Plastic induction of CD133AC133-positive cells in the microenvironment of glioblastoma spheroids

Ohnishi,Ken; Tani,Toshiaki; Bando,Shin-Ichi; Kubota,Nobuo; Fujii,Yoshihiro; Hatano,Osamu; Harada,Hirosi

doi:10.3892/ijo.2014.2483

Plastic induction of CD133AC133-positive cells in the microenvironment of glioblastoma spheroids

Authors:
- Ken Ohnishi
- Toshiaki Tani
- Shin-Ichi Bando
- Nobuo Kubota
- Yoshihiro Fujii
- Osamu Hatano
- Hirosi Harada
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Affiliations: Department of Biology, Center for Humanity and Sciences, Ibaraki Prefectural University of Health Sciences, Inashiki-gun, Ibaraki 300-0394, Japan, Department of Radiological Sciences, Ibaraki Prefectural University of Health Sciences, Inashiki-gun, Ibaraki 300-0394, Japan, Department of Anatomy, Nara Medical University, Kashihara, Nara 634-8521, Japan, Group of Radiation and Tumor Biology, Career-Path Promotion Unit for Young Life Scientists, Kyoto University, Yoshida-Konoe-Cho, Sakyo-ku 606-8501, Japan
Published online on: June 3, 2014 https://doi.org/10.3892/ijo.2014.2483
Pages: 581-586

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Abstract

Recent studies showed that the stemness of cancer stem cells is maintained under a hypoxic microenvironment. However, the relationship of the hypoxic microenvironment in a three-dimensional cell mass and the induction of cancer stem cell-like phenotype is not well known. We examined the relationship between CD133 expression and the hypoxic microenvironment using glioblastoma spheroids formed with the T98G cell line. CD133AC133- and HIF-1α-positive cells were observed in the marginal region of the central hypoxic area positive for HIF-1α 10 days after plating T98G cells. CD133AC133-positive cells were positive for nestin. Quantitative PCR analysis showed that the CD133 expression level is not different in spheroids during the tested period after spheroid formation, indicating that post-translational regulation of the CD133 protein mediates positivity to CD133AC133. When spheroids were trypsinized and the dissociated cells were cultured under the adherent monolayer conditions, the CD133AC133-positive cells gradually disappeared. These results show that CD133AC133-positive cells, which may incline toward undifferentiated cells because of nestin positivity, are plastically induced under the different culture conditions, spheroid and monolayer. In this plasticity, HIF-1α is involved in the induction and maintenance of CD133AC133-positive cells. Spheroids as an in vitro tumor model are useful to study the dynamic changes in the tumor cell phenotype in the different cell microenvironments.

