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Highly enriched CD133+CD44+ stem-like cells with CD133+CD44high metastatic subset in HCT116 colon cancer cells

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Abstract

Stem-like cancer cells (SLCCs) are distinct cellular subpopulation in colon cancer that is essential for tumor maintenance. Previous studies indicated that SLCCs accounted for only a minor subset in a given cancer model. However, we found that SLCCs frequency varied among a panel of colon cancer cell lines, with HCT116 cells composed mainly of SLCCs, as demonstrated by colonosphere forming capability and CD133 expression. Indeed, flow cytometric analysis revealed more than 60% HCT116 cells co-expressed the putative SLCCs markers CD133 and CD44. Compared with non-CD133+CD44+ cells, FACS sorted CD133+CD44+ cells were undifferentiated, endowed with extensive self-renewal and epithelial lineage differentiation capacity in vitro. CD133+CD44+ exhibited enhanced tumorigeneicity in NOD/SCID mice. One thousand CD133+CD44+ cells initiated xenograft tumors efficiently (3/6) while 1 × 105 non-CD133+CD44+ cells could only form palpable nodule with much slower growth rate (1/6). More interestingly, long-term cultured self-renewing CD133+CD44+ cells enriched CD133+CD44high subset, which expressed epithelial to mesenchymal transition marker, were more invasive in vitro and responsible solely for liver metastasis in vivo. In conclusion, these data demonstrated for the first time that CD133+CD44+ SLCCs were highly enriched in HCT116 cells and that metastatic SLCCs resided exclusively in a CD133+CD44high subpopulation.

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References

  1. Jemal A, Siegel R, Xu J et al (2010) Cancer statistics, 2010. CA Cancer J Clin 60:277–300

    Article  PubMed  Google Scholar 

  2. Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61(5):759–767

    Article  PubMed  CAS  Google Scholar 

  3. Preston SL, Wong WM, Chan AO et al (2003) Bottom-up histogenesis of colorectal adenomas: origin in the monocryptal adenoma and initial expansion by crypt fission. Cancer Res 63(13):3819–3825

    PubMed  CAS  Google Scholar 

  4. Barker N, Ridgway RA, van Es JH et al (2009) Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457(7229):608–611

    Article  PubMed  CAS  Google Scholar 

  5. Zhu L, Gibson P, Currle DS et al (2009) Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation. Nature 457(7229):603–607

    Article  PubMed  CAS  Google Scholar 

  6. Ricci-Vitiani L, Lombardi DG, Pilozzi E et al (2007) Identification and expansion of human colon-cancer-initiating cells. Nature 445(7123):111–115

    Article  PubMed  CAS  Google Scholar 

  7. O’Brien CA, Pollett A, Gallinger S et al (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445(7123):106–110

    Article  PubMed  Google Scholar 

  8. Fang DD, Kim YJ, Lee CN et al (2010) Expansion of CD133(+) colon cancer cultures retaining stem cell properties to enable cancer stem cell target discovery. Br J Cancer 102(8):1265–1275

    Article  PubMed  CAS  Google Scholar 

  9. Li CY, Li BX, Liang Y et al (2009) Higher percentage of CD133+ cells is associated with poor prognosis in colon carcinoma patients with stage IIIB. J Transl Med 7:56

    Article  PubMed  CAS  Google Scholar 

  10. Horst D, Kriegl L, Engel J et al (2009) Prognostic significance of the cancer stem cell markers CD133, CD44, and CD166 in colorectal cancer. Cancer Invest 27(8):844–850

    Article  PubMed  Google Scholar 

  11. Shmelkov S, Butler J, Hooper A et al (2008) CD133 expression is not restricted to stem cells, and both CD133+ and CD133− metastatic colon cancer cells initiate tumors. J Clin Investig 118(6):2111–2120

    PubMed  CAS  Google Scholar 

  12. Dittfeld C, Dietrich A, Peickert S et al (2009) CD133 expression is not selective for tumor-initiating or radioresistant cell populations in the CRC cell lines HCT-116. Radiother Oncol 92(3):353–361

    Article  PubMed  CAS  Google Scholar 

  13. Chu P, Clanton DJ, Snipas TS et al (2009) Characterization of a subpopulation of colon cancer cells with stem cell-like properties. Int J Cancer 124(6):1312–1321

    Article  PubMed  CAS  Google Scholar 

  14. Dalerba P, Dylla SJ, Park IK et al (2007) Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci USA 104(24):10158–10163

    Article  PubMed  CAS  Google Scholar 

  15. Du L, Wang H, He L et al (2008) CD44 is of functional importance for colorectal cancer stem cells. Clin Cancer Res 14(21):6751–6760

    Article  PubMed  CAS  Google Scholar 

  16. Ponti D, Costa A, Zaffaroni N et al (2005) Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res 65(13):5506–5511

    Article  PubMed  CAS  Google Scholar 

  17. Lee J, Kotliarova S, Kotliarov Y et al (2006) Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 9(5):391–403

    Article  PubMed  CAS  Google Scholar 

  18. Ieta K, Tanaka F, Haraguchi N et al (2008) Biological and genetic characteristics of tumor-initiating cells in colon cancer. Ann Surg Oncol 15(2):638–648

    Article  PubMed  Google Scholar 

  19. Dean M, Fojo T, Bates S (2005) Tumour stem cells and drug resistance. Nat Rev Cancer 5(4):275–284

    Article  PubMed  CAS  Google Scholar 

  20. Sack MJ, Roberts SA (1997) Cytokeratins 20 and 7 in the differential diagnosis of metastatic carcinoma in cytologic specimens. Diagn Cytopathol 16(2):132–136

