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An orthotopic mouse model of small cell lung cancer reflects the clinical course in patients

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Abstract

Small cell lung cancer (SCLC) is a highly aggressive subtype of lung cancer with very poor prognosis due to early metastatic spread and development of chemoresistance. In the last 30 years the study of SCLC has been constrained by a lack of primary human tumor specimen thus highlighting the need of a suitable mouse model. In this article we present the establishment of an orthotopic xenograft mouse model which accurately reproduced the clinical course of SCLC. Orthotopic implantation enabled engraftment of primary lung tumors in all injected mice. Furthermore, immunodeficiency of mice allowed formation of spontaneous metastases in characteristic organs. Bioluminescence Imaging, Magnetic Resonance Imaging and Positron emission tomography were applied to monitor engraftment, metabolism and the exact growth of tumors over time. In order to mimic the extensive disease stage, mice were injected with aggressive human chemoresistant cells leading to development of chemoresistant tumors and early metastatic spread. As a proof of concept treatment of tumor-bearing mice with conventional chemotherapeutics reduced tumor volumes, but a complete regression of tumors was not achieved. By mimicking the extensive disease stage our mouse model can facilitate the study of mechanisms contributing to chemoresistance and metastasis formation, as well as drug screening and evaluation of new treatment strategies for SCLC patients.

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Abbreviations

SCLC:

Small cell lung cancer

BLI:

Bioluminescence imaging

MRI:

Magnetic resonance imaging

PET:

Positron emission tomography

References

  1. Herbst RS, Heymach JV, Lippman SM (2008) Lung cancer. N Engl J Med 359(13):1367–1380

    Article  CAS  PubMed  Google Scholar 

  2. Abidin AZ et al (2010) Targeted therapies in small cell lung cancer: a review. Ther Adv Med Oncol 2(1):25–37

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Schiller JH (2001) Current standards of care in small-cell and non-small-cell lung cancer. Oncology 61(Suppl 1):3–13

    Article  CAS  PubMed  Google Scholar 

  4. Zakowski MF (2003) Pathology of small cell carcinoma of the lung. Semin Oncol 30(1):3–8

    Article  PubMed  Google Scholar 

  5. Kalemkerian GP, Gadgeel SM (2013) Modern staging of small cell lung cancer. J Natl Compr Canc Netw 11(1):99–104

    PubMed  Google Scholar 

  6. Hurwitz JL et al (2009) New advances in the second-line treatment of small cell lung cancer. Oncologist 14(10):986–994

    Article  CAS  PubMed  Google Scholar 

  7. Herter-Sprie GS, Kung AL, Wong KK (2013) New cast for a new era: preclinical cancer drug development revisited. J Clin Invest 123(9):3639–3645

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Mak IW, Evaniew N, Ghert M (2014) Lost in translation: animal models and clinical trials in cancer treatment. Am J Transl Res 6(2):114–118

    PubMed  PubMed Central  Google Scholar 

  9. Singla AK et al (2015) Characterization of a murine model of metastatic human non-small cell lung cancer and effect of CXCR4 inhibition on the growth of metastases. Oncoscience 2(3):263–271

    Article  PubMed  PubMed Central  Google Scholar 

  10. Onn A, Herbst RS (2003) Angiogenesis, metastasis, and lung cancer. An overview. Methods Mol Med 74:329–348

    CAS  PubMed  Google Scholar 

  11. Onn A et al (2003) Development of an orthotopic model to study the biology and therapy of primary human lung cancer in nude mice. Clin Cancer Res 9(15):5532–5539

    CAS  PubMed  Google Scholar 

  12. Fei XF et al (2010) Development of clinically relevant orthotopic xenograft mouse model of metastatic lung cancer and glioblastoma through surgical tumor tissues injection with trocar. J Exp Clin Cancer Res 29:84

    Article  PubMed  PubMed Central  Google Scholar 

  13. Sethi T et al (1999) Extracellular matrix proteins protect small cell lung cancer cells against apoptosis: a mechanism for small cell lung cancer growth and drug resistance in vivo. Nat Med 5(6):662–668

    Article  CAS  PubMed  Google Scholar 

  14. Calbo J et al (2011) A functional role for tumor cell heterogeneity in a mouse model of small cell lung cancer. Cancer Cell 19(2):244–256

    Article  CAS  PubMed  Google Scholar 

  15. Wood SL et al (2014) The role of the tumor-microenvironment in lung cancer-metastasis and its relationship to potential therapeutic targets. Cancer Treat Rev 40(4):558–566