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1	Bao S, Wu Q, McLendon RE, Hao Y, et al: Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 444:756–760. 2006. View Article : Google Scholar : PubMed/NCBI
2	Mannino M and Chalmers AJ: Radioresistance of glioma stem cells: intrinsic characteristic or property of the ‘microenvironment-stem cell unit’? Mol Oncol. 5:374–386. 2011.
3	Liu G, Yuan X, Zeng Z, et al: Analysis of gene expression and chemoresistance of CD133⁺ cancer stem cells in glioblastoma. Mol Cancer. 5:672006. View Article : Google Scholar : PubMed/NCBI
4	Kang MK and Kang SK: Tumorigenesis of chemotherapeutic drug-resistant cancer stem-like cells in brain glioma. Stem Cells Dev. 16:837–847. 2007. View Article : Google Scholar : PubMed/NCBI
5	Mohyeldin A, Garzón-Muvdi T and Quiñones-Hinojosa A: Oxygen in stem cell biology: a critical component of the stem cell niche. Cell Stem Cell. 7:150–161. 2010. View Article : Google Scholar : PubMed/NCBI
6	Parmar K, Mauch P, Vergilio JA, et al: Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Proc Natl Acad Sci USA. 104:5431–5436. 2007. View Article : Google Scholar : PubMed/NCBI
7	Heddleston JM, Li Z, McLendon RE, et al: The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype. Cell Cycle. 8:3274–3284. 2009. View Article : Google Scholar : PubMed/NCBI
8	Mao XG, Yan M, Xue XY, et al: Overexpression of ZNF217 in glioblastoma contributes to the maintenance of glioma stem cells regulated by hypoxia-inducible factors. Lab Invest. 91:1068–1078. 2011. View Article : Google Scholar : PubMed/NCBI
9	Soeda A, Park M, Lee D, et al: Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1alpha. Oncogene. 28:3949–3959. 2009. View Article : Google Scholar : PubMed/NCBI
10	Bar EE, Lin A, Mahairaki V, et al: Hypoxia increases the expression of stem-cell markers and promotes clonogenicity in glioblastoma neurospheres. Am J Pathol. 177:1491–1502. 2010. View Article : Google Scholar : PubMed/NCBI
11	Kolenda J, Jensen SS, Aaberg-Jessen C, et al: Effects of hypoxia on expression of a panel of stem cell and chemoresistance markers in glioblastoma-derived spheroids. J Neurooncol. 103:43–58. 2011. View Article : Google Scholar : PubMed/NCBI
12	Iida H, Suzuki M, Goitsuka R, et al: Hypoxia induces CD133 expression in human lung cancer cells by up-regulation of OCT3/4 and SOX2. Int J Oncol. 40:71–79. 2012.PubMed/NCBI
13	Mathieu J, Zhang Z, Zhou W, et al: HIF induces human embryonic stem cell markers in cancer cells. Cancer Res. 71:4640–4652. 2011. View Article : Google Scholar : PubMed/NCBI
14	Monzani E, Facchetti F, Galmozzi E, et al: Melanoma contains CD133 and ABCG2 positive cells with enhanced tumourigenic potential. Eur J Cancer. 43:935–946. 2007. View Article : Google Scholar : PubMed/NCBI
15	O’Brien CA, Pollett A, Gallinger S, et al: A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature. 445:106–110. 2007.PubMed/NCBI
16	Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al: Identification and expansion of human colon-cancer-initiating cells. Nature. 445:111–115. 2007. View Article : Google Scholar : PubMed/NCBI
17	Ma S, Chan KW, Hu L, et al: Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology. 132:2542–2556. 2007. View Article : Google Scholar : PubMed/NCBI
18	Tirino V, Desiderio V, Paino F, et al: Human primary bone sarcomas contain CD133⁺ cancer stem cells displaying high tumorigenicity in vivo. FASEB J. 25:2022–2030. 2011. View Article : Google Scholar : PubMed/NCBI
19	Singh SK, Hawkins C, Clarke ID, et al: Identification of human brain tumour initiating cells. Nature. 432:396–401. 2004. View Article : Google Scholar : PubMed/NCBI
20	Beier D, Hau P, Proescholdt M, et al: CD133(+) and CD133(−) glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res. 67:4010–4015. 2007.
21	Joo KM, Kim SY, Jin X, et al: Clinical and biological implications of CD133-positive and CD133-negative cells in glioblastomas. Lab Invest. 88:808–815. 2008. View Article : Google Scholar : PubMed/NCBI
22	Ogden AT, Waziri AE, Lochhead RA, et al: Identification of A2B5⁺CD133⁻ tumor-initiating cells in adult human gliomas. Neurosurgery. 62:505–514. 2008.
23	Wang J, Sakariassen P, Tsinkalovsky O, et al: CD133 negative glioma cells form tumors in nude rats and give rise to CD133 positive cells. Int J Cancer. 122:761–768. 2008. View Article : Google Scholar : PubMed/NCBI
24	Platet N, Liu SY, Atifi ME, et al: Influence of oxygen tension on CD133 phenotype in human glioma cell cultures. Cancer Lett. 258:286–290. 2007. View Article : Google Scholar : PubMed/NCBI
25	Yang Z, Wang Z, Fan Y, et al: Expression of CD133 in SW620 colorectal cancer cells is modulated by the microenvironment. Oncol Lett. 4:75–79. 2012.PubMed/NCBI
26	Sutherland RM: Cell and environment interactions in tumor microregions: the multicell spheroid model. Science. 240:177–184. 1988. View Article : Google Scholar : PubMed/NCBI
27	Freyer JP, Tustanoff E, Franko AJ, et al: In situ oxygen consumption rates of cells in V-79 multicellular spheroids during growth. J Cell Physiol. 118:53–61. 1984. View Article : Google Scholar : PubMed/NCBI
28	Freyer JP and Sutherland RM: A reduction in the in situ rates of oxygen and glucose consumption of cells in EMT6/Ro spheroids during growth. J Cell Physiol. 124:516–524. 1985. View Article : Google Scholar : PubMed/NCBI
29	Kemper K, Sprick MR, de Bree M, et al: The AC133 epitope, but not the CD133 protein, is lost upon cancer stem cell differentiation. Cancer Res. 70:719–729. 2010. View Article : Google Scholar : PubMed/NCBI