Recapitulation of cancer stem cell niches in glioblastoma on 3D microfluidic cell culture devices under gravity-driven perfusion

Jeonghun Han; Seunghan Oh; Hong-Hoa Hoang; Dao Thi Thuy Nguyen; Wanyoung Lim; Tae Hwan Shin; Gwang Lee; Sungsu Park

Journal of Industrial and Engineering Chemistry, Vol.62, 352-361, June, 2018

DOI10.1016/j.jiec.2018.01.015 Export Citation

Recapitulation of cancer stem cell niches in glioblastoma on 3D microfluidic cell culture devices under gravity-driven perfusion

Jeonghun Han, Seunghan Oh¹, Hong-Hoa Hoang, Dao Thi Thuy Nguyen, Wanyoung Lim², Tae Hwan Shin³, Gwang Lee³, and Sungsu Park^†

School of Mechanical Engineering, Sungkyunkwan University, Suwon, Republic of Korea
¹Division of Plant Biotechnology, College of Agriculture and Life Science, Chonnam National University, Gwangju, Republic of Korea
²Department of Global Biomedical Engineering, Sungkyunkwan University, Suwon, Republic of Korea
³Department of Physiology and Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, Republic of Korea

E-mail:

The low survival rate of patients with glioblastoma is in part due to the heterogeneity in the cellVpopulation of glioblastoma that includes cancer stem cells (CSCs). CSC niches include a hypoxic core thatVis also closely linked to self-renewal ability, migration, and drug resistance. Here, we report a CSC cultureVmethod in three-dimensional microfluidic cell culture devices under gravity-driven perfusion, which weVdub hypoxia chips (H-chips). In H-chips, glioblastoma cells, U87, spontaneously formed spheroids withinV12 h, even without any addition of growth factors. Compared to monolayer-cultured cells in dishes,Vspheroids in H-chips showed higher expression of CSC markers, such as hypoxia-inducible factor-1aV(HIF-1α), CD133, and nestin. Spheroids in H-chips were more resistant to doxorubicin than monolayer-Vcultured ones in dishes. Transcriptional profiling revealed that the expression of interleukin-6 (IL-6), oneVof the inflammatory cytokines, was higher in spheroids in H-chips than in monolayer-cultured cells inVdishes. IL-6 depleted cells failed to form spheroids in H-chips, and their drug resistance decreased. TheseVresults suggest that in H-chips, glioblastoma cells increased the production of IL-6, and promotedVspheroid formation and other cancer stem cell properties, such as drug resistance. Our microfluidic cellVculture method is highly useful for recapitulating CSC niches.

Keywords:Cancer stem cell;Microfluidic cell culture;IL-6;Spheroid;Doxorubicin

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[2] Reya T, Morrison SJ, Clarke MF, Weissman IL, Nature, 414, 105 (2001)

[3] Dirks PB, Nature, 444, 687 (2006)

[4] Wang P, Lan C, Xiong S, Zhao X, Shan Y, Hu R, Wan W, Yu S, Liao B, Li G, Wang J, Zou D, Chen B, Feng H, Wu N, Oncotarget, 8, 28074 (2017)

[5] Heddleston JM, Li Z, Lathia JD, Bao S, Hjelmeland AB, Rich JN, Br. J. Cancer, 102, 789 (2010)

[6] Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB, Nature, 432, 396 (2004)

[7] Xue L, Ding P, Xiao L, Hu M, Hu Z, Int. J. Exp. Pathol., 92, 377 (2011)

[8] Iida H, Suzuki M, Goitsuka R, Ueno H, Int. J. Oncol., 40, 71 (2012)

[9] Park EK, Lee JC, Park JW, Bang SY, Yi SA, Kim BK, Park JH, Kwon SH, You JS, Nam SW, Cho EJ, Han JW, Cell. Death Dis., 6, e1964 (2015)

[10] Cabarcas SM, Mathews LA, Farrar WL, Int. J. Cancer, 129, 2315 (2011)

[11] Nilsson CL, Dillon R, Devakumar A, Shi SD, Greig M, Rogers JC, et al., J. Proteome. Res., 9, 430 (2010)

