Malignant gliomas can be converted to non‑proliferating glial cells by treatment with a combination of small molecules

Oh,Jinsoo; Kim,Yongbo; Baek,Daye; Ha,Yoon

doi:10.3892/or.2018.6824

Malignant gliomas can be converted to non‑proliferating glial cells by treatment with a combination of small molecules

Authors:
- Jinsoo Oh
- Yongbo Kim
- Daye Baek
- Yoon Ha
View Affiliations

Affiliations: Department of Neurosurgery, Spine and Spinal Cord Institute, College of Medicine, Yonsei University, Seoul 03722, Republic of Korea
Published online on: October 25, 2018 https://doi.org/10.3892/or.2018.6824
Pages: 361-368

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Gliomas, the most highly malignant central nervous system tumors, are associated with an extremely poor patient survival rate. Given that gliomas are derived from mutations in glial precursor cells, a considerable number of them strongly react with glial precursor cell‑specific markers. Thus, we investigated whether malignant gliomas can be converted to glial cells through the regulation of endogenous gene expression implicated in glial precursor cells. In the present study, we used three small‑molecule compounds, [cyclic adenosine monophosphate (cAMP) enhancer, a mammalian target of rapamycin (mTOR) inhibitor, and a bromodomain and extra‑terminal motif (BET) inhibitor] for glial reprogramming. Small‑molecule‑induced gliomas (SMiGs) were not only transformed into exhibiting a glial‑specific morphology, but also showed positive reactions with glial‑specific markers such as glial fibrillary acidic protein (GFAP), 2',3'‑cyclic nucleotide 3'‑phosphohydrolase (CNP) and anti‑oligodendrocyte (RIP). A microarray analysis indicated that SMiGs exhibited a marked increase in specific gene levels, whereas that of a malignant cancer‑specific gene was greatly decreased. Moreover, proliferation of the cells was markedly suppressed after the conversion of malignant glioma cells into glial cells. Our findings confirmed that malignant gliomas can be reprogrammed to non‑proliferating glial cells, using a combination of small molecules, and their proliferation can be regulated by their differentiation. We suggest that our small‑molecule combination (with forskolin, rapamycin and I‑BET151) may be the next generation of anticancer agents that act by reprogramming malignant gliomas to differentiate into glial cells.

