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Clinical & Experimental Metastasis

, Volume 30, Issue 5, pp 695–710 | Cite as

In vivo animal models for studying brain metastasis: value and limitations

  • Inderjit Daphu
  • Terje Sundstrøm
  • Sindre Horn
  • Peter C. Huszthy
  • Simone P. Niclou
  • Per Ø. Sakariassen
  • Heike Immervoll
  • Hrvoje Miletic
  • Rolf Bjerkvig
  • Frits ThorsenEmail author
Review

Abstract

Brain metastasis is associated with a particular poor prognosis. Novel insight into the brain metastatic process is therefore warranted. Several preclinical models of brain tumor metastasis have been developed during the last 60 years, and they have in part revealed some of the mechanisms underlying the metastatic process. This review discusses mechanisms of brain metastasis with a key focus of the development of animal model systems. This includes the use of rodent, syngeneic brain metastasis models (spontaneous, chemically induced and genetically engineered models) and human xenotransplantation models (ectopic inoculation and orthotopic models). Current information indicates that none of these fully reflect tumor development seen in patients with metastatic disease. The various model systems used, however, have provided important insight into specific mechanisms of the metastatic process related to the brain. By combining the knowledge obtained from animal models, new important information on the molecular mechanisms behind metastasis will be obtained, leading to the future development of new therapeutic strategies.

Keywords

Brain metastasis Animal models Orthotopic Ectopic GEMMs 

Notes

Acknowledgments

The authors wish to thank Ingvild Wendelbo, Tove Johansen and Bodil Hansen for technical assistance, and Ian Pryme for a critical review of the manuscript. This work was supported by The Norwegian Cancer Society; the Norwegian Research Council; Innovest AS; Strategic Research Programme; Helse-Vest; Haukeland University Hospital; the Bergen Translational Research Program; and Centre de Recherche Public de la Santé, Luxembourg.

References

  1. 1.
    Nathoo N, Chahlavi A, Barnett G, Toms SA (2005) Pathobiology of brain metastases. J Clin Pathol 58:237–242PubMedCrossRefGoogle Scholar
  2. 2.
    Palmieri D, Chambers A, Felding-Habermann B, Huang S, Steeg PS (2007) The biology of metastasis to a sanctuary site. Clin Cancer Res 13:1656–1662PubMedCrossRefGoogle Scholar
  3. 3.
    Barnholtz-Sloan JS (2004) Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. J Clin Oncol 22:2865–2872PubMedCrossRefGoogle Scholar
  4. 4.
    Fife KM, Colman MH, Stevens GN, Firth IC, Moon D, Shannon KF, Harman R, Petersen-Schaefer K, Zacest AC, Besser M, Milton GW, McCarthy WH, Thompson JF (2004) Determinants of outcome in melanoma patients with cerebral metastases. J Clin Oncol 22:1293–1300PubMedCrossRefGoogle Scholar
  5. 5.
    Steeg P, Camphausen K, Smith Q (2011) Brain metastases as preventive and therapeutic targets. Nat Rev Cancer 11:352–363PubMedCrossRefGoogle Scholar
  6. 6.
    Schackert G (2002) Surgery of brain metastases—pro and contra. Onkologie 25:480–481PubMedCrossRefGoogle Scholar
  7. 7.
    Tosoni A, Ermani M, Brandes AA (2004) The pathogenesis and treatment of brain metastases: a comprehensive review. Crit Rev Oncol/Hematol 52:199–215CrossRefGoogle Scholar
  8. 8.
    Neves S, Mazal PR, Wanschitz J, Rudnay AC, Drlicek M, Czech T, Wüstinger C, Budka H (2001) Pseudogliomatous growth pattern of anaplastic small cell carcinomas metastatic to the brain. Clin Neuropathol 20:38–42PubMedGoogle Scholar
  9. 9.
    Gavrilovic IT (2005) Posner JB (2005) Brain metastases: epidemiology and pathophysiology. J Neurooncol 75(1):5–14PubMedCrossRefGoogle Scholar
  10. 10.
    Preusser M, Capper D, Ilhan-Mutlu A, Berghoff AS, Birner P, Bartsch R, Marosi C, Zielinski C, Mehta MP, Winkler F, Wick W, von Deimling A (2012) Brain metastases: pathobiology and emerging targeted therapies. Acta Neuropathol 123:205–222PubMedCrossRefGoogle Scholar
  11. 11.
    Santarelli J, Sarkissian V, Hou L, Veeravagu A, Tse V (2007) Molecular events of brain metastasis. Neurosurg Focus 22:1–5CrossRefGoogle Scholar
  12. 12.
    Chambers AF, Groom AC, MacDonald IC (2002) Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2:563–572PubMedCrossRefGoogle Scholar
  13. 13.
    Eichler AF, Chung E, Kodack DP, Loeffler JS, Fukumura D, Jain RK (2011) The biology of brain metastases—translation to new therapies. Nat Rev Clin Oncol 8:344–356PubMedGoogle Scholar
  14. 14.
    Mina LA, Sledge GW (2011) Rethinking the metastatic cascade as a therapeutic target. Nat Rev Clin Oncol 8:325–332PubMedGoogle Scholar
  15. 15.
    Valastyan S, Weinberg RA (2011) Tumor metastasis: molecular insights and evolving paradigms. Cell 147:275–292PubMedCrossRefGoogle Scholar
  16. 16.
