Hexagonally packed microwell plates for hypoxic microenvironment induction in tumorspheres

Dongbin Won; Ilkyoo Koh; Junghwa Cha; Pilnam Kim

Journal of Industrial and Engineering Chemistry, Vol.72, 67-72, April, 2019

DOI10.1016/j.jiec.2018.12.010 Export Citation

Hexagonally packed microwell plates for hypoxic microenvironment induction in tumorspheres

Dongbin Won, Ilkyoo Koh, Junghwa Cha, and Pilnam Kim^†

Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea

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The growth of a solid tumor in a confined microenvironment leads to increased compression, hypoxic/ nutrition gradient within the tumor. However, Tumorspheres (TSs) cultured in free of spatial confinement do not exhibit physiological compressive stress. Here, we designed a microwell-based sphero-plate that allowed TSs to experience spatial confinement. On this platform, TSs underwent growth-mediated compressive stress and formed hypoxic cores. Moreover, drug resistance was enhanced by the hypoxia-inducible signaling and decreased by HIF-1 targeted drug within compact TSs. These findings highlight the impact of the design of the TSs-based drug testing platform.

Keywords:Tumor microenvironment;Hypoxia;Spatial conferment;Compactness;Tumorspheres

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[1] Breslin S, O’Driscoll L, Oncotarget, 7, 45745 (2016)

[2] Kim C, Biochip J., 9, 105 (2015)

[3] Jang M, Yang S, Kim P, Biochip J., 10, 310 (2016)

[4] Cha J, Kim P, Front Mater., 4 (2017)

[5] Friedrich J, Seidel C, Ebner R, Kunz-Schughart LA, Nat. Protoc., 4, 309 (2009)

[6] Ivascu A, Kubbies M, J. Biomol. Screen., 11, 922 (2006)

[7] Nyberg SL, Hardin J, Amiot B, Argikar UA, Remmel RP, Rinaldo P, Liver Transpl., 11, 901 (2005)

[8] Northey JJ, Przybyla L, Weaver VM, Cancer Discov., 7, 1224 (2017)

[9] Dolega ME, Delarue M, Ingremeau F, Prost J, Delon A, Cappello G, Nat. Commun., 8 (2017)

[10] Stylianopoulos T, Martin JD, Snuderl M, Mpekris F, Jain SR, Jain RK, Cancer Res., 73, 3833 (2013)

[11] Hanahan D, Weinberg RA, Cell, 100, 57 (2000)

[12] Brown JM, William WR, Nat. Rev. Cancer, 4, 437 (2004)

[13] Karakashev SV, Reginato MJ, Cancer Manag. Res., 7, 253 (2015)

[14] Comerford KM, Wallace TJ, Karhausen J, Louis NA, Montalto MC, Colgan SP, Cancer Res., 62, 3387 (2002)

[15] Gottesman MM, Fojo T, Bates SE, Nat. Rev. Cancer, 2, 48 (2002)

[16] Rohwer N, Bogdanoff B, Wiedenmann B, Loddenkemper C, Schmitt CA, Cramer T, Onkologie, 33, 6 (2010)

[17] Rohwer N, Crame T, Drug Resist. Update, 14, 191 (2011)

[18] Sullivan R, Pare GC, Frederiksen LJ, Semenza GL, Graham CH, Mol. Cancer Ther., 7, 1961 (2008)

[19] Pampaloni F, Reynaud EG, Stelzer EHK, Nat. Rev. Mol. Cell Biol., 8, 839 (2007)

[20] Johnson JI, Decker S, Zaharevitz D, Rubinstein LV, Venditti J, Schepartz S, Kalyandrug S, Christian M, Arbuck S, Hollingshead M, Sausville EA, Br. J. Cancer, 84, 1424 (2001)

[21] Prestwich GD, J. Cell. Biochem., 101, 1370 (2007)