[12] Wang H, Lathia JD, Wu Q, Wang J, Li Z, Heddleston JM, Eyler CE, et al., Stem Cells, 27, 2393 (2009)

[13] Arai K, Sakamoto R, Kubota D, Kondo T, Proteomics, 13, 2351 (2013)

[14] Takagi A, Watanabe M, Ishii Y, Morita J, Hirokawa J, Matsuzaki T, Shiraishi T, Anticancer Res., 27, 45 (2007)

[15] Grimes DR, Kelly C, Bloch K, Partridge M, J. R. Soc. Interface, 11, 201311 (2014)

[16] Vinci M, Gowan S, Boxall F, Patterson L, Zimmermann M, Court W, Lomas C, Mendiola M, Hardisson D, Eccles SA, BMC Biol., 10, 29 (2012)

[17] Asghar W, El Assal R, Shafiee H, Pitteri S, Paulmurugan R, Demirci U, Mater. Today, 18, 539 (2015)

[18] Kelm JM, Timmins NE, Brown CJ, Fussenegger M, Nielsen LK, Biotechnol. Bioeng., 83(2), 173 (2003)

[19] Yap KK, Dingle AM, Palmer JA, Dhillon RS, Lokmic Z, Penington AJ, Yeoh GC, Morrison WA, Mitchell GM, Biomaterials, 34, 3992 (2013)

[20] Nashimoto Y, Hayashi T, Kunita I, Nakamasu A, Torisawa YS, Nakayama M, Takigawa-Imamura H, Kotera H, Nishiyama K, Miura T, Yokokawa R, Integr. Biol., 9, 506 (2017)

[21] Ong SM, Zhang C, Toh YC, Kim SH, Foo HL, Tan CH, van Noort D, Park S, Yu H, Biomaterials, 29, 3237 (2008)

[22] Choi J, Kim S, Jung J, Lim Y, Kang K, Park S, Kang S, Biomaterials, 32, 7013 (2011)

[23] Shiozawa Y, Nie B, Pienta KJ, Morgan TM, Taichman RS, Pharmacol. Ther., 138, 285 (2013)

[24] Schofield CJ, Ratcliffe PJ, Nat. Rev. Mol. Cell Biol., 5, 343 (2004)

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[26] Herrmann H, Aebi U, Curr. Opin. Cell Biol., 12, 79 (2000)

[27] Bar EE, Lin A, Mahairaki V, Matsui W, Eberhart CG, Am. J. Pathol., 177, 1491 (2010)

[28] Hodge DR, Hurt EM, Farrar WL, Eur. J. Cancer, 41, 2502 (2005)

[29] Choi C, Gillespie GY, Van Wagoner NJ, Benveniste EN, J. Neurooncol., 56, 13 (2002)

[30] Tchirkov A, Khalil T, Chautard E, Mokhtari K, Veronese L, Irthum B, Vago P, Kemeny JL, Verrelle P, Br. J. Cancer, 96, 474 (2007)

[31] Grivennikov S, Karin M, Cancer Cell, 13, 7 (2008)

[32] Richards R, Jenkinson MD, Haylock BJ, See V, PeerJ, 4, e1755 (2016)

[33] Gong X, Lin C, Cheng J, Su J, Zhao H, Liu T, Wen X, Zhao P, PLoS One, 10, e01303 (2015)

[34] Brown JM, Cancer Res., 59, 5863 (1999)

[35] Vidal SJ, Rodriguez-Bravo V, Galsky M, Cordon-Cardo C, Domingo-Domenech J, Oncogene, 33, 4451 (2014)

[36] Fukusumi T, Ishii H, Konno M, Yasui T, Nakahara S, Takenaka Y, Yamamoto Y, et al., Br. J. Cancer, 111, 506 (2014)

[37] Cortes-Dericks L, Carboni GL, Schmid RA, Karoubi G, Int. J. Oncol., 37, 437 (2010)

[38] Tacar O, Sriamornsak P, Dass CR, J. Pharm. Pharmacol., 65, 157 (2013)

[39] Woodworth GF, Dunn GP, Nance EA, Hanes J, Brem H, Front. Oncol., 4, 126 (2014)