    Zhang C, Yu D (2011) Microenvironment determinants of brain metastasis. Cell Biosci 1:8PubMedCrossRefGoogle Scholar
  17. 17.
    Cheng X, Hung M-C (2007) Breast cancer brain metastases. Cancer Metastasis Rev 26:635–643PubMedCrossRefGoogle Scholar
  18. 18.
    Gavrilovic IT, Posner JB (2005) Brain metastases: epidemiology and pathophysiology. J Neurooncol 75:5–14PubMedCrossRefGoogle Scholar
  19. 19.
    Marchetti D, Denkins Y, Reiland J, Greiter-Wilke A, Galjour J, Murry B, Blust J, Roy M (2003) Brain-metastatic melanoma: a neurotrophic perspective. Pathol Oncol Res 9:147–158PubMedCrossRefGoogle Scholar
  20. 20.
    Ray PS, Wang J, Qu Y, Sim MS, Shamonki J, Bagaria SP, Ye X, Liu B, Elashoff D, Hoon DS, Walter MA, Martens JW, Richardson AL, Giuliano AE, Cui X (2010) FOXC1 is a potential prognostic biomarker with functional significance in basal-like breast cancer. Cancer Res 70:3870–3876PubMedCrossRefGoogle Scholar
  21. 21.
    Paget S (1889) Distribution of secondary growths in cancer of the breast. Lancet 133:571–573CrossRefGoogle Scholar
  22. 22.
    Palmieri D, Bronder JL, Herring JM, Yoneda T, Weil RJ, Stark AM, Kurek R, Vega-Valle E, Feigenbaum L, Halverson D, Vortmeyer AO, Steinberg SM, Aldape K, Steeg PS (2007) Her-2 overexpression increases the metastatic outgrowth of breast cancer cells in the brain. Cancer Res 67:4190–4198PubMedCrossRefGoogle Scholar
  23. 23.
    Bendell JC, Domchek SM, Burstein HJ, Harris L, Younger J, Kuter I, Bunnell C, Rue M, Gelman R, Winer E (2003) Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer 97:2972–2977PubMedCrossRefGoogle Scholar
  24. 24.
    Clayton AJ, Danson S, Jolly S, Ryder WDJ, Burt PA, Stewart AL, Wilkinson PM, Welch RS, Magee B, Wilson G, Howell A, Wardley AM (2004) Incidence of cerebral metastases in patients treated with trastuzumab for metastatic breast cancer. Br J Cancer 91:639–643PubMedGoogle Scholar
  25. 25.
    Stemmler HJ, Kahlert S, Siekiera W, Untch M, Heinrich B, Heinemann V (2006) Characteristics of patients with brain metastases receiving trastuzumab for HER2 overexpressing metastatic breast cancer. Breast 15:219–225PubMedCrossRefGoogle Scholar
  26. 26.
    Ruan S, Fuller G, Levin V et al (1998) Detection of p21WAF1/Cip1 in brain metastases. J Neurooncol 37(3):223–228PubMedCrossRefGoogle Scholar
  27. 27.
    Stark AM, Tongers K, Maass N, Bruner JM, Zhang W (1998) Reduced metastasis-suppressor gene mRNA-expression in breast cancer brain metastases. J Cancer Res Clin Oncol 131:191–198CrossRefGoogle Scholar
  28. 28.
    Carvajal RD, Antonescu CR, Wolchok JD, Chapman PB, Roman RA, Teitcher J, Panageas KS, Busam KJ, Chmielowski B, Lutzky J, Pavlick AC, Fusco A, Cane L, Takebe N, Vemula S, Bouvier N, Bastian BC, Schwartz GK (2011) KIT as a therapeutic target in metastatic melanoma. JAMA 305:2327–2334PubMedCrossRefGoogle Scholar
  29. 29.
    Korabiowska M, König F, Verheggen R, Schlott T, Cordon-Cardo C, Romeike B, Brinck U (2004) Altered expression and new mutations in DNA mismatch repair genes MLH1 and MSH2 in melanoma brain metastases. Anticancer Res 24:981–986PubMedGoogle Scholar
  30. 30.
    Palmieri D, Fitzgerald D, Shreeve SM, Hua E, Bronder JL, Weil RJ, Davis S, Stark AM, Merino MJ, Kurek R, Mehdorn HM, Davis G, Steinberg SM, Meltzer PS, Aldape K, Steeg PS (2009) Analyses of resected human brain metastases of breast cancer reveal the association between up-regulation of hexokinase 2 and poor prognosis. Mol Cancer Res 7:1438–1445PubMedCrossRefGoogle Scholar
  31. 31.
    Grinberg-Rashi H, Ofek E, Perelman M, Skarda J, Yaron P, Hajduch M, Jacob-Hirsch J, Amariglio N, Krupsky M, Simansky DA, Ram Z, Pfeffer R, Galernter I, Steinberg DM, Ben-Dov I, Rechavi G, Izraeli S (2009) The expression of three genes in primary non-small cell lung cancer is associated with metastatic spread to the brain. Clin Cancer Res 15:1755–1761PubMedCrossRefGoogle Scholar
  32. 32.
    Davies MA, Stemke-Hale K, Lin E, Tellez C, Deng W, Gopal YN, Woodman SE, Calderone TC, Ju Z, Lazar AJ, Prieto VG, Aldape K, Mills GB, Gershenwald JE (2009) Integrated molecular and clinical analysis of AKT Activation in metastatic melanoma. Clin Cancer Res 15:7538–7546PubMedCrossRefGoogle Scholar
  33. 33.
