Skip to main content
SpringerLink
Log in

Orthotopic implantation is essential for the selection, growth and metastasis of human real cell cancer in nude mice

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

Human neoplasms are heterogeneous for a variety of biological properties that include invasion and metastasis. The presence of a small subpopulation of cells with a highly metastatic phenotype has important clinical implications for diagnosis and therapy of cancer. For this reason, it is important to develop an animal model for the selection and isolation of metastatic variants from human neoplasms and for testing the metastatic potential of human tumor cells.

We have implanted human renal cell carcinoma (HRCC) cells (obtained from a surgical specimen) into different organs of nude mice and then recovered the tumors and established each in culture. The 5 established lines differed in their biological-metastatic properties and had a unique karyotype, indicating that growth at different organs selects for different subpopulations of HRCC. Moreover, the HRCC did not metastasize unless they were implanted orthotopically. These findings indicate that the appropriate nude mouse model for studying the biology and therapy of HRCC must be based on the orthotopic implantation of tumor cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Fidler IJ, Balch CM: The biology of cancer metastasis and implications for therapy. Curr Probl Surg 24: 137–209, 1987

    Google Scholar 

  2. Weiss L: Principles of Metastasis. Academic Press, Orlando, 1985

    Google Scholar 

  3. Nicolson GL: Cancer metastasis: Tumor cell and host organ properties important in metastasis to specific secondary sites. Biochim Biophys Acta 948: 175–224, 1988

    Google Scholar 

  4. Nicolson GL, Dulski KM: Organ specificity of metastatic tumor colonization is related to organ-selective growth properties of malignant cells. Int J Cancer 38: 289–294, 1986

    Google Scholar 

  5. Paget S: The distribution of secondary growths in cancer of the breast. Lancet 1: 571–573, 1889

    Google Scholar 

  6. Fidler IJ, Kripke ML: Metastasis results from pre-existing variant cells within a malignant tumor. Science 197: 893–895, 1977

    Google Scholar 

  7. Heppner G: Tumor heterogeneity. Cancer Res 44: 2259–2265, 1984

    Google Scholar 

  8. Poste G: Pathogenesis of metastatic disease: Implications for current therapy and for the development of new therapeutic strategies. Cancer Treat Rep 70: 183–199, 1986

    Google Scholar 

  9. Nicolson GL: Tumor cell instability, diversification, and progression to the metastatic phenotype: From oncogene to oncofetal expression. Cancer Res 47: 1473–1487, 1987

    Google Scholar 

  10. Fidler IJ: Selection of successive tumor lines for metastasis. Nature (New Biol) 242: 148–149, 1973

    Google Scholar 

  11. Talmadge JE, Fidler IJ: Cancer metastasis is selective or random depending on the parent tumor population. Nature (Lond) 27: 593–594, 1982

    Google Scholar 

  12. Price JE, Aukerman SL, Fidler IJ: Evidence that the process of murine melanoma metastasis is sequential and selective and contains stochastic elements. Cancer Res 46: 5172–5178, 1986

    Google Scholar 

  13. Talmadge JE, Wolman SR, Fidler IJ: Evidence for the clonal origin of spontaneous metastasis. Science 217: 361–363, 1982

    Google Scholar 

  14. Ootsuyama A, Tanaka K, Tanooka H: Evidence by cellular mosaicism for monoclonal metastasis of spontaneous mouse mammary tumors. J Natl Cancer Inst 78: 1223–1227, 1987

    Google Scholar 

  15. Hu F, Wang RY, Hsu TC: Clonal origin of metastasis in B16 murine melanoma: A cytogenetic study. J Natl Cancer Inst 78: 155–163, 1987

    Google Scholar 

  16. Talmadge JE, Zbar B: Clonality of pulmonary metastases from the bladder 6 subline of the B16 melanoma studied by Southern hybridization. J Natl Cancer Inst 78: 315–320, 1987

    Google Scholar 

  17. Fidler IJ, Talmadge JE: Evidence that intravenously derived murine pulmonary metastases can originate from the expansion of a single tumor cell. Cancer Res 46: 5167–5171, 1986

