Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Mouse model for lung tumorigenesis through Cre/lox controlled sporadic activation of the K-Ras oncogene

Abstract

The onset of human lung cancer occurs through sequential mutations in oncogenes and tumor suppressor genes. Mutations in K-Ras play a prominent role in human non-small cell lung cancer. We have developed a mouse lung tumor model in which K-Ras can be sporadically activated through Cre-lox mediated somatic recombination. Adenoviral mediated delivery of Cre recombinase in lung epithelial cells gave rise to rapid onset of tumorigenesis, yielding pulmonary adenocarcinomas with 100% incidence after a short latency. The lung tumor lesions shared many features with human non-small cell lung cancer. Our data show that sporadic expression of the K-Ras oncogene is sufficient to elicit lung tumorigenesis. Therefore this model has many advantages over conventional transgenic models used thus far.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  • Akagi K, Sandig V, Vooijs M, van de Valk M, Giovannini M, Strauss M, Berns A . 1997 Nucleic Acids Res. 25: 1766–1773

  • Bohinski RJ, Huffman JA, Whitsett JA, Lattier DL . 1993 J. Biol. Chem. 268: 11160–11166

  • Bos JL . 1989 Cancer Res. 49: 4682–4689

  • Carey FA, Wallace WA, Fergusson RJ, Kerr KM, Lamb D . 1992 Thorax 47: 1041–1043

  • Chan GL, Weinstein SS, LeFor WW, Spoto E, Kahana L, Shires DL . 1992 Ther. Drug Monit. 14: 42–47

  • Contag CH, Jenkins D, Contag PR, Negrin RS . 2000 Neoplasia 2: 41–52

  • Cooper CA, Carby FA, Bubb VJ, Lamb D, Kerr KM, Wyllie AH . 1997 J. Pathol. 181: 401–404

  • Edwards CW . 1987 J. Clin. Pathol. 40: 125–135

  • Fijneman RJ, Oomen LC, Snoek M, Demant P . 1995 Immunogenetics 41: 106–109

  • Garcia SB, Park HS, Novelli M, Wright NA . 1999 J. Pathol. 187: 61–81

  • Gazdar AF . 1994 Anticancer Res. 14: 261–267

  • Gibbs JB . 2000 Science 287: 1969–1973

  • Hanahan D, Weinberg RA . 2000 Cell 100: 57–70

  • Howell JM, Lochmuller H, O'Hara A, Fletcher S, Kakulas BA, Massie B, Nalbantoglu J, Karpati G . 1998 Hum. Gene Ther. 9: 629–634

  • Huncharek M, Muscat J, Geschwind JF . 1999 Carcinogenesis 20: 1507–1510

  • Johnson L, Mercer K, Greenbaum D, Bronson RT, Crowley D, Tuveson DA, Jacks T . 2001 Nature 410: 1111–1116

  • Kaufmann O, Dietel M . 2000 Histopathology 36: 8–16

  • Khoor A, Stahlman MT, Gray ME, Whitsett JA . 1994 J. Histochem. Cytochem. 42: 1187–1199

  • Land H, Chen AC, Morgenstern JP, Parada LF, Weinberg RA . 1986 Mol. Cell Biol. 6: 1917–1925

  • Loonstra A, Vooijs M, Berna Beverloo H, Al Allak B, Van Drunen E, Kanaar R, Berns A, Jonkers J . 2001 Proc. Natl. Acad. Sci. USA 98: 9209–9214

  • Mahler JF, Stokes W, Mann PC, Takaoka M, Maronpot RR . 1996 Toxicol. Pathol. 24: 710–716

  • Malkinson AM . 1998 Exp. Lung Res. 24: 541–555

  • Manne V, Bekesi E, Kung HF . 1985 Proc. Natl. Acad. Sci. USA 82: 376–380

  • Maronpot RR, Palmiter RD, Brinster RL, Sandgren EP . 1991 Exp. Lung Res. 17: 305–320

  • McGrath JP, Capon DJ, Goeddel DV, Levinson AD . 1984 Nature 310: 644–649

  • Mills NE, Fishman CL, Rom WN, Dubin N, Jacobson DR . 1995 Cancer Res. 55: 1444–1447

  • Omer CA, Chen Z, Diehl RE, Conner MW, Chen HY, Trumbauer ME, Gopal-Truter S, Seeburger G, Bhimnathwala H, Abrams MT, Davide JP, Ellis MS, Gibbs JB, Greenberg I, Koblan KS, Kral AM, Liu D, Lobell RB, Miller PJ, Mosser SD, O'Neill TJ, Rands E, Schaber MD, Senderak ET, Oliff A, Kohl NE . 2000 Cancer Res. 60: 2680–2688