    Tx Xie (2006) Activation of stat3 in human melanoma promotes brain metastasis. Cancer Res 66:3188–3196CrossRefGoogle Scholar
  34. 34.
    Liu L, Nam S, Tian Y, Yang F, Wu J, Wang Y, Scuto A, Polychronopoulos P, Magiatis P, Skaltsounis L, Jove R (2011) 6-Bromoindirubin-3′-Oxime inhibits JAK/STAT3 signaling and induces apoptosis of human melanoma cells. Cancer Res 71:3972–3979PubMedCrossRefGoogle Scholar
  35. 35.
    Kurebayashi J, McLeskey SW, Johnson MD, Lippman ME, Dickson RB, Kern FG (1993) Quantitative demonstration of spontaneous metastasis by MCF-7 human breast cancer cells cotransfected with fibroblast growth factor 4 and LacZ. Cancer Res 53:2178–2187PubMedGoogle Scholar
  36. 36.
    Bos PD, Zhang XH-F, Nadal C, Shu W, Gomis RR, Nguyen DX, Minn AJ, Vijver MJ, Gerald WL, Foekens JA, Massagué J (2009) Genes that mediate breast cancer metastasis to the brain. Nature 459:1005–1009PubMedCrossRefGoogle Scholar
  37. 37.
    Küsters B, Leenders WPJ, Wesseling P, Smits D, Verrijp K, Ruiter DJ, Peterw JPW, van der Kogel AJ, de Waal RMW (2002) Vascular endothelial growth factor-A(165) induces progression of melanoma brain metastases without induction of sprouting angiogenesis. Cancer Res 62:341–345PubMedGoogle Scholar
  38. 38.
    Yano S, Shinohara H, Herbst RS, Kuniyasu H, Bucana CD, Ellis LM, Davis DW, McConkey DJ, Fidler IJ (2000) Expression of vascular endothelial growth factor is necessary but not sufficient for production and growth of brain metastasis. Cancer Res 60:4959–4967PubMedGoogle Scholar
  39. 39.
    JuanYin J, Tracy K, Zhang L, Munasinghe J, Shapiro E, Koretsky A, Kelly K (2009) Noninvasive imaging of the functional effects of anti-VEGF therapy on tumor cell extravasation and regional blood volume in an experimental brain metastasis model. Clin Exp Metastasis 26:403–414PubMedCrossRefGoogle Scholar
  40. 40.
    Nguyen DX, Chiang AC, Zhang XHF, Kim JY, Kris MG, Ladanyi M, Gerald WL, Massagué J (2009) WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis. Cell 138:51–62PubMedCrossRefGoogle Scholar
  41. 41.
    Nam DH, Jeon HM, Kim S, Kim MH, Lee YJ, Lee MS, Kim H, Joo KM, Lee DS, Price JE, Bang SI, Park WY (2008) Activation of notch signaling in a xenograft model of brain metastasis. Clin Cancer Res 14:4059–4066PubMedCrossRefGoogle Scholar
  42. 42.
    Zhang C, Zhang F, Tsan R, Fidler IJ (2009) Transforming growth factor-2 is a molecular determinant for site-specific melanoma metastasis in the brain. Cancer Res 69:828–835PubMedCrossRefGoogle Scholar
  43. 43.
    Kato M, Liu W, Yi H, Asai N, Hayakawa A, Kozaki K, Takahashi M, Nakashima I (1998) The herbal medicine Sho-saiko-to inhibits growth and metastasis of malignant melanoma primarily developed in ret-transgenic mice. J Invest Dermatol 111:640–644PubMedCrossRefGoogle Scholar
  44. 44.
    MacPherson D, Conkrite K, Tam M, Mukai S, Mu D, Jacks T (2007) Murine bilateral retinoblastoma exhibiting rapid-onset, metastatic progression and N-myc gene amplification. EMBO J 26:784–794PubMedCrossRefGoogle Scholar
  45. 45.
    Meuwissen R, Linn SC, Linnoila RI, Zevenhoven J, Mooi WJ, Berns A (2003) Induction of small cell lung cancer by somatic inactivation of both Trp53 and Rb1 in a conditional mouse model. Cancer Cell 4:181–189PubMedCrossRefGoogle Scholar
  46. 46.
    Nguyen DX, Massagué J (2007) Genetic determinants of cancer metastasis. Nat Rev Genetics 8:341–352CrossRefGoogle Scholar
  47. 47.
    Nicolson G, Brunson K, Fidler IJ (1978) Specificity of arrest, survival, and growth of selected metastatic variant cell lines. Cancer Res 38:4105–4111PubMedGoogle Scholar
  48. 48.
    Yoneda T, Williams PJ, Hiraga T, Niewolna M, Nishimura R (2001) A bone-seeking clone exhibits different biological properties from the MDA-MB-231 parental human breast cancer cells and a brain-seeking clone in vivo and in vitro. J Bone Miner Res 16:1486–1495PubMedCrossRefGoogle Scholar
  49. 49.
    Weber GF, Ashkar S (2000) Molecular mechanisms of tumor dissemination in primary and metastatic brain cancers. Brain Res Bull 53:421–424PubMedCrossRefGoogle Scholar
  50. 50.
    Sagar D, Foss C, Baz R, Pomper MG, Khan ZK, Jain P (2011) Mechanisms of dendritic cell trafficking across the blood–brain barrier. J Neuroimmune Pharmacol 7:74–94PubMedCrossRefGoogle Scholar
  51. 51.