View Figures

View References

1	Thier M, Wörsdörfer P, Lakes YB, Gorris R, Herms S, Opitz T, Seiferling D, Quandel T, Hoffmann P, Nöthen MM, et al: Direct conversion of fibroblasts into stably expandable neural stem cells. Cell Stem Cell. 10:473–479. 2012. View Article : Google Scholar : PubMed/NCBI
2	Tian E, Sun G, Sun G, Chao J, Ye P, Warden C, Riggs AD and Shi Y: Small-molecule-based lineage reprogramming creates functional astrocytes. Cell Rep. 16:781–792. 2016. View Article : Google Scholar : PubMed/NCBI
3	Zhang M, Lin YH, Sun YJ, Zhu S, Zheng J, Liu K, Cao N, Li K, Huang Y and Ding S: Pharmacological reprogramming of fibroblasts into neural stem cells by signaling-directed transcriptional activation. Cell Stem Cell. 18:653–667. 2016. View Article : Google Scholar : PubMed/NCBI
4	Caiazzo M, Giannelli S, Valente P, Lignani G, Carissimo A, Sessa A, Colasante G, Bartolomeo R, Massimino L, Ferroni S, et al: Direct conversion of fibroblasts into functional astrocytes by defined transcription factors. Stem Cell Reports. 4:pp. 25–36. 2015, View Article : Google Scholar : PubMed/NCBI
5	Cheng L, Hu W, Qiu B, Zhao J, Yu Y, Guan W, Wang M, Yang W and Pei G: Generation of neural progenitor cells by chemical cocktails and hypoxia. Cell Res. 25:645–646. 2015. View Article : Google Scholar : PubMed/NCBI
6	Xue Y, Ouyang K, Huang J, Zhou Y, Ouyang H, Li H, Wang G, Wu Q, Wei C, Bi Y, et al: Direct conversion of fibroblasts to neurons by reprogramming PTB-regulated microRNA circuits. Cell. 152:82–96. 2013. View Article : Google Scholar : PubMed/NCBI
7	Ladewig J, Mertens J, Kesavan J, Doerr J, Poppe D, Glaue F, Herms S, Wernet P, Kögler G, Müller FJ, et al: Small molecules enable highly efficient neuronal conversion of human fibroblasts. Nat Methods. 9:575–578. 2012. View Article : Google Scholar : PubMed/NCBI
8	Pang ZP, Yang N, Vierbuchen T, Ostermeier A, Fuentes DR, Yang TQ, Citri A, Sebastiano V, Marro S, Südhof TC and Wernig M: Induction of human neuronal cells by defined transcription factors. Nature. 476:220–223. 2011. View Article : Google Scholar : PubMed/NCBI
9	Ambasudhan R, Talantova M, Coleman R, Yuan X, Zhu S, Lipton SA and Ding S: Direct reprogramming of adult human fibroblasts to functional neurons under defined conditions. Cell Stem Cell. 9:113–118. 2011. View Article : Google Scholar : PubMed/NCBI
10	Su Z, Zang T, Liu ML, Wang LL, Niu W and Zhang CL: Reprogramming the fate of human glioma cells to impede brain tumor development. Cell Death Dis. 5:e14632014. View Article : Google Scholar : PubMed/NCBI
11	Guichet PO, Bieche I, Teigell M, Serguera C, Rothhut B, Rigau V, Scamps F, Ripoll C, Vacher S, Taviaux S, et al: Cell death and neuronal differentiation of glioblastoma stem-like cells induced by neurogenic transcription factors. Glia. 61:225–239. 2013. View Article : Google Scholar : PubMed/NCBI
12	Hu W, Qiu B, Guan W, Wang Q, Wang M, Li W, Gao L, Shen L, Huang Y, Xie G, et al: Direct conversion of normal and Alzheimer's disease human fibroblasts into neuronal cells by small molecules. Cell Stem Cell. 17:204–212. 2015. View Article : Google Scholar : PubMed/NCBI
13	Li X, Zuo X, Jing J, Ma Y, Wang J, Liu D, Zhu J, Du X, Xiong L, Du Y, et al: Small-molecule-driven direct reprogramming of mouse fibroblasts into functional neurons. Cell Stem Cell. 17:195–203. 2015. View Article : Google Scholar : PubMed/NCBI
14	Galvao RP, Kasina A, McNeill RS, Harbin JE, Foreman O, Verhaak RG, Nishiyama A, Miller CR and Zong H: Transformation of quiescent adult oligodendrocyte precursor cells into malignant glioma through a multistep reactivation process. Proc Natl Acad Sci USA. 111:E4214–E4223. 2014. View Article : Google Scholar : PubMed/NCBI
15	Hayes J, Thygesen H, Droop A, Hughes TA, Westhead D, Lawler SE, Wurdak H and Short SC: Prognostic microRNAs in high-grade glioma reveal a link to oligodendrocyte precursor differentiation. Oncoscience. 2:252–262. 2014. View Article : Google Scholar : PubMed/NCBI
16	Kim JB, Lee H, Araúzo-Bravo MJ, Hwang K, Nam D, Park MR, Zaehres H, Park KI and Lee SJ: Oct4-induced oligodendrocyte progenitor cells enhance functional recovery in spinal cord injury model. EMBO J. 34:2971–2983. 2015. View Article : Google Scholar : PubMed/NCBI
17	Tyler WA, Gangoli N, Gokina P, Kim HA, Covey M, Levison SW and Wood TL: Activation of the mammalian target of rapamycin (mTOR) is essential for oligodendrocyte differentiation. J Neurosci. 29:6367–6378. 2009. View Article : Google Scholar : PubMed/NCBI
18	Garnier JM, Sharp PP and Burns CJ: BET bromodomain inhibitors: A patent review. Expert Opin Ther Pat. 24:185–199. 2014. View Article : Google Scholar : PubMed/NCBI
