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CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway

Abstract

The recent discovery of cancer stem cells (CSCs) has played a pivotal role in changing our view of carcinogenesis and chemotherapy. Based on this concept, CSCs are responsible for the formation and growth of neoplastic tissue and are naturally resistant to chemotherapy, explaining why traditional chemotherapies can initially shrink a tumor but fails to eradicate it in full, allowing eventual recurrence. Recently, we identified a CSC population in hepatocellular carcinoma (HCC) characterized by their CD133 phenotype. However, the molecular mechanism by which it escapes conventional therapies remains unknown. Here, we examined the sensitivity of these cells to chemotherapeutic agents (doxorubicin and fluorouracil) and the possible mechanistic pathway by which resistance may be regulated. Purified CD133+ HCC cells isolated from human HCC cell line and xenograft mouse models survived chemotherapy in increased proportions relative to most tumor cells which lack the CD133 phenotype; the underlying mechanism of which required the preferential expression of survival proteins involved in the Akt/PKB and Bcl-2 pathway. Treatment of CD133+ HCC cells with an AKT1 inhibitor, specific to the Akt/PKB pathway, significantly reduced the expression of the survival proteins that was normally expressed endogenously. In addition, treatment of unsorted HCC cells with both anticancer drugs in vitro significantly enriched the CD133+ subpopulation. In conclusion, our results show that CD133+ HCC cells contribute to chemoresistance through preferential activation of Akt/PKB and Bcl-2 cell survival response. Targeting of this specific survival signaling pathway in CD133+ HCC CSCs may provide a novel therapeutic model for the disease.

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References

  • Adams JM, Cory S . (1998). The Bcl-2 protein family: arbiters of cell survival. Science 281: 1322–1326.

    Article  CAS  Google Scholar 

  • Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF . (2003). Prospective identification of tumorigenic breast cancer cells. 100: 3983–3988.

  • 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.

    CAS  Google Scholar 

  • Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ . (2005). Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 65: 10946–10951.

    Article  CAS  Google Scholar 

  • Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y et al. (1997). Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91: 231–241.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Fabregat I, Roncero C, Fernandez M . (2007). Survival and apoptosis: a dysregulated balance in liver cancer. Liver Int 27: 155–162.

    Article  CAS  Google Scholar 

  • Fesik SW . (2005). Promoting apoptosis as a strategy for cancer drug discovery. Nat Rev Cancer 5: 876–885.

    Article  CAS  Google Scholar 

  • Hanahan D, Weinberg RA . (2000). The hallmarks of cancer. Cell 100: 57–70.

    Article  CAS  Google Scholar 

  • Haraguchi N, Utsunomiya T, Inoue H, Tanaka F, Mimori K, Barnard GF et al. (2006). Characterization of a side population of cancer cells from human gastrointestinal system. Stem Cells 24: 506–513.

    Article  CAS  Google Scholar 

  • Hemmati HD, Nakano I, Lazareff JA, Masterman-Smith M, Geschwind DH, Bronner-Fraser M et al. (2003). Cancerous stem cells can arise from pediatric brain tumors. 100: 15178–15183.

  • Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J et al. (1994). A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367: 645–648.

    Article  CAS  Google Scholar 

  • Li CW, Heidt DG, Dalerba P, Burant CF, Zhang LJ, Adsay V et al. (2007). Identification of pancreatic cancer stem cells. Cancer Res 67: 1030–1037.

    Article  CAS  Google Scholar 

  • Ma S, Chan KW, Hu L, Lee TK, Wo JY, Ng IO et al. (2007). Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology 132: 2542–2556.

    Article  CAS  Google Scholar 

  • Nakabayashi H, Taketa K, Miyano K, Yamane T, Sato J . (1982). Growth of human hepatoma cell lines with differentiated functions in chemically defined medium. Cancer Res 42: 3858–3863.

    CAS  Google Scholar 

  • Nicholson KM, Anderson NG . (2002). The protein kinase B/Akt signaling pathway in human malignancy. Cell Signal 14: 381–395.

    Article  CAS  Google Scholar 

  • O’Brien CA, Pollett A, Gallinger S, Dick JE . (2007). A human colon cancer cell capable of initiating tumor growth in immunodeficient mice. Nature 445: 106–110.

    Article  Google Scholar 

  • Pardal R, Clarke MF, Morrison SJ . (2003). Applying the principles of stem-cell biology to cancer. Nat Rev Cancer 3: 895–902.

    Article  CAS  Google Scholar 

  • Patrawala L, Calhoun T, Schneider-Broussard R, Li H, Bhatia B, Tang S et al. (2006). Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Oncogene 25: 1696–1708.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Reya T, Morrison SJ, Clarke MF, Weissman IL . (2001). Stem cells, cancer and cancer stem cells. Nature 414: 105–111.

    Article  CAS  Google Scholar 

  • Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C et al. (2007). Identification and expansion of human colon-cancer-initiating cells. Nature 445: 111–115.

    Article  CAS  Google Scholar 

  • Sebolt-Leopold JS, Herrera R . (2004). Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer 4: 937–947.

    Article  CAS  Google Scholar 

  • Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J et al. (2003). Identification of a cancer stem cell in human brain tumors. Cancer Res 63: 5821–5828.

    CAS  Google Scholar 

  • Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T et al. (2004). Identification of human brain tumor initiating cells. Nature 432: 396–401.

    Article  CAS  Google Scholar 

  • Suetsugu A, Nagaki M, Aoki H, Motohashi T, Kunisada T, Moriwaki H . (2006). Characterization of CD133+ hepatocellular carcinoma cells as cancer stem/progenitor cells. Biochem Biophys Res Commun 351: 820–824.

    Article  CAS  Google Scholar 

  • Thorgeirsson SS, Grisham JW . (2002). Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet 31: 339–346.

    Article  CAS  Google Scholar 

  • Vivanco I, Sawyers CL . (2002). The phosphatidylinositol 3-Kinase Akt pathway in human cancer. Nat Rev Cancer 2: 489–501.

    Article  CAS  Google Scholar 

  • Yin S, Li J, Hu C, Chen X, Yao M, Yan M et al. (2007). CD133 positive hepatocellular carcinoma cells possess high capacity for tumorigenicity. Int J Cancer 120: 1436–1442.

    Article  Google Scholar 

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Acknowledgements

We would like to thank Fai Ng for his help with the cell sorting facility. This study is supported by the Research Fund for the Control of Infectious Diseases (02040162) and the Research Grant Council (HKU 7393/04M).

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Correspondence to X-Y Guan.

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Ma, S., Lee, T., Zheng, BJ. et al. CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway. Oncogene 27, 1749–1758 (2008). https://doi.org/10.1038/sj.onc.1210811

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