang X, Wei C, Li J, et al. MicroRNA-361-5p inhibits epithelial-to-mesenchymal transition of glioma cells through targeting Twist1[J]. Oncol Rep, 2017, 37(3):1849-1856.
[48] Xia S, Ji R, Zhan W. Long noncoding RNA papillary thyroid carcinoma susceptibility candidate 3(PTCSC3) inhibits proliferation and invasion of glioma cells by suppressing the Wnt/β-catenin signaling pathway[J]. BMC Neurol, 2017, 17(1):30-40.
[49] Polireddy K, Dong R, McDonald PR, et al. Targeting epithelial-mesenchymal transition for identification of inhibitors for pancreatic cancer cell invasion and tumor spheres formation[J]. PLoS One, 2016, 11(10):e0164811.