    Article  CAS  PubMed  Google Scholar 

  16. McLemore TL et al (1987) Novel intrapulmonary model for orthotopic propagation of human lung cancers in athymic nude mice. Cancer Res 47(19):5132–5140

    CAS  PubMed  Google Scholar 

  17. Dutt A, Wong KK (2006) Mouse models of lung cancer. Clin Cancer Res 12(14 Pt 2):4396s–4402s

    Article  CAS  PubMed  Google Scholar 

  18. Yamaura T et al (2000) Solitary lung tumors and their spontaneous metastasis in athymic nude mice orthotopically implanted with human non-small cell lung cancer. Neoplasia 2(4):315–324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Talmadge JE, Fidler IJ (2010) AACR centennial series: the biology of cancer metastasis: historical perspective. Cancer Res 70(14):5649–5669

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chiang AC, Massague J (2008) Molecular basis of metastasis. N Engl J Med 359(26):2814–2823

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. McAllister SS, Weinberg RA (2010) Tumor-host interactions: a far-reaching relationship. J Clin Oncol 28(26):4022–4028

    Article  PubMed  Google Scholar 

  22. Chaffer CL, Weinberg RA (2011) A perspective on cancer cell metastasis. Science 331(6024):1559–1564

    Article  CAS  PubMed  Google Scholar 

  23. Kallianos A et al (2013) Therapeutic procedure in small cell lung cancer. J Thorac Dis 5(Suppl 4):S420–S424

    PubMed  PubMed Central  Google Scholar 

  24. Gupta GP, Massague J (2006) Cancer metastasis: building a framework. Cell 127(4):679–695

    Article  CAS  PubMed  Google Scholar 

  25. Ribatti D, Mangialardi G, Vacca A (2006) Stephen Paget and the ‘seed and soil’ theory of metastatic dissemination. Clin Exp Med 6(4):145–149

    Article  CAS  PubMed  Google Scholar 

  26. Fidler IJ, Kim SJ, Langley RR (2007) The role of the organ microenvironment in the biology and therapy of cancer metastasis. J Cell Biochem 101(4):927–936

    Article  CAS  PubMed  Google Scholar 

  27. Liu X et al (2012) Establishment of an orthotopic lung cancer model in nude mice and its evaluation by spiral CT. J Thorac Dis 4(2):141–145

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Mordant P et al (2011) Bioluminescent orthotopic mouse models of human localized non-small cell lung cancer: feasibility and identification of circulating tumour cells. PLoS ONE 6(10):e26073

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Isobe T et al (2013) Evaluation of novel orthotopic nude mouse models for human small-cell lung cancer. J Thorac Oncol 8(2):140–146

    Article  PubMed  Google Scholar 

  30. Kang Y et al (2006) Development of an orthotopic transplantation model in nude mice that simulates the clinical features of human lung cancer. Cancer Sci 97(10):996–1001

    Article  CAS  PubMed  Google Scholar 

  31. Sodeur S et al (2009) Increased numbers of spontaneous SCLC metastasis in absence of NK cells after subcutaneous inoculation of different SCLC cell lines into pfp/rag2 double knock out mice. Cancer Lett 282(2):146–151

    Article  CAS  PubMed  Google Scholar 

  32. Disibio G, French SW (2008) Metastatic patterns of cancers: results from a large autopsy study. Arch Pathol Lab Med 132(6):931–939

    PubMed  Google Scholar 

  33. Sakamoto S et al (2015) New metastatic model of human small-cell lung cancer by orthotopic transplantation in mice. Cancer Sci 106(4):367–374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kuo TH et al (1993) Site-specific chemosensitivity of human small-cell lung carcinoma growing orthotopically compared to subcutaneously in SCID mice: the importance of orthotopic models to obtain relevant drug evaluation data. Anticancer Res 13(3):627–630

    CAS  PubMed  Google Scholar 

  35. Kubota T et al (1994) Antitumor activity of hexamethylmelamine on human tumor xenografts serially transplanted in nude mice. Anticancer Res 14(6B):2521–2524

    CAS  PubMed  Google Scholar 

  36. Donelli MG, Rosso R, Garattini S (1967) Selective chemotherapy in relation to the site of tumor transplantation. Int J Cancer 2(5):421–424