    Arshad F, Wang L, Sy C, Avraham S, Avraham HK (2011) Blood-brain barrier integrity and breast cancer metastasis to the brain. Pathol Res Int 2011:1–12CrossRefGoogle Scholar
  52. 52.
    Fidler IJ, Yano S, Zhang R, Fujimaki T, Bucana CD (2002) The seed and soil hypothesis: vascularisation and brain metastases. Lancet Oncol 3:53–57PubMedCrossRefGoogle Scholar
  53. 53.
    Kienast Y, von Baumgarten L, Fuhrmann M, Klinkert WEF, Goldbrunner R, Herms J, Winkler F (2010) Real-time imaging reveals the single steps of brain metastasis formation. Nat Med 16:116–122PubMedCrossRefGoogle Scholar
  54. 54.
    Nguyen D, Bos P, Massagué J (2009) Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer 9:274–284PubMedCrossRefGoogle Scholar
  55. 55.
    Yoshimasu T, Sakurai T, Oura S, Hirai I, Tanino H, Kokawa Y, Naito Y, Okamura Y, Ota I, Tani N, Matsuura N (2004) Increased expression of integrin alpha3beta1 in highly brain metastatic subclone of a human non-small cell lung cancer cell line. Cancer Sci 95:142–148PubMedCrossRefGoogle Scholar
  56. 56.
    Hinton CV, Avraham S, Avraham HK (2010) Role of the CXCR4/CXCL12 signaling axis in breast cancer metastasis to the brain. Clin Exp Metastasis 27:97–105PubMedCrossRefGoogle Scholar
  57. 57.
    Lee BC, Lee TH, Avraham S, Avraham HK (2004) Involvement of the chemokine receptor CXCR4 and its ligand stromal cell-derived factor 1alpha in breast cancer cell migration through human brain microvascular endothelial cells. Mol Cancer Res 2:327–338PubMedGoogle Scholar
  58. 58.
    Salmaggi A, Maderna E, Calatozzolo C, Gaviani P, Canazza A, Milanesi I, Silvani A, DiMeco F, Carbone A, Pollo B (2009) CXCL12, CXCR4 and CXCR7 expression in brain metastases. Cancer Biol Ther 8:1608–1614PubMedCrossRefGoogle Scholar
  59. 59.
    Brunson K, Beattie G, Nicolson G (1978) Selection and altered properties of brain-colonising metastatic melanoma. Nature 272:543–545PubMedCrossRefGoogle Scholar
  60. 60.
    Leenders WPJ, Küsters B, Verrijp K, Maass C, Wesseling P, Heerschap A, Ruiter D, Ryan A, de Waal R (2004) Antiangiogenic therapy of cerebral melanoma metastases results in sustained tumor progression via vessel co-option. Clin Cancer Res 10:6222–6230PubMedCrossRefGoogle Scholar
  61. 61.
    McGrady B, McCormick D (1992) A murine model of intracranial invasion: morphological observations on central nervous system invasion by murine melanoma cells. Clin Exp Metastasis 10:387–393PubMedCrossRefGoogle Scholar
  62. 62.
    Nicolson GL, Kawaguchi T, Kawaguchi M, Van Pelt C (1987) Brain surface invasion and metastasis of murine malignant melanoma variants. J Neurooncol 4:209–218PubMedCrossRefGoogle Scholar
  63. 63.
    Carbonell WS, Ansorge O, Sibson N, Muschel R (2009) The vascular basement membrane as “soil” in brain metastasis. PLoS ONE 4:e5857PubMedCrossRefGoogle Scholar
  64. 64.
    Fazakas C, Wilhelm I, Nagyőszi P, Farkas AE, Hasko J, Molnar J, Bauer H, Bauer HC, Ayaydin F, Dung NTK, Siklos L, Krizbai IA (2011) Transmigration of melanoma cells through the blood-brain barrier: role of endothelial tight junctions and melanoma-released serine proteases. PLoS ONE 6:e20758PubMedCrossRefGoogle Scholar
  65. 65.
    Mendes O, Kim H, Lungu G, Stoica G (2007) MMP2 role in breast cancer brain metastasis development and its regulation by TIMP2 and ERK1/2. Clin Exp Metastasis 24:341–351PubMedCrossRefGoogle Scholar
  66. 66.
    Perides G, Zhuge Y, Lin T, Stins MF, Bronson RT, Wu JK (2006) The fibrinolytic system facilitates tumor cell migration across the blood-brain barrier in experimental melanoma brain metastasis. BMC Cancer 6:56PubMedCrossRefGoogle Scholar
  67. 67.
    Bugyik E, Dezso K, Reiniger L, László V, Tóvári J, Tímár J, Nagy P, Klepekto W, Döme B, Paku S (2011) Lack of angiogenesis in experimental brain metastases. J Neuropathol Exp Neurol 70:979–991PubMedCrossRefGoogle Scholar
  68. 68.
    Kaplan RN, Rafii S, Lyden D (2006) Preparing the “soil”: the premetastatic niche. Cancer Res 66:11089–11093PubMedCrossRefGoogle Scholar
  69. 69.
    Cranmer L, Trevor K, Bandlamuri S, Hersh EM (2005) Rodent models of brain metastasis in melanoma. Melanoma Res 15:325–356PubMedCrossRefGoogle Scholar
  70. 70.