    Article  PubMed  CAS  Google Scholar 

  21. Mani SA, Guo W, Liao MJ et al (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133(4):704–715

    Article  PubMed  CAS  Google Scholar 

  22. Haraguchi N, Ohkuma M, Sakashita H et al (2008) CD133+CD44+ population efficiently enriches colon cancer initiating cells. Ann Surg Oncol 15(10):2927–2933

    Article  PubMed  Google Scholar 

  23. Kai K, Nagano O, Sugihara E et al (2009) Maintenance of HCT116 colon cancer cell line conforms to a stochastic model but not a cancer stem cell model. Cancer Sci 100(12):2275–2282

    Article  PubMed  CAS  Google Scholar 

  24. Stuelten CH, Mertins SD, Busch JI et al (2010) Complex display of putative tumor stem cell markers in the NCI60 tumor cell line panel. Stem Cells 28(4):649–660

    Article  PubMed  CAS  Google Scholar 

  25. Botchkina G, Zuniga E, Das M et al (2010) New-generation taxoid SB-T-1214 inhibits stem cell-related gene expression in 3D cancer spheroids induced by purified colon tumor-initiating cells. Mol Cancer 9(1):192

    Article  PubMed  Google Scholar 

  26. Yeung TM, Gandhi SC, Wilding JL et al (2010) Cancer stem cells from colorectal cancer-derived cell lines. Proc Natl Acad Sci USA 107(8):3722–3727

    Article  PubMed  CAS  Google Scholar 

  27. Zeppernick F, Ahmadi R, Campos B et al (2008) Stem cell marker CD133 affects clinical outcome in glioma patients. Clin Cancer Res 14(1):123–129

    Article  PubMed  CAS  Google Scholar 

  28. Rasheed ZA, Yang J, Wang Q et al (2010) Prognostic significance of tumorigenic cells with mesenchymal features in pancreatic adenocarcinoma. J Natl Cancer Inst 102(5):340–351

    Article  PubMed  CAS  Google Scholar 

  29. Zheng X, Shen G, Yang X et al (2007) Most C6 cells are cancer stem cells: evidence from clonal and population analyses. Cancer Res 67(8):3691–3697

    Article  PubMed  CAS  Google Scholar 

  30. Bexell D, Gunnarsson S, Siesjo P et al (2009) CD133+ and nestin+ tumor-initiating cells dominate in N29 and N32 experimental gliomas. Int J Cancer 125(1):15–22

    Article  PubMed  CAS  Google Scholar 

  31. Huang Q, Zhang Q-B, Dong J et al (2008) Glioma stem cells are more aggressive in recurrent tumors with malignant progression than in the primary tumor, and both can be maintained long-term in vitro. BMC Cancer 8(1):304

    Article  PubMed  Google Scholar 

  32. Xu X-L, Xing B-C, Han H-B et al (2010) The properties of tumor-initiating cells from a hepatocellular carcinoma patient’s primary and recurrent tumor. Carcinogenesis 31(2):167–174

    Article  PubMed  CAS  Google Scholar 

  33. Pece S, Tosoni D, Confalonieri S et al (2010) Biological and molecular heterogeneity of breast cancers correlates with their cancer stem cell content. Cell 140(1):62–73

    Article  PubMed  CAS  Google Scholar 

  34. Bacac M, Stamenkovic I (2008) Metastatic cancer cell. Annu Rev Pathol 3:221–247

    Article  PubMed  CAS  Google Scholar 

  35. Yang ZF, Ho DW, Ng MN et al (2008) Significance of CD90+ cancer stem cells in human liver cancer. Cancer Cell 13(2):153–166

    Article  PubMed  CAS  Google Scholar 

  36. Hermann PC, Huber SL, Herrler T et al (2007) Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 1(3):313–323

    Article  PubMed  CAS  Google Scholar 

  37. Pang R, Law WL, Chu ACY et al (2010) A subpopulation of CD26+ cancer stem cells with metastatic capacity in human colorectal cancer. Cell Stem Cell 6(6):603–615

    Article  PubMed  CAS  Google Scholar 

  38. Hope K, Jin L, Dick J (2004) Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nat Immunol 5(7):738–743

    Article  PubMed  CAS  Google Scholar 

  39. Chen R, Nishimura M, Bumbaca S et al (2010) A hierarchy of self-renewing tumor-initiating cell types in glioblastoma. Cancer Cell 17(4):362–375

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Dr. Jia-si Bai (Central Laboratory, Southwest Hospital, Chongqing, China) for technical assistance in laser confocal scanning microscopy. This work was supported by the grants from the National Basic Research Program of China (973 Program, No 2010CB529403) and the Natural Science Foundation Project of CQ CSTC (No. CSTC2009BB5328).

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We declared that no conflicts of interest should be disclosed.

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Authors and Affiliations

  1. Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China

    Ke-li Chen, Feng Pan, Heng Jiang, Jian-fang Chen, Li Pei, Fang-wei Xie & Hou-jie Liang

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  1. Ke-li Chen
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  2. Feng Pan
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  3. Heng Jiang
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  4. Jian-fang Chen
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  7. Hou-jie Liang
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Correspondence to Hou-jie Liang.

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Ke-li Chen and Feng Pan are contributed equally to this work.

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Chen, Kl., Pan, F., Jiang, H. et al. Highly enriched CD133+CD44+ stem-like cells with CD133+CD44high metastatic subset in HCT116 colon cancer cells. Clin Exp Metastasis 28, 751–763 (2011). https://doi.org/10.1007/s10585-011-9407-7

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