19	Shi J and Vakoc CR: The mechanisms behind the therapeutic activity of BET bromodomain inhibition. Mol Cell. 54:728–736. 2014. View Article : Google Scholar : PubMed/NCBI
20	Gacias M, Gerona-Navarro G, Plotnikov AN, Zhang G, Zeng L, Kaur J, Moy G, Rusinova E, Rodriguez Y, Matikainen B, et al: Selective chemical modulation of gene transcription favors oligodendrocyte lineage progression. Chem Biol. 21:841–854. 2014. View Article : Google Scholar : PubMed/NCBI
21	Meyer M, Reimand J, Lan X, Head R, Zhu X, Kushida M, Bayani J, Pressey JC, Lionel AC, Clarke ID, et al: Single cell-derived clonal analysis of human glioblastoma links functional and genomic heterogeneity. Proc Natl Acad Sci USA. 112:851–856. 2015. View Article : Google Scholar : PubMed/NCBI
22	Tang Y, He W, Wei Y, Qu Z, Zeng J and Qin C: Screening key genes and pathways in glioma based on gene set enrichment analysis and meta-analysis. J Mol Neurosci. 50:324–332. 2013. View Article : Google Scholar : PubMed/NCBI
23	Nanda A, Buckhaults P, Seaman S, Agrawal N, Boutin P, Shankara S, Nacht M, Teicher B, Stampfl J, Singh S, et al: Identification of a binding partner for the endothelial cell surface proteins TEM7 and TEM7R. Cancer Res. 64:8507–8511. 2004. View Article : Google Scholar : PubMed/NCBI
24	Davies G, Rmali KA, Watkins G, Mansel RE, Mason MD and Jiang WG: Elevated levels of tumour endothelial marker-8 in human breast cancer and its clinical significance. Int J Oncol. 29:1311–1317. 2006.PubMed/NCBI
25	Song MH, Kim YR, Lee JW, Lee CH and Lee SY: Cancer/testis antigen NY-SAR-35 enhances cell proliferation, migration, and invasion. Int J Oncol. 48:569–576. 2016. View Article : Google Scholar : PubMed/NCBI
26	Tomiyoshi G, Nakanishi A, Takenaka K, Yoshida K and Miki Y: Novel BRCA2-interacting protein BJ-HCC-20A inhibits the induction of apoptosis in response to DNA damage. Cancer Sci. 99:747–754. 2008. View Article : Google Scholar : PubMed/NCBI
27	Ikeda J, Morii E, Liu Y, Qiu Y, Nakamichi N, Jokoji R, Miyoshi Y, Noguchi S and Aozasa K: Prognostic significance of CD55 expression in breast cancer. Clin Cancer Res. 14:4780–4786. 2008. View Article : Google Scholar : PubMed/NCBI
28	Park SY, Piao Y, Jeong KJ, Dong J and de Groot JF: Periostin (POSTN) regulates tumor resistance to antiangiogenic therapy in glioma models. Mol Cancer Ther. 15:2187–2197. 2016. View Article : Google Scholar : PubMed/NCBI
29	Che Mat MF, Abdul Murad NA, Ibrahim K, Mohd Mokhtar N, Wan Ngah WZ, Harun R and Jamal R: Silencing of PROS1 induces apoptosis and inhibits migration and invasion of glioblastoma multiforme cells. Int J Oncol. 49:2359–2366. 2016. View Article : Google Scholar : PubMed/NCBI
30	Annovazzi L, Mellai M, Caldera V, Valente G and Schiffer D: SOX2 expression and amplification in gliomas and glioma cell lines. Cancer Genomics Proteomics. 8:139–147. 2011.PubMed/NCBI
31	Schmitz M, Temme A, Senner V, Ebner R, Schwind S, Stevanovic S, Wehner R, Schackert G, Schackert HK, Fussel M, et al: Identification of SOX2 as a novel glioma-associated antigen and potential target for T cell-based immunotherapy. Br J Cancer. 96:1293–1301. 2007. View Article : Google Scholar : PubMed/NCBI
32	Phi JH, Park SH, Kim SK, Paek SH, Kim JH, Lee YJ, Cho BK, Park CK, Lee DH and Wang KC: Sox2 expression in brain tumors: A reflection of the neuroglial differentiation pathway. Am J Surg Pathol. 32:103–112. 2008. View Article : Google Scholar : PubMed/NCBI
33	Wehler TC, Frerichs K, Graf C, Drescher D, Schimanski K, Biesterfeld S, Berger MR, Kanzler S, Junginger T, Galle PR, et al: PDGFRalpha/beta expression correlates with the metastatic behavior of human colorectal cancer: A possible rationale for a molecular targeting strategy. Oncol Rep. 19:697–704. 2008.PubMed/NCBI
34	Heldin CH: Targeting the PDGF signaling pathway in tumor treatment. Cell Commun Signal. 11:972013. View Article : Google Scholar : PubMed/NCBI
35	Golfinos JG, Norman SA, Coons SW, Norman RA, Ballecer C and Scheck AC: Expression of the genes encoding myelin basic protein and proteolipid protein in human malignant gliomas. Clin Cancer Res. 3:799–804. 1997.PubMed/NCBI
36	Popko B, Pearl DK, Walker DM, Comas TC, Baerwald KD, Burger PC, Scheithauer BW and Yates AJ: Molecular markers that identify human astrocytomas and oligodendrogliomas. J Neuropathol Exp Neurol. 61:329–338. 2002. View Article : Google Scholar : PubMed/NCBI
37	Nakada M, Kita D, Watanabe T, Hayashi Y, Teng L, Pyko IV and Hamada J: Aberrant signaling pathways in glioma. Cancers. 3:3242–3278. 2011. View Article : Google Scholar : PubMed/NCBI
38	Motegi H, Kamoshima Y, Terasaka S, Kobayashi H and Houkin K: Type 1 collagen as a potential niche component for CD133-positive glioblastoma cells. Neuropathology. 34:378–385. 2014.PubMed/NCBI