    Green E (1968) Handbook on genetically standardized Jax mice. The Jackson Laboratory, Bar Harbor, MaineGoogle Scholar
  71. 71.
    Stephenson EM, Stephenson NG (1970) Karyotype analysis of the B16 mouse melanoma with reassessment of the normal mouse idiogram. J Natl Cancer Inst 45:789–800PubMedGoogle Scholar
  72. 72.
    Fidler IJ (1973) Selection of successive tumour lines for metastasis. Nat New Biol 242:148–149PubMedGoogle Scholar
  73. 73.
    Schackert G, Fidler IJ (1988) Site-specific metastasis of mouse melanomas and a fibrosarcoma in the brain or meninges of syngeneic animals. Cancer Res 48:3478–3484PubMedGoogle Scholar
  74. 74.
    Kallman RF, Silini G, Van Putten LM (1967) Factors influencing the quantitative estimation of the in vivo survival of cells from solid tumors. J Natl Cancer Inst 39:539–549PubMedGoogle Scholar
  75. 75.
    Conley FK (1979) Development of a metastatic brain tumor model in mice. Cancer Res 39:1001–1007PubMedGoogle Scholar
  76. 76.
    McCutcheon IE, Baranco RA, Katz DA, Saris SC (1990) Adoptive immunotherapy of intracerebral metastases in mice. Journal Neurosurg 72:102–109CrossRefGoogle Scholar
  77. 77.
    Miller FR (1983) Tumor subpopulation interactions in metastasis. Invasion Metastasis 3:234–242PubMedGoogle Scholar
  78. 78.
    Yamashina K, Heppner GH (2006) Correlation of frequency of induced mutation and metastatic potential in tumor cell lines from a single mouse mammary tumor. Cancer Res 45:4015–4019Google Scholar
  79. 79.
    Lelekakis M, Moseley JM, Martin TJ, Hards D, Williams E, Ho P, Lowen D, Javni J, Miller FR, Slavin J, Anderson RL (1999) A novel orthotopic model of breast cancer metastasis to bone. Clin Exp Metastasis 17:163–170PubMedCrossRefGoogle Scholar
  80. 80.
    Pulaski BA, Ostrand-Rosenberg S (1998) Reduction of established spontaneous mammary carcinoma metastases following immunotherapy with major histocompatibility complex class II and B7.1 cell-based tumor vaccines. Cancer Res 58:1486–1493PubMedGoogle Scholar
  81. 81.
    Lockman PR, Mittapalli RK, Taskar KS, Rudraraju V, Gril B, Bohn KA, Adkins CE, Roberts A, Thorsheim HR, Gaasch JA, Huang S, Palmieri D, Steeg PS, Smith QR (2010) Heterogeneous Blood-Tumor Barrier Permeability Determines Drug Efficacy in Experimental Brain Metastases of Breast Cancer. Clin Cancer Res 16:5664–5678PubMedCrossRefGoogle Scholar
  82. 82.
    Kripke ML (1979) Speculations on the role of ultraviolet radiation in the development of malignant melanoma. J Natl Cancer Inst 63:541–548PubMedGoogle Scholar
  83. 83.
    Fidler IJ, Gruys E, Cifone MA, Barnes Z, Bucana C (1981) Demonstration of multiple phenotypic diversity in a murine melanoma of recent origin. J Natl Cancer Inst 67:947–956PubMedGoogle Scholar
  84. 84.
    Price JE, Tarin D, Fidler IJ (1988) Influence of organ microenvironment on pigmentation of a metastatic murine melanoma. Cancer Res 48:2258–2264PubMedGoogle Scholar
  85. 85.
    Radinsky R, Beltran PJ, Tsan R, Zhang R, Cone RD, Fidler IJ (1995) Transcriptional induction of the melanocyte-stimulating hormone receptor in brain metastases of murine K-1735 melanoma. Cancer Res 55:141–148PubMedGoogle Scholar
  86. 86.
    Fujimaki T, Fan D, Staroselsky A, Gohji K, Bucana C, Fidler I (1993) Critical factors regulating site-specific brain metastasis of murine melanomas. Int J Oncol 3:789–799PubMedGoogle Scholar
  87. 87.
    Schackert G, Simmons RD, Buzbee TM, Huma DA, Fidler IJ (1988) Macrophage infiltration into experimental brain metastases: occurrence through an intact blood-brain barrier. J Natl Cancer Inst 80:1027–1034PubMedCrossRefGoogle Scholar
  88. 88.
    Berkelhammer J, Oxenhandler RW, Hook RR, Hennessy JM (1982) Development of a new melanoma model in C57BL/6 mice. Cancer Res 42:3157–3163PubMedGoogle Scholar
  89. 89.
    Hearing VJ, Cannon GB, Vieira WD, Jiménez-Atiénzar M, Kameyama K, Law LW (1988) JB/MS murine melanoma: a new model for studies on the modulation of differentiation and of tumorigenic and metastatic potential. Int J Cancer 41:275–282PubMedCrossRefGoogle Scholar
  90. 90.
    Foureau DM, McKillop IH, Jones CP, Amin A, White RL, Salo JC (2011) Skin tumor responsiveness to interleukin-2 treatment and CD8 Foxp3 + T cell expansion in an immunocompetent mouse model. Cancer Immunol Immunother 60:1347–1356PubMedCrossRefGoogle Scholar
  91. 91.
