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Role of natural killer cells in hormone-independent rapid tumor formation and spontaneous metastasis of breast cancer cells in vivo

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Abstract

Natural killer (NK) cells play a central role in host defense against tumor and virus-infected cells. Direct role of NK cells in tumor growth and metastasis remains to be elucidated. We here demonstrated that NOD/SCID/γcnull (NOG) mice lacking T, B and NK cells inoculated with breast cancer cells were efficient in the formation of a large tumor and spontaneous organ-metastasis. In contrast, breast cancer cells produced a small tumor at inoculated site in T and B cell knock-out NOD/SCID mice with NK cells while completely failed to metastasize into various organs. Immunosupression of NOD/SCID by treatment with an anti-murine TM-β1 antibody, which transiently abrogates NK cell activity in vivo, resulted in enhancing tumor formation and organ-metastasis in comparison with non-treated NOD/SCID mice. Activated NK cells inhibited tumor growth in vivo. The rapid and efficient engraftment of the breast cancer cells in NOG mice suggests that this new animal model could provide a unique opportunity to understand and investigate the mechanism of tumor cell growth and metastasis. Our results suggest that NK cells play an important role in cancer growth and metastasis and could be a promising immunotherapeutic strategy against cancer either alone or in combination with conventional therapy.

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References

  1. Ghafoor A, Jemal A, Ward E, Cokkinides V, Smith R, Thun M (2003) Trends in breast cancer by race and ethnicity. CA Cancer J Clin 53:342–355

    Article  PubMed  Google Scholar 

  2. Nicolson GL (1993) Paracrine and autocrine growth mechanisms in tumor metastasis to specific sites with particular emphasis on brain and lung metastasis. Cancer Metastasis Rev 12:325–343

    Article  PubMed  CAS  Google Scholar 

  3. Kim H, Muller WJ (1999) The role of the epidermal growth factor receptor family in mammary tumorigenesis and metastasis. Exp Cell Res 253:78–87

    Article  PubMed  CAS  Google Scholar 

  4. Hyder SM, Chiappetta C, Stancel GM (2001) Pharmacological and endogenous progestins induce vascular endothelial growth factor expression in human breast cancer cells. Int J Cancer 92:469–473

    Article  PubMed  CAS  Google Scholar 

  5. McEarchern JA, Kobie JJ, Mack V et al (2001) Invasion and metastasis of a mammary tumor involves TGF-beta signaling. Int J Cancer 91:76–82

    Article  PubMed  CAS  Google Scholar 

  6. Muller A, Homey B, Soto H et al (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature 410:50–56

    Article  PubMed  CAS  Google Scholar 

  7. Dewan MZ, Watanabe M, Terashima K, Aoki M, Sata T, Honda M, Ito M, Yamaoka S, Watanabe T, Horie R, Yamamoto N (2004) Prompt tumor formation and maintenance of constitutive NF-kappaB activity of multiple myeloma cells in NOD/SCID/gammacnull mice. Cancer Sci 95:564–568

    Article  PubMed  CAS  Google Scholar 

  8. Beckhove P, Schutz F, Diel IJ, Solomayer EF, Bastert G, Foerster J, Feuerer M, Bai L, Sinn HP, Umansky V, Schirrmacher V (2003) Efficient engraftment of human primary breast cancer transplants in nonconditioned NOD/Scid mice. Int J Cancer 105:444–453

    Article  PubMed  CAS  Google Scholar 

  9. Phillips RA, Jewett MA, Gallie BL (1989) Growth of human tumors in immune-deficient scid mice and nude mice. Curr Top Microbiol Immunol 152:259–263

    PubMed  CAS  Google Scholar 

  10. Sharkey FE, Fogh J (1979) Metastasis of human tumors in athymic nude mice. Int J Cancer 24:733–738

    Article  PubMed  CAS  Google Scholar 

  11. Kubota T, Yamaguchi H, Watanabe M, Yamamoto T, Takahara T, Takeuchi T, Furukawa T, Kase S, Kodaira S, Ishibiki K (1993) Growth of human tumor xenografts in nude mice and mice with severe combined immunodeficiency (SCID). Surg Today 23:375–377

    Article  PubMed  CAS  Google Scholar 

  12. Garofalo A, Chirivi RG, Scanziani E, Mayo JG, Vecchi A, Giavazzi R. (1993) Comparative study on the metastatic behavior of human tumors in nude, beige/nude/xid and severe combined immunodeficient mice. Invasion Metastasis 13:82–91

    PubMed  CAS  Google Scholar 

  13. Zietman AL, Sugiyama E, Ramsay JR, Silobrcic V, Yeh ET, Sedlacek RS, Suit HD. (1991) A comparative study on the xenotransplantability of human solid tumors into mice with different genetic immune deficiencies. Int J Cancer 47:755–759

    Article  PubMed  CAS  Google Scholar 

  14. Rae-Venter B, Reid LM. (1980) Growth of human breast carcinomas in nude mice and subsequent establishment in tissue culture. Cancer Res 40:95–100