    Google Scholar 

  18. Hart IR: ‘Seed and soil’ revisited: Mechanisms of sitespecific metastasis. Cancer Metastasis Rev 1: 5–17, 1982

    Google Scholar 

  19. Tarin D, Price JE, Kettlewell MGW, Souter RG, Vass ACR, Crossley B: Clinicopathological observations on metastasis in man studied in patients treated with peritoneovenous shunts. Br Med J 288: 749–751, 1984

    Google Scholar 

  20. Fidler IJ: Rationale and methods for the use of nude mice to study the biology and therapy of human cancer metastasis. Cancer Metastasis Rev 5: 29–49, 1986

    Google Scholar 

  21. Rygaard J, Povlsen CO: Heterotransplantation of a human malignant tumor to ‘nude’ mice. Acta Pathol Microbiol Scand [A] 77: 758–760, 1969

    Google Scholar 

  22. Sharkey FE, Fogh J: Considerations in the use of nude mice for cancer research. Cancer Metastasis Rev 3: 341–360, 1984

    Google Scholar 

  23. Kyriazis APL, DiPersio GJ, Michael GJ, Pesce AJ, Stinnett JD: Growth patterns and metastatic behavior of human tumors growing in athymic nude mice. Cancer Res 38: 3186–3190, 1978

    Google Scholar 

  24. Kyriazis AA, Kyriazis AP: Preferential site of growth of human tumors in nude mice following subcutaneous transplantation. Cancer Res 40: 4509–4511, 1980

    Google Scholar 

  25. Kozlowski JM, Hart IR, Fidler IJ, Hanna N: A human melanoma line heterogeneous with respect to metastatic capacity in athymic nude mice. J Natl Cancer Inst 72: 913–917, 1984

    Google Scholar 

  26. Kozlowski JM, Fidler IJ, Campbell D, Xu Z, Kaighn ME, Hart IR: Metastatic behavior of human tumor cell lines grown in the nude mouse. Cancer Res 44: 3522–3529, 1984

    Google Scholar 

  27. Giavazzi R, Jessup JM, Campbell DE, Walker SM, Fidler IJ: Experimental nude mouse model of human colorectal cancer liver metastases. J Natl Cancer Inst 77: 1303–1308, 1986

    Google Scholar 

  28. Giavazzi R, Campbell DE, Jessup JM, Cleary K, Fidler IJ: Metastatic behavior of tumor cells isolated from primary and metastatic human colorectal carcinomas implanted into different sites in nude mice. Cancer Res 46: 1928–1933, 1986

    Google Scholar 

  29. Morikawa R, Walker SM, Jessup JM, Fidler IJ: In vivo selection of highly metastatic cells from surgical specimens of different primary human colon carcinomas implanted into nude mice. Cancer Res 48: 1943–1948, 1988

    Google Scholar 

  30. Morikawa K, Walker SM, Nakajima M, Pathak S, Jessup JM, Fidler IJ: Influence of organ environment on the growth, selection, and metastasis of human colon carcinoma cells in nude mice. Cancer Res 48: 6863–6871, 1988

    Google Scholar 

  31. Naito S, von Eschenbach AC, Giavazzi R, Fidler IJ: Growth and metastasis of tumor cells isolated from a human renal cell carcinoma implanted into different organs of nude mice. Cancer Res 46: 4109–4115, 1986

    Google Scholar 

  32. Katsuoka Y, Baba S, Hata M: Transplantation of human renal cell carcinoma to the nude mice: As an intermediate of in vivo and in vitro studies. J Urol 115: 373–376, 1976

    Google Scholar 

  33. Hoehn WA, Schroeder FH: Renal cell carcinoma: Two new cell lines and a serially transplantable nude mouse tumor (NC 65). Invest Urol 16: 106–112, 1978

    Google Scholar 

  34. Otto U, Kollermann MW, Kloppel G: Transplantation von menschlichem Nierenadenokarzinomgewebe auf die nackte Maus. Urol Int 36: 110–123, 1981

    Google Scholar 

  35. Naito S, Kanamori T, Hisano S: Human renal cell carcinoma: Establishment and characterization of two new cell lines. J Urol 128: 1117–1121, 1982

    Google Scholar 

  36. Otto U, Kloppel G, Baisch H, Huland H: Transplantation of human renal cell carcinoma into NMRI nu/nu mice. I. Reliability of an experimental tumor model. J Urol 131: 130–133, 1984