    Kripke ML (1977) Latency, histology, and antigenicity of tumors induced by ultraviolet light in three inbred mouse strains. Cancer Res 37:1395–1400PubMedGoogle Scholar
  92. 92.
    Raz A, Hanna N, Fidler IJ (1981) In vivo isolation of a metastatic tumor cell variant involving selective and nonadaptive processes. J Natl Cancer Inst 66:183–189PubMedGoogle Scholar
  93. 93.
    Fidler IJ (2011) The role of the organ microenvironment in brain metastasis. Semin Cancer Biol 21:107–112PubMedCrossRefGoogle Scholar
  94. 94.
    Politi K, Pao W (2011) How genetically engineered mouse tumor models provide insights into human cancers. J Clin Oncol 29:2273–2281PubMedCrossRefGoogle Scholar
  95. 95.
    Bos PD, Nguyen DX, Massague J (2010) Modeling metastasis in the mouse. Curr Opin Pharmacol 10:571–577PubMedCrossRefGoogle Scholar
  96. 96.
    Winter SF, Cooper AB, Greenberg NM (2003) Models of metastatic prostate cancer: a transgenic perspective. Prostate Cancer Prostatic Dis 6:204–211PubMedCrossRefGoogle Scholar
  97. 97.
    Schackert G, Fidler IJ (1988) Development of in vivo models for studies of brain metastasis. Int J Cancer 41:589–594PubMedCrossRefGoogle Scholar
  98. 98.
    Higuchi M, Robinson DS, Cailleau R, Irie RF, Morton DL (1980) A serologic study of cultured breast cancer cell lines: lack of antibody response to tumour specific membrane antigens in patients. Clin Exp Immunol 39:90–96PubMedGoogle Scholar
  99. 99.
    Young RK, Cailleau RM, Mackay B, Reeves WJ (1974) Establishment of epithelial cell line MDA-MB-157 from metastatic pleural effusion of human breast carcinoma. In Vitro 9:239–245PubMedCrossRefGoogle Scholar
  100. 100.
    Zhang RD, Fidler IJ, Price JE (1991) Relative malignant potential of human breast carcinoma cell lines established from pleural effusions and a brain metastasis. Invasion Metastasis 11:204–215PubMedGoogle Scholar
  101. 101.
    Lorger M, Felding-Habermann B (2010) Capturing changes in the brain microenvironment during initial steps of breast cancer brain metastasis. Am J Pathol 176:2958–2971PubMedCrossRefGoogle Scholar
  102. 102.
    Heyn C, Ronald JA, Ramadan SS, Snir JA, Barry AM, MacKenzie LT, Mikulis DJ, Palmieri D, Bronder JL, Steeg PS, Yoneda T, MacDonald IC, Chambers AF, Rutt BK, Foster PJ (2006) In vivo MRI of cancer cell fate at the single-cell level in a mouse model of breast cancer metastasis to the brain. Magn Reson Med 56:1001–1010PubMedCrossRefGoogle Scholar
  103. 103.
    Tester AM, Waltham M, Oh S-J, Bae SN, Bills MM, Walker EC, Kern FG, Stetler-Stevenson WG, Lippman ME, Thompson EW (2004) Pro-matrix metalloproteinase-2 transfection increases orthotopic primary growth and experimental metastasis of MDA-MB-231 human breast cancer cells in nude mice. Cancer Res 64:652–658PubMedCrossRefGoogle Scholar
  104. 104.
    Rae JM, Creighton CJ, Meck JM, Haddad BR, Johnson MD (2007) MDA-MB-435 cells are derived from M14 melanoma cells-a loss for breast cancer, but a boon for melanoma research. Breast Cancer Res Treat 104:13–19PubMedCrossRefGoogle Scholar
  105. 105.
    Chambers AF (2009) MDA-MB-435 and M14 cell lines: identical but not M14 melanoma? Cancer Res 69:5292–5293PubMedCrossRefGoogle Scholar
  106. 106.
    Soule HD, Vazguez J, Long A, Albert S, Brennan M (1973) A human cell line from a pleural effusion derived from a breast carcinoma. J Natl Cancer Inst 51:1409–1416PubMedGoogle Scholar
  107. 107.
    Grossi PM, Ochiai H, Archer GE, McLendon RE, Zalutsky MR, Friedman AH, Friedman HS, Bigner DD, Sampson JH (2003) Efficacy of intracerebral microinfusion of trastuzumab in an athymic rat model of intracerebral metastatic breast cancer. Clin Cancer Res 9:5514–5520PubMedGoogle Scholar
  108. 108.
    Engel LW, Young NA, Tralka TS, Lippman ME, O′Brien SJ, Joyce MJ (1978) Establishment and characterization of three new continuous cell lines derived from human breast carcinomas. Cancer Res 38:3352–3364PubMedGoogle Scholar
  109. 109.
    Monsky WL, Mouta Carreira C, Tsuzuki Y, Gohongi T, Fukumura D, Jain RK (2002) Role of host microenvironment in angiogenesis and microvascular functions in human breast cancer xenografts: mammary fat pad versus cranial tumors. Clin Cancer Res 8:1008–1013PubMedGoogle Scholar
  110. 110.
    Price JE (1996) Metastasis from human breast cancer cell lines. Breast Cancer Res Treat 39:93–102PubMedCrossRefGoogle Scholar
  111. 111.
