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Stem Cells

Human mesenchymal stem cells inhibit cancer cell proliferation by secreting DKK-1

Abstract

Mesenchymal stem cells (MSCs) have an inhibitory effect on tumor proliferation, but the precise mechanisms are not fully understood. Here, we identified DKK-1 (dickkopf-1), secreted by MSCs and acting as a negative regulator of WNT signaling pathway, to be one of the molecules responsible for the inhibitory effect. When DKK-1 was neutralized by anti-DKK-1 antibodies, or when the expression of DKK-1 was downregulated by RNA interference (RNAi), the inhibitory effects of MSCs on K562 cell proliferation were attenuated. We also provide evidence that the expression of DKK-1 by MSCs is regulated by NANOG, a transcriptional factor ubiquitously expressed in some stem cells. Using the Cellmax artificial capillary modules that eliminate the immunosuppressive properties of MSCs, we further showed that MSCs were able to inhibit proliferation of K562 cells in a humoral microenvironment. Meanwhile, we recapture this effect of MSCs on primary leukemic hematopoietic progenitors from patients. MSCs probably have a general inhibitory effect on their neighboring cells, including malignant cells, en route to achieving tissue homeostasis.

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References

  1. Hall B, Dembinski J, Sasser AK, Studeny M, Andreeff M, Marini F . Mesenchymal stem cells in cancer: tumor-associated fibroblasts and cell-based delivery vehicles. Int J Hematol 2007; 86: 8–16.

    Article  CAS  Google Scholar 

  2. Xin H, Kanehira M, Mizuguchi H, Hayakawa T, Kikuchi T, Nukiwa T et al. Targeted delivery of CX3CL1 to multiple lung tumors by mesenchymal stem cells. Stem Cells 2007; 25: 1618–1626.

    Article  CAS  Google Scholar 

  3. Fang B, Song YP, Liao LM, Han Q, Zhao RC . Treatment of severe therapy-resistant acute graft-versus-host disease with human adipose tissue-derived mesenchymal stem cells. Bone Marrow Transplant 2006; 38: 389–390.

    Article  CAS  Google Scholar 

  4. Glennie S, Soeiro I, Dyson PJ, Lam EW, Dazzi F . Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood 2005; 105: 2821–2827.

    Article  CAS  Google Scholar 

  5. Aggarwal S, Pittenger MF . Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005; 105: 1815–1822.

    Article  CAS  Google Scholar 

  6. Corcione A, Benvenuto F, Ferretti E, Giunti D, Cappiello V, Cazzanti F et al. Human mesenchymal stem cells modulate B-cell functions. Blood 2006; 107: 367–372.

    Article  CAS  Google Scholar 

  7. Sotiropoulou PA, Perez SA, Gritzapis AD, Baxevanis CN, Papamichail M . Interactions between human mesenchymal stem cells and natural killer cells. Stem Cells 2006; 24: 74–85.

    Article  Google Scholar 

  8. Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002; 99: 3838–3843.

    Article  CAS  Google Scholar 

  9. Nasef A, Chapel A, Mazurier C, Bouchet S, Lopez M, Mathieu N et al. Identification of IL-10 and TGF-beta transcripts involved in the inhibition of T-lymphocyte proliferation during cell contact with human mesenchymal stem cells. Gene Exp 2007; 13: 217–226.

    Article  Google Scholar 

  10. Ohlsson LB, Varas L, Kjellman C, Edvardsen K, Lindvall M . Mesenchymal progenitor cell-mediated inhibition of tumor growth in vivo and in vitro in gelatin matrix. Exp Mol Pathol 2003; 75: 248–255.

    Article  CAS  Google Scholar 

  11. Ramasamy R, Lam EW, Soeiro I, Tisato V, Bonnet D, Dazzi F . Mesenchymal stem cells inhibit proliferation and apoptosis of tumor cells: impact on in vivo tumor growth. Leukemia 2007; 21: 304–310.

    Article  CAS  Google Scholar 

  12. Khakoo AY, Pati S, Anderson SA, Reid W, Elshal MF, Rovira II et al. Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi's sarcoma. J Exp Med 2007; 203: 1235–1247.

    Article  Google Scholar 

  13. Moon RT, Kohn AD, De Ferrari GV, Kaykas A . Wnt and β-catenin signalling: diseases and therapies. Nat Rev Genet 2004; 5: 691–701.

    Article  CAS  Google Scholar 

  14. Fodde R, Brabletz T . Wnt/beta-catenin signaling in cancer stemness and malignant behavior. Curr Opin Cell Biol 2007; 19: 150–158.

    Article  CAS  Google Scholar 

  15. Glinka A, Wu W, Delius H, Monaghan AP, Blumenstock C, Niehrs C . Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction. Nature 1998; 391: 357–362.

    Article  CAS  Google Scholar 

  16. Fedi P, Bafico A, Nieto Soria A, Burgess WH, Miki T, Bottaro DP et al. Isolation and biochemical characterization of the human Dkk-1 homologue, a novel inhibitor of mammalian Wnt signaling. J Biol Chem 1999; 274: 19465–19472.