    Google Scholar 

  37. Otto U, Huland H, Baisch H, Kloppel G: Transplantation of human renal cell carcinoma into NMRI nu/nu mice. II. Evaluation of response to vinblastine sulfate monotherapy. J Urol 131: 134–138, 1984

    Google Scholar 

  38. Clayman RV, Figenshau RS, Bear A: Transplantation of human renal carcinomas into athymic mice. Cancer Res 45: 2650–2653, 1985

    Google Scholar 

  39. Naito S, von Eschenbach AC, Fidler IJ: Different growth pattern and biologic behavior of human and renal cell carcinoma implanted into different organs of nude mice. J Natl Cancer Inst 78: 377–385, 1987

    Google Scholar 

  40. Salup RR, Herberman RB, Chirigos MA, Wiltrout RH: Therapy of peritoneal murine cancer with biological response modifiers. J Immunopharmacol 7: 417–436, 1985

    Google Scholar 

  41. Salup RR, Herberman RB, Wiltrout RH: Role of natural killer activity in the development of spontaneous metastases in murine renal cancer. J Urol 134: 1236–1241, 1985

    Google Scholar 

  42. Bogden AE, Ketton DE, Cobb WR: A rapid screening method for testing chemotherapeutic agents against human tumor xenografts. In: Houchens DP, Ovejera AA (eds) Proceedings of the Symposium on the Use of Athymic (nude) Mice in Cancer Research. Fischer, New York, 1978, pp 231–250

    Google Scholar 

  43. Bogden AE, Hoff DD: Comparison of the human tumor cloning and subrenal capsule assays. Cancer Res 44: 1087–1090, 1984

    Google Scholar 

  44. Pathak S: Chromosome banding techniques. J Reprod Med 17: 25–28, 1976

    Google Scholar 

  45. Hanna N: Role of natural killer cells in control of cancer metastasis. Cancer Metastasis Rev 1: 45–64, 1982

    Google Scholar 

  46. Hanna N: Expression of metastatic potential of tumor cells in young nude mice is correlated with low levels of natural killer cell-mediated cytotoxicity. Int J Cancer 26: 675–680, 1980

    Google Scholar 

  47. Hanna N, Fidler IJ: Role of natural killer cells in the destruction of circulating tumor emboli. J Natl Cancer Inst 65: 801–809, 1980

    Google Scholar 

  48. Hanna N, Fidler IJ: Relationship between metastatic potential and resistance to natural killer cell-mediated cytotoxicity in three murine tumor systems. J Natl Cancer Inst 66: 1183–1190, 1981

    Google Scholar 

  49. Hanna N, Fidler IJ: Expression of metastatic potential of allogeneic and xenogeneic neoplasms in young nude mice. Cancer Res 41: 438–444, 1981

    Google Scholar 

  50. Hanna N, Schneider M: Enhancement of tumor metastasis and suppression of natural killer cell activity by β-estradiol treatment. J Immunol 130: 974–980, 1983

    Google Scholar 

  51. Barlozzari T, Reynolds CW, Herberman RB: In vivo role of natural killer cells: Involvement of large granular lymphocytes in the clearance of tumor cells in anti-asialo GM1-treated rats. J Immunol 131: 1024–1027, 1983

    Google Scholar 

  52. Barlozzari T, Leomhardt J, Wiltrout RH, Herberman RB, Reynolds CW: Direct evidence for the role of LGL in the inhibition of experimental tumor metastases. J Immunol 134: 2783–2789, 1985

    Google Scholar 

  53. Riccardi C, Pucetti P, Santoni A, Herberman RB: Rapid in vitro assay of mouse natural killer cell activity. J Natl Cancer Inst 63: 1041–1045, 1979

    Google Scholar 

  54. Riccardi C, Pucetti P, Santoni A, Herberman RB: Role of NK cells in rapid in vivo clearance of radiolabeled tumor cells. In: Herberman RB (ed) Natural Cell-Mediated Immunity against Tumors. Academic Press, New York, 1980, pp 1121–1139

    Google Scholar 

  55. Talmadge JE, Meyers KM, Prieur DJ, Starkey JR: Role of NK cells in tumor growth and metastasis in beige mice. Nature 284: 622–624, 1980

    Google Scholar 

  56. Windhorst DB, Pagett D: The Chediak-Higashi syndrome and the homologous trait in animals. J Invest Dermatol 60: 529–537, 1973