    Rye PD, Norum L, Olsen DR, Garman-Vik S, Kaul S, Fodstad O (1996) Brain metastasis model in athymic nude mice using a novel MUC1-secreting human breast-cancer cell line, MA11. Int J Cancer 68:682–687PubMedCrossRefGoogle Scholar
  112. 112.
    Lieber M, Smith B, Szakal A, Nelson-Rees W (1976) Todaro G (1976) A continuous tumor-cell line from a human lung carcinoma with properties of type II alveolar epithelial cells. Int J Cancer 17:62–70PubMedCrossRefGoogle Scholar
  113. 113.
    Mathieu A, Remmelink M, D’Haene N, Penant S, Gaussin JF, Van Ginckel R, Darro F, Kiss R (2004) Salmon I (2004) Development of a chemoresistant orthotopic human nonsmall cell lung carcinoma model in nude mice: analysis of tumor heterogeneity in relation to the immunohistochemical levels of expression of cyclooxygenase-2, ornithine decarboxylase, lung-related resistance protein, prostaglandin E synthetase, and gluthathione-S-transferase-alpha (GST)-alpha, GST-mu and GST-pi. Cancer 101(8):1908–1918PubMedCrossRefGoogle Scholar
  114. 114.
    Sundstrøm T, Daphu I, Wendelbo I, Hodneland E, Lundervold A, Immervoll H, Skaftnesmo KO, Babic M, Jendelova P, Sykova E, Lund-Johansen M, Bjerkvig R, Thorsen F (2013) Automated tracking of nanoparticle labeled melanoma cells improves the predictive power of a brain metastasis model. Cancer Res (in press)Google Scholar
  115. 115.
    Hart I, Fidler I (1980) Role of organ selectivity in the determination of metastatic patterns of B16 melanoma. Cancer Res 40:2281–2287PubMedGoogle Scholar
  116. 116.
    Oskarsson T, Acharyya S, Zhang XH, Vanharanta S, Tavazoie SF, Moris PG, Downey RJ, Manova-Todorova K, Brogi E, Massagué J (2011) Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nat Med 17:867–874PubMedCrossRefGoogle Scholar
  117. 117.
    Wang J, Daphu I, Pedersen PH, Miletic H, Hovland R, Mørk S, Bjerkvig R, Tiron C, McCormack E, Mickelm D, Lorens JB, Immervoll H, Thorsen F (2010) A novel brain metastases model developed in immunodeficient rats closely mimics the growth of metastatic brain tumours in patients. Neuropathol Appl Neurobiol 37:189–205CrossRefGoogle Scholar
  118. 118.
    Gunasinghe NP, Wells A, Thompson EW, Hugo HJ (2012) Mesenchymal–epithelial transition (MET) as a mechanism for metastatic colonisation in breast cancer. Cancer Metastasis Rev 31:469–478PubMedCrossRefGoogle Scholar
  119. 119.
    Kraljevic Pavelic S, Sedic M, Bosnjak H, Spaventi S, Pavelic K (2011) Metastasis: new perspectives on an old problem. Mol Cancer 10:22PubMedCrossRefGoogle Scholar
  120. 120.
    Fenouille N, Tichet M, Dufies M, Pottier A, Mogha A, Soo JK, Rocchi S, Mallavialle A, Galibert MD, Khammari A, Lacour JP, Ballotti R, Deckert M, Tartare-Deckert S (2012) The epithelial-mesenchymal transition (EMT) regulatory factor slug (SNAI2) is a downstream target of sparc and AKT in promoting melanoma cell invasion. PLoS ONE 7:e40378PubMedCrossRefGoogle Scholar
  121. 121.
    Ke XS, Li WC, Hovland R, Qu Y, Liu RH, McCormack E, Thorsen F, Olsen JR, Molven A, Kogan-Sakin I, Rotter V, Akslen LA, Oyan AM, Kalland KH (2010) Reprogramming of cell junction modules during stepwise epithelial to mesenchymal transition and accumulation of malignant features in vitro in a prostate cell model. Exp Cell Res 317:234–247PubMedCrossRefGoogle Scholar
  122. 122.
    Rahmathulla G, Toms SA, Weil RJ (2012) The molecular biology of brain metastasis. J Oncol 2012:723541PubMedCrossRefGoogle Scholar
  123. 123.
    Gjerdrum C, Tiron C, Høiby T, Stefansson I, Haugen H, Sandal T, Collett K, Li S, McCormack E, Gjertsen BT, Micklem DR, Akslen LA, Glackin C, Lorens JB (2010) Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival. Proc Nat Acad Sci U S A 107:1124–1129CrossRefGoogle Scholar
  124. 124.
    Bonnomet A, Syne L, Brysse A, Feyereisen E, Thompson EW, Noël A, Birembaut P, Foidart JM, Polette M, Gilles C (2012) A dynamic in vivo model of epithelial-to-mesenchymal transitions in circulating tumor cells and metastases of breast cancer. Oncogene 31:3741–3753PubMedCrossRefGoogle Scholar
  125. 125.
    Cruz-Munoz W, Man S, Xu P, Kerbel RS (2008) Development of a preclinical model of spontaneous human melanoma central nervous system metastasis. Cancer Res 68:4500–4505PubMedCrossRefGoogle Scholar
  126. 126.
    Hoffman RM (1999) Orthotopic metastatic mouse models for anticancer drug discovery and evaluation: a bridge to the clinic. Invest New Drugs 17:343–360PubMedCrossRefGoogle Scholar
  127. 127.