    Article  CAS  Google Scholar 

  17. Etheridge SL, Spencer GJ, Heath DJ, Genever PG . Expression profiling and functional analysis of wnt signaling mechanisms in mesenchymal stem cells. Stem Cells 2004; 22: 849–860.

    Article  CAS  Google Scholar 

  18. Cao Y, Sun Z, Liao L, Meng Y, Han Q, Zhao RC . Human adipose tissue-derived stem cells differentiate into endothelial cells in vitro and improve postnatal neovascularization in vivo. Biochem Biophys Res Commun 2005; 332: 370–379.

    Article  CAS  Google Scholar 

  19. Reynolds A, Leake D, Boese Q, Scaringe S, Marshall WS, Khvorova A . Rational siRNA design for RNA interference. Nat Biotechnol 2004; 22: 326–330.

    Article  CAS  Google Scholar 

  20. Li J, Shi M, Cao Y, Yuan W, Pang T, Li B et al. Knockdown of hypoxia-inducible factor-1alpha in breast carcinoma MCF-7 cells results in reduced tumor growth and increased sensitivity to methotrexate. Biochem Biophys Res Commun 2006; 342: 1341–1351.

    Article  CAS  Google Scholar 

  21. Maruyama M, Ichisaka T, Nakagawa M, Yamanaka S . Differential roles for sox15 and sox2 in transcriptional control in mouse embryonic stem cells. J Biol Chem 2005; 280: 24371–24379.

    Article  CAS  Google Scholar 

  22. Mitsui K, Tokuzawa Y, Itoh H, Segawa K, Murakami M, Takahashi K et al. The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 2003; 113: 631–642.

    Article  CAS  Google Scholar 

  23. Konopleva M, Konoplev S, Hu W, Zaritskey AY, Afanasiev BV, Andreeff M . Stromal cells prevent apoptosis of AML cells by upregulation of anti-apoptotic proteins. Leukemia 2002; 16: 1713–1724.

    Article  CAS  Google Scholar 

  24. Shih CC, Hu MC, Hu J, Medeiros J, Forman SJ . Long-term ex vivo maintenance and expansion of transplantable human hematopoietic stem cells. Blood 1999; 94: 1623–1636.

    CAS  PubMed  Google Scholar 

  25. Cordero EA, Da Rocha Silla LM, Cañedo AD, Allebrandt WF, Fogliatto L, Nardi NB . Interaction between normal and CML hematopoietic progenitors and stroma influences abnormal hematopoietic development. Stem Cells Dev 2004; 13: 225–228.

    Article  CAS  Google Scholar 

  26. Chambers I, Colby D, Robertson M, Nichols J, Lee S, Tweedie S et al. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 2003; 113: 643–655.

    Article  CAS  Google Scholar 

  27. Zhu W, Xu W, Jiang R, Qian H, Chen M, Hu J et al. Mesenchymal stem cells derived from bone marrow favor tumor cell growth in vivo. Exp Mol Pathol 2006; 80: 267–274.

    Article  CAS  Google Scholar 

  28. Puissant B, Barreau C, Bourin P, Clavel C, Corre J, Bousquet C et al. Immunomodulatory effect of human adipose tissue-derived adult stem cells: comparison with bone marrow mesenchymal stem cells. Br J Haematol 2005; 129: 118–129.

    Article  Google Scholar 

  29. Kuphal S, Lodermeyer S, Bataille F, Schuierer M, Hoang BH, Bosserhoff AK . Expression of Dickkopf genes is strongly reduced in malignant melanoma. Oncogene 2006; 25: 5027–5036.

    Article  CAS  Google Scholar 

  30. Aguilera O, Fraga MF, Ballestar E, Paz MF, Herranz M, Espada J et al. Epigenetic inactivation of the Wnt antagonist DICKKOPF-1 (DKK-1) gene in human colorectal cancer. Oncogene 2006; 25: 4116–4121.

    Article  CAS  Google Scholar 

  31. Vibhakar R, Foltz G, Yoon JG, Field L, Lee H, Ryu GY et al. Dickkopf-1 is an epigenetically silenced candidate tumor suppressor gene in medulloblastoma. Neuro Oncol 2007; 9: 135–144.

    Article  CAS  Google Scholar 

  32. Bhowmick NA, Chytil A, Plieth D, Gorska AE, Dumont N, Shappell S et al. TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 2004; 303: 848–851.

    Article  CAS  Google Scholar 

  33. Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 2005; 121: 335–348.

    Article  CAS  Google Scholar 

  34. Pan G, Thomson JA . Nanog and transcriptional networks in embryonic stem cell pluripotency. Cell Res 2007; 17: 42–49.

    Article  CAS  Google Scholar 

  35. Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 2007; 449: 557–565.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported by grants from the ‘863 Projects’ of Ministry of Science and Technology of PR China (no. 2006AA02A109, 2006AA02A115); National Natural Science Foundation of China (no. 30570771); Beijing Ministry of Science and Technology (no. D07050701350701) and Cheung Kong Scholars program.

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Correspondence to R C Zhao.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Zhu, Y., Sun, Z., Han, Q. et al. Human mesenchymal stem cells inhibit cancer cell proliferation by secreting DKK-1. Leukemia 23, 925–933 (2009). https://doi.org/10.1038/leu.2008.384

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