    PubMed  CAS  Google Scholar 

  15. Sebesteny A, Taylor-Papadimitriou J, Ceriani R, Millis R, Schmitt C, Trevan D. (1979) Primary human breast carcinomas transplantable in the nude mouse. J Natl Cancer Inst 63:1331–1337

    PubMed  CAS  Google Scholar 

  16. Price JE (1996) Metastasis from human breast cancer cell lines. Breast Cancer Res Treat 39:93–102

    Article  PubMed  CAS  Google Scholar 

  17. Brunner N, Osborne CK, Spang-Thomsen M (1987) Endocrine therapy of human breast cancer grown in nude mice. Breast Cancer Res Treat 10:229–242

    Article  PubMed  CAS  Google Scholar 

  18. Clarke R (1996) Human breast cancer cell line xenografts as models of breast cancer. The immunobiologies of recipient mice and the characteristics of several tumorigenic cell lines. Breast Cancer Res Treat 39:69–86

    Article  PubMed  CAS  Google Scholar 

  19. Visonneau S, Cesano A, Torosian MH, Miller EJ, Santoli D (1998) Growth characteristics and metastatic properties of human breast cancer xenografts in immunodeficient mice. Am J Pathol 152:1299–1311

    PubMed  CAS  Google Scholar 

  20. Castro JE, Cass W (1974) Maintenance of human tumours and tissues in immunosuppressed mice. Br J Surg 61:421–426

    Article  PubMed  CAS  Google Scholar 

  21. Taylor-Papadimitriou J, Berdichevsky F, D’Souza B, Burchell J (1993) Human models of breast cancer. Cancer Surv 16:59–78

    PubMed  CAS  Google Scholar 

  22. Outzen HC, Custer RP (1975) Growth of human normal and neoplastic mammary tissues in the cleared mammary fat pad of the nude mouse. J Natl Cancer Inst 55:1461–1466

    PubMed  CAS  Google Scholar 

  23. Miller FR, Medina D, Heppner GH (1981) Preferential growth of mammary tumors in intact mammary fatpads. Cancer Res 41:3863–3867

    PubMed  CAS  Google Scholar 

  24. Sweeney TM, Kibbey MC, Zain M, Fridman R, Kleinman HK (1991) Basement membrane and the SIKVAV laminin-derived peptide promote tumor growth and metastases. Cancer Metastasis Rev 10:245–254

    Article  PubMed  CAS  Google Scholar 

  25. Kuperwasser C, Chavarria T, Wu M, Magrane G, Gray JW, Carey L, Richardson A, Weinberg RA (2004) Reconstruction of functionally normal and malignant human breast tissues in mice. Proc Natl Acad Sci USA 101:4966–4971

    Article  PubMed  CAS  Google Scholar 

  26. Ito M, Hiramatsu H, Kobayashi K et al (2002) NOD/SCID/γcnull mouse: An excellent recipient mouse model for engraftment of human cells. Blood 100:3175–182

    Article  PubMed  CAS  Google Scholar 

  27. Dorshkind K, Pollack SB, Bosma MJ, Phillips RA (1985) Natural killer (NK) cells are present in mice with severe combined immunodeficiency (scid). J Immunol 134:3798–3801

    PubMed  CAS  Google Scholar 

  28. Feuer G, Stewart SA, Baird SM, Lee F, Feuer R, Chen ISY (1994) Potential role of natural killer cells in controlling tumorigenesis by human T-cell leukemia Viruses. J Virol 69:1328–1333

    Google Scholar 

  29. Welsh RM (1986) Regulation of virus infections by natural killer cells: a review. Nat Immun Cell Growth Regul 5:169–199

    PubMed  CAS  Google Scholar 

  30. Trinchieri G (1989) Biology of natural killer cells. Adv Immunol 47:187–376

    Article  PubMed  CAS  Google Scholar 

  31. Dewan MZ, Uchihara JN, Terashima K et al (2006) Efficient intervention of growth and infiltration of primary adult T-cell leukemia cells by an HIV protease inhibitor, ritonavir. Blood 107:716–724

    Article  PubMed  CAS  Google Scholar 

  32. Imai K, Matsuyama S, Miyake S, Suga K, Nakachi K (2000) Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population. Lancet 356:1795–1799

    Article  PubMed  CAS  Google Scholar 

  33. Bonaparte MI, Barker E (2003) Inability of natural killer cells to destroy autologous HIV-infected T lymphocytes. AIDS 17:487–494

    Article  PubMed  Google Scholar 

  34. Koo GC, Dumont FJ, Tutt M, Hackett J, Jr Kumar V (1989) The NK-1.1(-) mouse: a model to study differentiation of murine NK cells. J Immunol 137:3742–3747

    Google Scholar 

  35. Smyth MJ, Crowe NY, Godfrey DI (2001) NK cells and NKT cells collaborate in host protection from methylcholanthrene-induced fibrosarcoma. Int Immunol 13:459–463