    Google Scholar 

  57. Roder J, Duwe A: The beige mutation in the mouse selectivity impairs natural killer cell function. Nature 278: 451–453, 1979

    Google Scholar 

  58. Shimanura K, Mauro K, Ueyama Y, Habu S, Okumura K, Tamaoki N: Role of NK cells in solid tumor metastasis in beige, nude mice and normal mice. In: Immune-deficient Animals, 4th International Workshop on Immune-deficient Animals in Experimental Research, Chexbres 1982. Karger, Basel, 1984, pp 353–356

    Google Scholar 

  59. Karre K, Klein GO, Kiessling R, Roder JE: Low natural in vivo resistance to syngeneic leukemias in natural killer-deficient mice. Nature 284: 624–626, 1980

    Google Scholar 

  60. Karre K, Klein GO, Kiessling R, Roder JC: In vitro NK activity and in vivo resistance to leukemia: Studies of beige, beige nude, and wild-type hosts on C57BL background. Int J Cancer 26: 789–797, 1980

    Google Scholar 

  61. Naito S, Giavazzi R, Walker SM, Itoh K, Mayo J, Fidler IJ: Growth and metastatic behavior of human tumor cells implanted into nude and beige nude mice. Clin Expl Metastasis 5: 135–146, 1987

    Google Scholar 

  62. Fodstad O, Hansen CT, Cannon GB, Statham CN, Lichtenstein GR, Boyd MR: Lack of correlation between natural killer activity and tumor growth control in nude mice with different immune defects. Cancer Res 44: 4403–4408, 1984

    Google Scholar 

  63. Pollack VA, Fidler IJ: The use of young nude mice for selection of subpopulations of cells with increased metastatic potential from nonsyngeneic neoplasms. J Natl Cancer Inst 69: 137–141, 1982

    Google Scholar 

  64. Naito S, Walker SM, Fidler IJ: In vivo selection of human renal cell carcinoma cells with high metastatic potential in nude mice. Clin Expl Metastasis 7: 381–389, 1989

    Google Scholar 

  65. Nicolson GL, Custead SE: Tumor metastasis is not due to adaptation of cells to a new organ environment. Science 215: 176–178, 1982

    Google Scholar 

  66. Fidler IJ: The Ernst W. Bertner Memorial Award Lecture: The evolution of biological heterogeneity in metastatic neoplasm. In: Nicolson GL, Milas L (eds) Cancer Invasion and Metastasis: Biologic and Therapeutic Aspects. Raven Press, New York, 1984, pp 5–26

    Google Scholar 

  67. Raz A, Hanna N, Fidler IJ: In vivo isolation of a metastatic tumor cell variant involving selective and nonadaptive process. J Natl Cancer Inst 66: 183–189, 1981

    Google Scholar 

  68. Naito S, Walker SM, von Eschenbach AC, Fidler IJ: Evidence for metastatic heterogeneity of human renal cell carcinoma. Anticancer Res 8: 1163–1168, 1988

    Google Scholar 

  69. Kripke ML, Gruys E, Fidler IJ: Metastatic heterogeneity of cells from an ultraviolet light-induced murine fibrosarcoma of recent origin. Cancer Res 38: 2962–2967, 1978

    Google Scholar 

  70. Kerbel RS, Man MS, Dexter D: A model of human cancer metastasis: Extensive spontaneous and artificial metastasis of a human pigmented melanoma and derived variant sublines in nude mice. J Natl Cancer Inst 72: 93–108, 1984

    Google Scholar 

  71. Kerbel RS, Man MS: Single-step selection of unique human melanoma variants displaying unusually aggressive metastatic behavior in nude athymic mice. Inv Metastasis 4: 31–43, 1984

    Google Scholar 

  72. Cornil T, Man MS, Fernandez B, Kerbel RS: Enhanced tumorigenicity, melanogenesis and metastasis of the human malignant melanoma observed after subdermal implantation in nude mice. J Natl Cancer Inst 81: 938–944, 1989

    Google Scholar 

  73. Wang WR, Sordat B, Paiguet D, Sordat M: Human colon tumors in nude mice: Implantation site and expression of the invasive phenotype. In: Sordat B (ed) Immune-deficient Animals. Karger, Basel, 1984, pp 239–245

    Google Scholar 

  74. Bresalier RS, Raper SE, Hujanen ES, Kim YS: A new model for human colon cancer metastasis. Int J Cancer 39: 625–630, 1987

