The Use of Mouse Models for Lung Cancer Chemoprevention Studies

  • Yian Wang
  • Michael S. You
  • Lucina C. Rouggly
  • Ming You
Protocol
Part of the Methods in Pharmacology and Toxicology book series (MIPT)

Abstract

Mouse lung tumor models are widely used in lung cancer chemopreventive studies. Lung cancer is a heterogeneous disease histologically classified as small-cell lung carcinoma (SCLC) and non-small-cell lung carcinoma (NSCLC), which is usually divided into adenocarcinoma, squamous cell carcinoma (SCC), and large cell carcinoma. In order to illustrate the power of the mouse model in preclinical lung cancer investigations, comprehensive instructions for the selection of mice, genotyping, and induction of lung tumors (e.g., adenoma/adenocarcinoma, lung SCC, and SCLC) in mice are provided. We have described in detail the histological features of these tumors and the application of these features in lung cancer chemoprevention studies. We have also provided detailed information on how to semiquantitatively phenotype lung tumor development. The basic protocol described here could easily be applied to other approaches to lung cancer prevention such as chemoprevention or immunoprevention.

Key words

Lung cancer Chemoprevention Animal models Adenocarcinoma Squamous cell carcinoma Small-cell lung cancer 

References

  1. 1.
    Siegel R, Naishadham D, Jemal A (2013) Cancer statistics, 2013. CA Cancer J Clin 63(1):11–30. doi: 10.3322/caac.21166 PubMedCrossRefGoogle Scholar
  2. 2.
    Doll R, Hill AB (1952) A study of the aetiology of carcinoma of the lung. Br Med J 2(4797):1271–1286PubMedCrossRefGoogle Scholar
  3. 3.
    Herzog CR, Lubet RA, You M (1997) Genetic alterations in mouse lung tumors: implications for cancer chemoprevention. J Cell Biochem Suppl 28–29:49–63PubMedCrossRefGoogle Scholar
  4. 4.
    Shopland DR, Eyre HJ, Pechacek TF (1991) Smoking-attributable cancer mortality in 1991: is lung cancer now the leading cause of death among smokers in the United States? J Natl Cancer Inst 83(16):1142–1148PubMedCrossRefGoogle Scholar
  5. 5.
    Minna JD (1993) The molecular biology of lung cancer pathogenesis. Chest 103(4 Suppl):449S–456SPubMedCrossRefGoogle Scholar
  6. 6.
    Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60(5):277–300. doi: 10.3322/caac.20073 PubMedCrossRefGoogle Scholar
  7. 7.
    Herbst RS, Heymach JV, Lippman SM (2008) Lung cancer. N Engl J Med 359(13):1367–1380. doi: 10.1056/NEJMra0802714 PubMedCrossRefGoogle Scholar
  8. 8.
    Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, Rami-Porta R, Postmus PE, Rusch V, Sobin L (2007) The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol 2(8):706–714. doi: 10.1097/JTO.0b013e31812f3c1a PubMedCrossRefGoogle Scholar
  9. 9.
    Mountain CF, Dresler CM (1997) Regional lymph node classification for lung cancer staging. Chest 111(6):1718–1723PubMedCrossRefGoogle Scholar
  10. 10.
    Mountain CF (1997) Revisions in the international system for staging lung cancer. Chest 111(6):1710–1717PubMedCrossRefGoogle Scholar
  11. 11.
    Alifano M, Souaze F, Dupouy S, Camilleri-Broet S, Younes M, Ahmed-Zaid SM, Takahashi T, Cancellieri A, Damiani S, Boaron M, Broet P, Miller LD, Gespach C, Regnard JF, Forgez P (2010) Neurotensin receptor 1 determines the outcome of non-small cell lung cancer. Clin Cancer Res 16(17):4401–4410. doi: 10.1158/1078-0432.CCR-10-0659 PubMedCrossRefGoogle Scholar
  12. 12.
    Lovly CM, Carbone DP (2011) Lung cancer in 2010: one size does not fit all. Nat Rev Clin Oncol 8(2):68–70. doi: 10.1038/nrclinonc.2010.224 PubMedCrossRefGoogle Scholar
  13. 13.
    (2012) Comprehensive genomic characterization of squamous cell lung cancers. Nature 489(7417):519–525. doi: 10.1038/nature11404
  14. 14.
