Abstract
Cancer stem cells (CSCs) have the characteristics of self-renewal, unlimited proliferation, and initiating new tumors. However, the origin of CSCs is still controversial. F6, a tumor cell line transformed from human fetal mesenchymal stem cells, was established in our previous study. Whether CSCs exist in this mutated cell line remains unclear. In the present study, we isolated CSCs from F6 cells based on CD133 expression using flow cytometry and investigated the biological characteristics of CD133+ F6 cells (F6-CD133+). We observed that the F6-CD133+ cells grew faster and had a higher capacity of colony formation than the F6-CD133− cells and parental F6 cells in vitro. In addition, F6-CD133+ cells had a higher tumorigenic ability than F6-CD133− cells in vivo since 1,000 F6-CD133+ cells were able to form tumors in nude mice. Cell viability assay revealed that F6-CD133+ cells were more sensitive to cisplatin while less to 5-fluorouracil. Furthermore, gene expression profile analysis showed that there were 673 differentially expressed genes between F6-CD133+ and F6-CD133− cells, many of which were involved in key cell signaling pathways. Taken together, our findings confirm that F6 cells contain a population of CSCs that contribute to its heterogeneity and tumorigenic potential, indicating that transformed stem cells could be the source of CSCs, and targeting this population may lead to more effective tumor treatments.
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References
Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111
Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3:730–737
Dontu G, Al-Hajj M, Abdallah WM, Clarke MF, Wicha MS (2003) Stem cells in normal breast development and breast cancer. Cell Prolif 36(Suppl 1):59–72
Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, Dirks PB (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63:5821–5828
Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ (2005) Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 65:10946–10951. doi:10.1158/0008-5472.CAN-05-2018
O'Brien CA, Pollett A, Gallinger S, Dick JE (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445:106–110
Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, De Maria R (2007) Identification and expansion of human colon-cancer-initiating cells. Nature 445:111–115
Zhang S, Balch C, Chan MW, Lai HC, Matei D, Schilder JM, Yan PS, Huang TH, Nephew KP (2008) Identification and characterization of ovarian cancer-initiating cells from primary human tumors. Cancer Res 68:4311–4320
Kondo T, Setoguchi T, Taga T (2004) Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. Proc Natl Acad Sci USA 101:781–786
Haraguchi N, Utsunomiya T, Inoue H, Tanaka F, Mimori K, Barnard GF, Mori M (2006) Characterization of a side population of cancer cells from human gastrointestinal system. Stem Cells 24:506–513
Baksh D, Song L, Tuan RS (2004) Adult mesenchymal stem cells: characterization, differentiation, and application in cell and gene therapy. J Cell Mol Med 8:301–316
Zhu W, Xu W, Jiang R, Qian H, Chen M, Hu J, Cao W, Han C, Chen Y (2006) Mesenchymal stem cells derived from bone marrow favor tumor cell growth in vivo. Exp Mol Pathol 80:267–274
Rubio D, Garcia-Castro J, Martin MC, de la Fuente R, Cigudosa JC, Lloyd AC, Bernad A (2005) Spontaneous human adult stem cell transformation. Cancer Res 65:3035–3039
Xu W, Qian H, Zhu W, Chen Y, Shao Q, Sun X, Hu J, Han C, Zhang X (2004) A novel tumor cell line cloned from mutated human embryonic bone marrow mesenchymal stem cells. Oncol Rep 12:501–508
Jiang R, Xu W, Zhu W, Chen M, Qian H, Qiao C, Yang H, Wang X, Chen Y (2006) Histological type of oncogenity and expression of cell cycle genes in tumor cells from human mesenchymal stem cells. Oncol Rep 16:1021–1028
Eramo A, Lotti F, Sette G, Pilozzi E, Biffoni M, Di Virgilio A, Conticello C, Ruco L, Peschle C, De Maria R (2008) Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ 15:504–514
Hirschmann-Jax C, Foster AE, Wulf GG, Goodell MA, Brenner MK (2005) A distinct “side population” of cells in human tumor cells: implications for tumor biology and therapy. Cell Cycle 4:203–205
Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C, Huang Y, Hu X, Su F, Lieberman J et al (2007) let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 131:1109–1123
Wang J, Guo LP, Chen LZ, Zeng YX, Lu SH (2007) Identification of cancer stem cell-like side population cells in human nasopharyngeal carcinoma cell line. Cancer Res 67:3716–3724
Cozzio A, Passegue E, Ayton PM, Karsunky H, Cleary ML, Weissman IL (2003) Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors. Genes Dev 17:3029–3035
del Re EC, Shuja S, Cai J, Murnane MJ (2000) Alterations in cathepsin H activity and protein patterns in human colorectal carcinomas. Br J Cancer 82:1317–1326
Acknowledgements
We thank Maozhi Hu for excellent assistance in flow cytometry analysis. This work was supported by the National Natural Science Foundation of China, grant no. 30471983, Jiangsu Province's Outstanding Medical Academic Leader Program, grant no. LJ200614, the Natural Science Foundation of the Jiangsu Province, grant no. BK2007705, and the Sci-Tech innovation team and talents of Jiangsu University (grant no. 2008-018-02).
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The authors declare no conflict of interests related to this study.
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Xuejing Xu and Hui Qian contributed equally to this paper.
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Xu, X., Qian, H., Zhu, W. et al. Isolation of cancer stem cells from transformed human mesenchymal stem cell line F6. J Mol Med 88, 1181–1190 (2010). https://doi.org/10.1007/s00109-010-0659-5
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DOI: https://doi.org/10.1007/s00109-010-0659-5