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
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
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
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
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
Corresponding author
Rights 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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1204837
Keywords
This article is cited by
-
Cre toxicity in mouse models of cardiovascular physiology and disease
Nature Cardiovascular Research (2022)
-
A step towards valid detection and quantification of lung cancer volume in experimental mice with contrast agent-based X-ray microtomography
Scientific Reports (2019)
-
A non-cell autonomous mouse model of CNS haemangioblastoma mediated by mutant KRAS
Scientific Reports (2017)
-
Predictive biomarkers in precision medicine and drug development against lung cancer
Chinese Journal of Cancer (2015)
-
Frequent alterations in cytoskeleton remodelling genes in primary and metastatic lung adenocarcinomas
Nature Communications (2015)