    Lockwood WW, Wilson IM, Coe BP, Chari R, Pikor LA, Thu KL, Solis LM, Nunez MI, Behrens C, Yee J, English J, Murray N, Tsao MS, Minna JD, Gazdar AF, Wistuba II, MacAulay CE, Lam S, Lam WL (2012) Divergent genomic and epigenomic landscapes of lung cancer subtypes underscore the selection of different oncogenic pathways during tumor development. PLoS One 7(5):e37775. doi: 10.1371/journal.pone.0037775 PubMedCrossRefGoogle Scholar
  15. 15.
    Hainsworth JD, Cebotaru CL, Kanarev V, Ciuleanu TE, Damyanov D, Stella P, Ganchev H, Pover G, Morris C, Tzekova V (2010) A phase II, open-label, randomized study to assess the efficacy and safety of AZD6244 (ARRY-142886) versus pemetrexed in patients with non-small cell lung cancer who have failed one or two prior chemotherapeutic regimens. J Thorac Oncol 5(10):1630–1636. doi: 10.1097/JTO.0b013e3181e8b3a3 PubMedCrossRefGoogle Scholar
  16. 16.
    Huynh H, Soo KC, Chow PK, Tran E (2007) Targeted inhibition of the extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) in the treatment of hepatocellular carcinoma. Mol Cancer Ther 6(1):138–146. doi: 10.1158/1535-7163.MCT-06-0436 PubMedCrossRefGoogle Scholar
  17. 17.
    Ball DW, Jin N, Rosen DM, Dackiw A, Sidransky D, Xing M, Nelkin BD (2007) Selective growth inhibition in BRAF mutant thyroid cancer by the mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244. J Clin Endocrinol Metab 92(12):4712–4718. doi: 10.1210/jc.2007-1184 PubMedCrossRefGoogle Scholar
  18. 18.
    Haass NK, Sproesser K, Nguyen TK, Contractor R, Medina CA, Nathanson KL, Herlyn M, Smalley KS (2008) The mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor AZD6244 (ARRY-142886) induces growth arrest in melanoma cells and tumor regression when combined with docetaxel. Clin Cancer Res 14(1):230–239. doi: 10.1158/1078-0432.CCR-07-1440 PubMedCrossRefGoogle Scholar
  19. 19.
    Ammoun S, Ristic N, Matthies C, Hilton DA, Hanemann CO (2010) Targeting ERK1/2 activation and proliferation in human primary schwannoma cells with MEK1/2 inhibitor AZD6244. Neurobiol Dis 37(1):141–146. doi: 10.1016/j.nbd.2009.09.017 PubMedCrossRefGoogle Scholar
  20. 20.
    Estensen RD, Wattenberg LW (1993) Studies of chemopreventive effects of myo-inositol on benzo[a]pyrene-induced neoplasia of the lung and forestomach of female A/J mice. Carcinogenesis 14(9):1975–1977PubMedCrossRefGoogle Scholar
  21. 21.
    Wattenberg LW, Wiedmann TS, Estensen RD, Zimmerman CL, Steele VE, Kelloff GJ (1997) Chemoprevention of pulmonary carcinogenesis by aerosolized budesonide in female A/J mice. Cancer Res 57(24):5489–5492PubMedGoogle Scholar
  22. 22.
    Wang Y, Zhang Z, Kastens E, Lubet RA, You M (2003) Mice with alterations in both p53 and Ink4a/Arf display a striking increase in lung tumor multiplicity and progression: differential chemopreventive effect of budesonide in wild-type and mutant A/J mice. Cancer Res 63(15):4389–4395PubMedGoogle Scholar
  23. 23.
    Zhang Z, Liu Q, Lantry LE, Wang Y, Kelloff GJ, Anderson MW, Wiseman RW, Lubet RA, You M (2000) A germ-line p53 mutation accelerates pulmonary tumorigenesis: p53-independent efficacy of chemopreventive agents green tea or dexamethasone/myo-inositol and chemotherapeutic agents taxol or adriamycin. Cancer Res 60(4):901–907PubMedGoogle Scholar
  24. 24.
    Anderson MW, Goodin C, Zhang Y, Kim S, Estensen RD, Wiedmann TS, Sekar P, Buncher CR, Khoury JC, Garbow JR, You M, Tichelaar JW (2008) Effect of dietary green tea extract and aerosolized difluoromethylornithine during lung tumor progression in A/J strain mice. Carcinogenesis 29(8):1594–1600. doi: 10.1093/carcin/bgn129 PubMedCrossRefGoogle Scholar
  25. 25.
    Fu H, He J, Mei F, Zhang Q, Hara Y, Ryota S, Lubet RA, Chen R, Chen DR, You M (2009) Lung cancer inhibitory effect of epigallocatechin-3-gallate is dependent on its presence in a complex mixture (polyphenon E). Cancer Prev Res (Phila) 2(6):531–537. doi: 10.1158/1940-6207.CAPR-08-0185 CrossRefGoogle Scholar