    Google Scholar 

  75. Jessup JM, Giavazzi R, Campbell D, Cleary K, Morikawa K, Fidler IJ: Growth potential of human colorectal carcinomas in nude mice: Association with preoperative serum concentration of carcinoembryonic antigen. Cancer Res 48: 1689–1692, 1988

    Google Scholar 

  76. Schackert H, Fidler IJ: Development of an animal model to study the biology of recurrent colorectal cancer originating from mesenteric lymph system metastases. Int J Cancer 44: 177–181, 1989

    Google Scholar 

  77. Price JE, Polyzos A, Zhang RD, Daniels LM: Tumorigenicity and metastasis of human breast carcinoma cell lines in nude mice. Cancer Res 50: 717–721, 1990

    Google Scholar 

  78. Ibrahiem EHI, Nigam VN, Brailovsky CA, Madarnas P, Elhilali M: Orthotopic implantation of primary N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide-induced bladder cancer in bladder submucosa: An animal model for bladder cancer study. Cancer Res 43: 617–622, 1983

    Google Scholar 

  79. Ahlering TE, Dubeau L, Jones PA: A new in vivo model to study invasion and metastasis of human bladder carcinoma. Cancer Res 47: 6660–6665, 1987

    Google Scholar 

  80. Kajiji SM, Meitner PA, Bogaars HA, Dexter DL, Calabresi P, Turner MD: Metastasis of a human pancreatic adenocarcinoma (RWP-1) in nude mice. Br J Cancer 46: 970–975, 1982

    Google Scholar 

  81. Vezeridis MP, Turner MD, Kajiji SM, Yankee RA, Meither PA: Metastasis of human pancreatic cancer (HPC) to liver in nude mice. Proc Am Assn Cancer Res 26: 53, 1985

    Google Scholar 

  82. McLemore TL, Liu MC, Blacker PC, Gregg M, Alley MC, Abbott BJ, Shoemaker RH, Bohlman ME, Litterst CC, Hubbard WC, Brennan RH, McMahon JB, Fine DL, Eggleston JC, Mayo JG, Boyd MR: Novel intrapulmonary model for orthotopic propagation of human lung cancers in athymic nude mice. Cancer Res 47: 5132–5140, 1987

    Google Scholar 

  83. Meyvisch C: Influence of implantation site on formation of metastasis. Cancer Metastasis Rev 2: 295–306, 1983

    Google Scholar 

  84. Poste G: Experimental systems for analysis of the malignant phenotype. Cancer Metastasis Rev 1: 141–199, 1982

    Google Scholar 

  85. Miller FR: Comparison of metastasis of mammary tumors growing in the mammary fatpad versus the subcutis. Inv Metastasis 1: 220–226, 1981

    Google Scholar 

  86. Malave I, Blanca I, Fuji H: Influence of inoculation site on development of the Lewis lung carcinoma and suppressor cell activity in syngeneic mice. J Natl Cancer Inst 62: 83–88, 1979

    Google Scholar 

  87. Talmadge JE, Fidler IJ: Enhanced metastatic potential of tumor cells harvested from spontaneous metastases of heterogeneous murine tumors. J Natl Cancer Inst 69: 975–980, 1982

    Google Scholar 

  88. Pal K, Kopper L, Lapis K: Increased metastatic capacity of Lewis lung tumor cells by in vivo selection procedure. Inv Metastasis 3: 174–182, 1983

    Google Scholar 

  89. Brodt P: Characterization of two highly metastatic variants of Lewis lung carcinoma with different organ specificities. Cancer Res 46: 2442–2448, 1986

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cell Biology, University of Texas M.D. Anderson Cancer Center, 77030, Houston, TX, U.S.A.

    Isaiah J. Fidler & Sen Pathak

  2. Department of Urology, Faculty of Medicine, Kyushu University, 812, Fukuoka, Japan

    Seiji Naito

Authors
  1. Isaiah J. Fidler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Seiji Naito
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sen Pathak
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fidler, I.J., Naito, S. & Pathak, S. Orthotopic implantation is essential for the selection, growth and metastasis of human real cell cancer in nude mice. Cancer Metast Rev 9, 149–165 (1990). https://doi.org/10.1007/BF00046341

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00046341

Key words

Search

Navigation