    Article  PubMed  CAS  Google Scholar 

  36. Smyth MJ, Godfery DI, Trapani JA (2001) A fresh look at tumor immunosurveillance and immunotherapy. Nature 2:293–299

    CAS  Google Scholar 

  37. Dorshkind K, Pollack SB, Bosma MJ, Phillips RA (1985) Natural killer (NK) cells are present in mice with severe combined immunodeficiency (scid). J Immunol 134:3798–3801

    PubMed  CAS  Google Scholar 

  38. Schuler W, Bosma MJ (1989) Nature of the scid defect: a defective VDJ recombinase system. Curr Top Microbiol Immunol 152:55–62

    PubMed  CAS  Google Scholar 

  39. Noguchi M, Yi H, Rosenblatt HM et al (1993) Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell 73:147–157

    Article  PubMed  CAS  Google Scholar 

  40. Puck JM, Deschenes SM, Porter JC et al (1993) The interleukin-2 receptor gamma chain maps to Xq13.1 and is mutated in X-linked severe combined immunodeficiency, SCIDX1. Hum Mol Genet 2:1099–1104

    Article  PubMed  CAS  Google Scholar 

  41. Cavacini LA, Giles-Komar J, Kennel M, Quinn A (1992) Effect of immunosuppressive therapy on cytolytic activity of immunodeficient mice: implications for xenogeneic transplantation. Cell Immunol 144:296–310

    Article  PubMed  CAS  Google Scholar 

  42. Hochman PS, Cudkowicz G, Dausset J (1978) Decline of natural killer cell activity in sublethally irradiated mice. J Natl Cancer Inst 61:265–268

    PubMed  CAS  Google Scholar 

  43. Taghian A, Budach W, Zietman A, Freeman J, Gioioso D, Suit HD (1993) Quantitative comparison between the transplantability of human and murine tumors into the brain of NCr/Sed-nu/nu nude and severe combined immunodeficient mice. Cancer Res 53:5018–5021

    PubMed  CAS  Google Scholar 

  44. Whiteside TL, Vujanovic NL, Herberman RB (1998) Natural killer cells and tumor therapy. Curr Top Microbiol Immunol 230:221–244

    PubMed  CAS  Google Scholar 

  45. Trapani JA, Davis J, Sutton VR, Smyth MJ (2000) Proapoptotic functions of cytotoxic lymphocyte granule constituents in vitro and in vivo. Curr Opin Immunol 12:323–329

    Article  PubMed  CAS  Google Scholar 

  46. Kagi D, Ledermann B, Burki K et al (1994) Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice. Nature 369:31–37

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We thank K. Ohba of Department of Molecular Virology, S. Ichinose of Instrumental Analysis Research Center and S. Endo of Animal Research Center, Tokyo Medical and Dental University for their advice and assistance with the experiments. We also thank Y. Sato of the National Institute of Infectious Diseases for her excellent technical assistance. This work was supported by grants from the Ministry of Education, Science and Culture; the Ministry of Health, Labor and Welfare; and Human Health Science of Japan.

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Authors and Affiliations

  1. Department of Molecular Virology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan

    Md. Zahidunnabi Dewan & Naoki Yamamoto

  2. AIDS Research Center, National institute of Infectious Disease, 1-23-1 Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan

    Md. Zahidunnabi Dewan & Naoki Yamamoto

  3. Biotherapy Institute of Japan, 2-4-8 Edagawa, Koutou-ku, Tokyo, 135-0051, Japan

    Hiroshi Terunuma

  4. Kudan Clinic, 1-9-5 Kudankita, Chiyoda-ku, Tokyo, 102-0073, Japan

    Hiroshi Terunuma & Hiroyuki Abe

  5. Division of Clinical Trials and Research, Breast Cancer Research and Treatment Program, Tokyo Metropolitan Komagome Hospital, Tokyo Medical Center for Cancer and Infectious Disease, Tokyo, Japan

    Masahiro Takada & Masakazu Toi

  6. Department of Infectious Disease and Immunology, Faculty of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa, 903-0215, Japan

    Yuetsu Tanaka

  7. Department of Pathology, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjyuku-ku, Tokyo, 162-8640, Japan

    Tetsutaro Sata

Authors
  1. Md. Zahidunnabi Dewan
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  2. Hiroshi Terunuma
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  3. Masahiro Takada
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  4. Yuetsu Tanaka
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  6. Tetsutaro Sata
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  7. Masakazu Toi
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  8. Naoki Yamamoto
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Correspondence to Masakazu Toi or Naoki Yamamoto.

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Dewan, M.Z., Terunuma, H., Takada, M. et al. Role of natural killer cells in hormone-independent rapid tumor formation and spontaneous metastasis of breast cancer cells in vivo. Breast Cancer Res Treat 104, 267–275 (2007). https://doi.org/10.1007/s10549-006-9416-4

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  • DOI: https://doi.org/10.1007/s10549-006-9416-4

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