  26. 26.
    Wang Y, Zhang Z, Garbow JR, Rowland DJ, Lubet RA, Sit D, Law F, You M (2009) Chemoprevention of lung squamous cell carcinoma in mice by a mixture of Chinese herbs. Cancer Prev Res (Phila) 2(7):634–640. doi: 10.1158/1940-6207.CAPR-09-0052 CrossRefGoogle Scholar
  27. 27.
    Wang Y, James M, Wen W, Lu Y, Szabo E, Lubet RA, You M (2010) Chemopreventive effects of pioglitazone on chemically induced lung carcinogenesis in mice. Mol Cancer Ther 9(11):3074–3082. doi: 10.1158/1535-7163.MCT-10-0510 PubMedCrossRefGoogle Scholar
  28. 28.
    Khan N, Afaq F, Kweon MH, Kim K, Mukhtar H (2007) Oral consumption of pomegranate fruit extract inhibits growth and progression of primary lung tumors in mice. Cancer Res 67(7):3475–3482. doi: 10.1158/0008-5472.CAN-06-3941 PubMedCrossRefGoogle Scholar
  29. 29.
    Wang Y, Wen W, Yi Y, Zhang Z, Lubet RA, You M (2009) Preventive effects of bexarotene and budesonide in a genetically engineered mouse model of small cell lung cancer. Cancer Prev Res (Phila) 2(12):1059–1064. doi: 10.1158/1940-6207.CAPR-09-0221 CrossRefGoogle Scholar
  30. 30.
    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(3):181–189PubMedCrossRefGoogle Scholar
  31. 31.
    Lavigueur A, Maltby V, Mock D, Rossant J, Pawson T, Bernstein A (1989) High incidence of lung, bone, and lymphoid tumors in transgenic mice overexpressing mutant alleles of the p53 oncogene. Mol Cell Biol 9(9):3982–3991PubMedGoogle Scholar
  32. 32.
    Wang Y, Zhang Z, Yao R, Jia D, Wang D, Lubet RA, You M (2006) Prevention of lung cancer progression by bexarotene in mouse models. Oncogene 25(9):1320–1329. doi: 10.1038/sj.onc.1209180 PubMedCrossRefGoogle Scholar
  33. 33.
    Hecht SS (1999) Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst 91(14):1194–1210PubMedCrossRefGoogle Scholar
  34. 34.
    Kassie F, Melkamu T, Endalew A, Upadhyaya P, Luo X, Hecht SS (2010) Inhibition of lung carcinogenesis and critical cancer-related signaling pathways by N-acetyl-S-(N-2-phenethylthiocarbamoyl)-l-cysteine, indole-3-carbinol and myo-inositol, alone and in combination. Carcinogenesis 31(9):1634–1641. doi: 10.1093/carcin/bgq139 PubMedCrossRefGoogle Scholar
  35. 35.
    Zhang Z, Wang Y, Lantry LE, Kastens E, Liu G, Hamilton AD, Sebti SM, Lubet RA, You M (2003) Farnesyltransferase inhibitors are potent lung cancer chemopreventive agents in A/J mice with a dominant-negative p53 and/or heterozygous deletion of Ink4a/Arf. Oncogene 22(40):6257–6265. doi: 10.1038/sj.onc.1206630 PubMedCrossRefGoogle Scholar
  36. 36.
    Wang Y, Zhang Z, Yan Y, Lemon WJ, LaRegina M, Morrison C, Lubet R, You M (2004) A chemically induced model for squamous cell carcinoma of the lung in mice: histopathology and strain susceptibility. Cancer Res 64(5):1647–1654PubMedCrossRefGoogle Scholar
  37. 37.
    Rehm S, Lijinsky W, Singh G, Katyal SL (1991) Mouse bronchiolar cell carcinogenesis. Histologic characterization and expression of Clara cell antigen in lesions induced by N-nitrosobis-(2-chloroethyl) ureas. Am J Pathol 139(2):413–422PubMedGoogle Scholar
  38. 38.
    DuPage M, Dooley AL, Jacks T (2009) Conditional mouse lung cancer models using adenoviral or lentiviral delivery of Cre recombinase. Nat Protoc 4(7):1064–1072. doi: 10.1038/nprot.2009.95 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Yian Wang
    • 1
  • Michael S. You
    • 1
  • Lucina C. Rouggly
    • 1
  • Ming You
    • 2
  1. 1.Department of Surgery and The Alvin J. Siteman Cancer CenterWashington University School of MedicineSt LouisUSA
  2. 2.Department of Pharmacology and ToxicologyMedical College of WisconsinMilwaukeeUSA

Personalised recommendations