    Fu XY, Besterman JM, Monosov A, Hoffman RM (1991) Models of human metastatic colon cancer in nude mice orthotopically constructed by using histologically intact patient specimens. Proc Natl Acad Sci U S A 88:9345–9349PubMedCrossRefGoogle Scholar
  128. 128.
    Fu X, Le P, Hoffman RM (1993) A metastatic orthotopic-transplant nude-mouse model of human patient breast cancer. Anticancer Res 13:901–904PubMedGoogle Scholar
  129. 129.
    Kim MY, Oskarsson T, Acharyya S, Nguyen DX, Zhang XH, Norton L, Massagué J (2009) Tumor self-seeding by circulating cancer cells. Cell 139:1315–1326PubMedCrossRefGoogle Scholar
  130. 130.
    Lucignani G, Ottobrini L, Martelli C, Rescigno M, Clerici M (2006) Molecular imaging of cell-mediated cancer immunotherapy. Trends Biotechnol 24:410–418PubMedCrossRefGoogle Scholar
  131. 131.
    Lockshin A, Giovanella BC, Stehlin JS (1986) Quantitative evaluation of anticancer agents against human melanoma cells implanted in nude mice. Exp Cell Biol 54:149–154PubMedGoogle Scholar
  132. 132.
    Price J, Aukerman S, Fidler I (1986) Evidence that the process of murine melanoma metastasis is sequential and selective and contains stochastic elements. Cancer Res 46:5172–5178PubMedGoogle Scholar
  133. 133.
    Schabet M, Herrlinger U (1998) Animal models of leptomeningeal metastasis. J Neurooncol 38:199–205PubMedCrossRefGoogle Scholar
  134. 134.
    Siegal T, Sandbank U, Gabizon A, Siegal T, Mizrachi R, Ben-David E, Catane R (1987) Alteration of blood-brain-CSF barrier in experimental meningeal carcinomatosis. A morphologic and adriamycin-penetration study. J Neurooncol 4:233–242PubMedCrossRefGoogle Scholar
  135. 135.
    Hall WA, Myklebust A, Godal A, Nesland JM, Fodstad O (1994) In vivo efficacy of intrathecal transferrin-Pseudomonas exotoxin A immunotoxin against LOX melanoma. Neurosurgery 34:649–655PubMedCrossRefGoogle Scholar
  136. 136.
    Poste G (1982) Experimental systems for analysis of the malignant phenotype. Cancer Metastasis Rev 1:141–199PubMedCrossRefGoogle Scholar
  137. 137.
    Yi M, Schnitzer J (2009) Impaired tumor growth, metastasis, angiogenesis and wound healing in annexin A1-null mice. Proc Natl Acad Sci U S A 106:17886–17891PubMedCrossRefGoogle Scholar
  138. 138.
    Francia G, Cruz-Munoz W, Man S, Xu P, Kerbel RS (2011) Mouse models of advanced spontaneous metastasis for experimental therapeutics. Nat Rev Cancer 11:135–141PubMedCrossRefGoogle Scholar
  139. 139.
    Wagner KU (2004) Models of breast cancer: quo vadis, animal modeling? Breast Cancer Res 6:31–38PubMedCrossRefGoogle Scholar
  140. 140.
    Hüsemann Y, Klein CA (2009) The analysis of metastasis in transgenic mouse models. Transgenic Res 18:1–5PubMedCrossRefGoogle Scholar
  141. 141.
    Klein CA (2003) The systemic progression of human cancer: a focus on the individual disseminated cancer cell–the unit of selection. Adv Cancer Res 89:35–67PubMedCrossRefGoogle Scholar
  142. 142.
    Ossowski L, Aguirre-Ghiso JA (2010) Dormancy of metastatic melanoma. Pigment Cell Melanoma Res 23:41–56PubMedCrossRefGoogle Scholar
  143. 143.
    Goss PE, Chambers AF (2010) Does tumour dormancy offer a therapeutic target? Nat Rev Cancer 10:871–877PubMedCrossRefGoogle Scholar
  144. 144.
    Townson JL, Chambers AF (2006) Dormancy of solitary metastatic cells. Cell Cycle 5:1744–1750PubMedCrossRefGoogle Scholar
  145. 145.
    Naumov GN, MacDonald IC, Weinmeister PM, Kerkvliet N, Nadkarni KV, Wilson SM, Morris VL, Groom AC, Chambers AF (2002) Persistence of solitary mammary carcinoma cells in a secondary site: a possible contributor to dormancy. Cancer Res 62:2162–2168PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Inderjit Daphu
    • 1
  • Terje Sundstrøm
    • 1
    • 4
    • 5
  • Sindre Horn
    • 1
  • Peter C. Huszthy
    • 1
  • Simone P. Niclou
    • 2
  • Per Ø. Sakariassen
    • 1
  • Heike Immervoll
    • 3
  • Hrvoje Miletic
    • 1
    • 3
  • Rolf Bjerkvig
    • 1
    • 2
  • Frits Thorsen
    • 1
    Email author
  1. 1.NorLux Neuro-Oncology Laboratory, Department of BiomedicineUniversity of BergenBergenNorway
  2. 2.NorLux Neuro-Oncology LaboratoryCentre de Recherche Public de la SantéLuxembourgLuxembourg
  3. 3.Department of PathologyHaukeland University HospitalBergenNorway
  4. 4.Department of Surgical SciencesUniversity of BergenBergenNorway
  5. 5.Department of NeurosurgeryHaukeland University HospitalBergenNorway

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