    Article  CAS  PubMed  Google Scholar 

  37. Minna JD, Kurie JM, Jacks T (2003) A big step in the study of small cell lung cancer. Cancer Cell 4(3):163–166

    Article  CAS  PubMed  Google Scholar 

  38. Park KS et al (2011) Characterization of the cell of origin for small cell lung cancer. Cell Cycle 10(16):2806–2815

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Meuwissen R et al (2003) Induction of small cell lung cancer by somatic inactivation of both Trp53 and Rb1 in a conditional mouse model. Cancer Cell 4(3):181–189

    Article  CAS  PubMed  Google Scholar 

  40. Zheng S et al (2007) A genetic mouse model for metastatic lung cancer with gender differences in survival. Oncogene 26(48):6896–6904

    Article  CAS  PubMed  Google Scholar 

  41. Buckle T, van Leeuwen FW (2010) Validation of intratracheal instillation of lung tumour cells in mice using single photon emission computed tomography/computed tomography imaging. Lab Anim 44(1):40–45

    Article  CAS  PubMed  Google Scholar 

  42. Fushiki H et al (2009) Quantification of mouse pulmonary cancer models by microcomputed tomography imaging. Cancer Sci 100(8):1544–1549

    Article  CAS  PubMed  Google Scholar 

  43. Puaux AL et al (2011) A comparison of imaging techniques to monitor tumor growth and cancer progression in living animals. Int J Mol Imaging 2011:321538

    Article  PubMed  PubMed Central  Google Scholar 

  44. Kwon MC, Berns A (2013) Mouse models for lung cancer. Mol Oncol 7(2):165–177

    Article  CAS  PubMed  Google Scholar 

  45. de Jong M, Essers J, van Weerden WM (2014) Imaging preclinical tumour models: improving translational power. Nat Rev Cancer 14(7):481–493

    Article  PubMed  Google Scholar 

  46. Iochmann S et al (2012) Monitoring of tumour progression using bioluminescence imaging and computed tomography scanning in a nude mouse orthotopic model of human small cell lung cancer. Lung Cancer 77(1):70–76

    Article  PubMed  Google Scholar 

  47. Montelius M et al (2012) Tumour size measurement in a mouse model using high resolution MRI. BMC Med Imaging 12:12

    Article  PubMed  PubMed Central  Google Scholar 

  48. Pautler RG (2004) Mouse MRI: concepts and applications in physiology. Physiology (Bethesda) 19:168–175

    Article  Google Scholar 

  49. Thomson D et al (2011) The role of positron emission tomography in management of small cell lung cancer. Lung Cancer 73(2):121–126

    Article  CAS  PubMed  Google Scholar 

  50. Beer AJ et al (2011) PET Imaging of Integrin alphaVbeta3 Expression. Theranostics 1:48–57

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

Supported by the Deutsche Forschungsgemeinschaft (DFG), project C3, CRC 850 (to MB) and Z2 (to RZ).

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Authors and Affiliations

  1. Department of Hematology/Oncology and Stem Cell Transplantation, University Medical Center, Hugstetter Str. 55, 70106, Freiburg, Germany

    Sanaz Taromi, Robert Zeiser & Meike Burger

  2. Department of Pathology, University Medical Center, Freiburg, Germany

    Gian Kayser

  3. Department of Radiology Medical Physics, University Medical Center, Freiburg, Germany

    Dominik von Elverfeldt & Wilfried Reichardt

  4. Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, USA

    Wolfgang A. Weber

  5. Institute of Nuclear Medicine, University Medical Center, Freiburg, Germany

    Friederike Braun & Wolfgang A. Weber

  6. Faculty of Medical and Life Sciences, University Futwangen, Campus Schwenningen, Jakob-Kienzle-Str. 17, 78054, Villingen-Schwenningen, Germany

    Meike Burger

Authors
  1. Sanaz Taromi
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  2. Gian Kayser
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  3. Dominik von Elverfeldt
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  7. Robert Zeiser
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  8. Meike Burger
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Corresponding author

Correspondence to Meike Burger.

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The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving animals were in accordance with the ethical standards on the Use and Care of Laboratory Animals at Albert Ludwig University and of the Regierungspraesidium of Freiburg, Germany.

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Taromi, S., Kayser, G., von Elverfeldt, D. et al. An orthotopic mouse model of small cell lung cancer reflects the clinical course in patients. Clin Exp Metastasis 33, 651–660 (2016). https://doi.org/10.1007/s10585-016-9808-8

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  • DOI: https://doi.org/10.1007/s10585-016-9808-8

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