  • Oomen LC, van der Valk MA, Demant P . 1991 Exp. Lung Res. 17: 283–304

  • Ordonez NG . 2000 Adv. Anat. Pathol. 7: 123–127

  • Otake K, Ennist DL, Harrod K, Trapnell BC . 1998 Hum. Gene Ther. 9: 2207–2222

  • Oudejans JJ, Slebos RJ, Zoetmulder FA, Mooi WJ, Rodenhuis S . 1991 Int. J. Cancer 49: 875–879

  • Park JY, Jeon HS, Park SH, Park TI, Son JW, Kim CH, Park JH, Kim IS, Jung TH, Jun SH . 2000 Lung Cancer 30: 83–89

  • Pellegata NS, Sessa F, Renault B, Bonato M, Leone BE, Solcia E, Ranzani GN . 1994 Cancer Res. 54: 1556–1560

  • Rodenhuis S, Slebos RJ . 1992 Cancer Res. 52: 2665s–2669s

  • Rodenhuis S, Slebos RJ, Boot AJ, Evers SG, Mooi WJ, Wagenaar SS, van Bodegom PC, Bos JL . 1988 Cancer Res. 48: 5738–5741

  • Rom WN, Hay JG, Lee TC, Jiang Y, Tchou-Wong KM . 2000 Am. J. Respir. Crit Care Med. 161: 1355–1367

  • Saitoh A, Kimura M, Takahashi R, Yokoyama M, Nomura T, Izawa M, Sekiya T, Nishimura S, Katsuki M . 1990 Oncogene 5: 1195–1200

  • Sauer B . 1998 Methods 14: 381–392

  • Schmidt EE, Taylor DS, Prigge JR, Barnett S, Capecchi MR . 2000 Proc. Natl. Acad. Sci. USA 97: 13702–13707

  • Shields JM, Pruitt K, McFall A, Shaub A, Der CJ . 2000 Trends Cell Biol. 10: 147–154

  • Shimkin MB, Stoner GD . 1975 Adv. Cancer Res. 21: 1–58

  • Slebos RJ, Kibbelaar RE, Dalesio O, Kooistra A, Stam J, Meijer CJ, Wagenaar SS, Vanderschueren RG, van Zandwijk N, Mooi WJ . 1990 N. Engl. J. Med. 323: 561–565

  • Soriano P . 1999 Nat. Genet. 21: 70–71

  • Sozzi G, Miozzo M, Pastorino U, Pilotti S, Donghi R, Giarola M, De Gregorio L, Manenti G, Radice P, Minoletti F . 1995 Cancer Res. 55: 135–140

  • Suda Y, Aizawa S, Hirai S, Inoue T, Furuta Y, Suzuki M, Hirohashi S, Ikawa Y . 1987 EMBO J. 6: 4055–4065

  • Ten Have-Opbroek AA, Benfield JR, van Krieken JH, Dijkman JH . 1997 Histol. Histopathol. 12: 319–336

  • Tsuchiya E, Furuta R, Wada N, Nakagawa K, Ishikawa Y, Kawabuchi B, Nakamura Y, Sugano H . 1995 J. Cancer Res. Clin. Oncol. 121: 577–581

  • Tuveson DA, Jacks T . 1999 Oncogene 18: 5318–5324

  • Whitsett JA, Nogee LM, Weaver TE, Horowitz AD . 1995 Physiol Rev. 75: 749–757

  • Wingo PA, Ries LA, Giovino GA, Miller DS, Rosenberg HM, Shopland DR, Thun MJ, Edwards BK . 1999 J. Natl. Cancer Inst. 91: 675–690

  • World Health Organization . Histological Typing of Lung Tumours, 2nd ed. Geneva: World Health Organization, 1981

  • Zsengeller ZK, Wert SE, Hull WM, Hu X, Yei S, Trapnell BC, Whitsett JA . 1995 Hum. Gene Ther. 6: 457–467

Download references

Acknowledgements

We thank Loes Rijswijk and Fina van de Ahe for expert assistance with the microsurgical procedures, Nell Bosnie for supervising the daily care of the mice, Jurjen Bulthuis for preparation of the histological slides, Paul Krimpenfort for injecting fertilized oocytes and Olaf van Tellingen for determination of cyclosporin A blood levels. This work was supported by a grant of the Dutch Cancer Society. SC Linn was a recipient of a KWF fellowship.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Anton Berns.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Meuwissen, R., Linn, S., van der Valk, M. et al. Mouse model for lung tumorigenesis through Cre/lox controlled sporadic activation of the K-Ras oncogene. Oncogene 20, 6551–6558 (2001). https://doi.org/10.1038/sj.onc.1204837

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1204837

Keywords

This article is cited by

Search

Quick links