Abstract
A/J mice with genetic alterations in K-ras, p53, or Ink4a/Arf were employed to investigate whether mice carrying these germline mutations would be susceptible to tobacco smoke-induced lung tumorigenesis. Transgenic mice of both genders and their wild-type littermates were exposed to environmental cigarette smoke for 6 months, followed by recovery in air for 5 months. A significant increase of lung tumor multiplicity was observed in K-ras, p53, or Ink4a/Arf mutant mice when compared with wild-type mice. Furthermore, an additive effect was observed between the mice with a mutant p53 transgene and an Ink4A/Arf deletion during tobacco smoke-induced lung tumorigenesis. Sequence analysis of the K-ras gene indicated that the mutations had occurred at either codon 12/13 or 61 in both spontaneously occurring (air control) and tobacco smoke-induced lung tumors. K-ras mutations were found in 62% of the tumors from air-control animals and 83% in those exposed to tobacco smoke. The mutation spectrum found in tumors from mice exposed to tobacco smoke is somewhat similar to that in tumors from air-control mice. In addition, we identified three novel mutations at codon 12: GGT (Gly) → TTT (Phe), ATT (Ile), and CTT (Leu). These findings provide evidence that K-ras, p53, and Ink4a/Arf mutations play a role in tobacco smoke-related lung carcinogenesis. The similarity of the mutation spectra in the K-ras oncogene observed in tobacco smoke-induced tumors, as compared to spontaneous tumors, suggests that tobacco smoke enhances lung tumorigenesis primarily through promoting spontaneously occurring K-ras mutations.
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
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Bardeesy N, Morgan J, Sinha M, Signoretti S, Srivastava S, Loda M, Merlino G and DePinho RA . (2002). Mol. Cell. Biol., 22, 635–643.
Carbone D . (1992). Am. J. Med., 93, 13–17.
Chen B, Liu L, Castonguay A, Maronpot RR, Anderson MW and You M . (1993). Carcinogenesis, 14, 1603–1608.
Chiba I, Takahashi T, Nau MM, D'Amico D, Curiel DT, Mitsudomi T, Buchhagen DL, Carbone D, Piantadosi S Koga H, Reissman PT, Slamon DJ, Holmes EC and Minna JD . (1990). Oncogene, 5, 1603–1610.
D'Agostini F, Balansky RM, Bennicelli C, Lubet RA, Kelloff GJ and De Flora S . (2001). Int. J. Oncol., 18, 607–615.
De Flora S, Balansky RM, D'Agostini F, Izzotti A, Camoirano A, Bennicelli C, Zhang Z, Wang Y, Lubet RA and You M . (2003). Cancer Res., 63, 793–800.
Devereux TR, Anderson MW and Belinsky SA . (1991). Carcinogenesis, 12, 299–303.
Fontanini G, Vignati S, Bigini D, Merlo GR, Ribecchini A, Angeletti CA, Basolo F, Pingitore R and Bevilacqua G . (1994). J. Pathol., 174, 23–31.
Gazzeri S, Gouyer V, Vour'ch C, Brambilla C and Brambilla E . (1998). Oncogene, 16, 497–504.
Hamada K, Kohno T, Kawanishi M, Ohwada S and Yokota J . (1998). Genes Chromosomes Cancer, 22, 232–240.
Hecht SS . (1999). J. Natl. Cancer Inst., 91, 1194–1210.
Herzog CR, Schut HA, Maronpot RR and You M . (1993). Mol. Carcinog., 8, 202–207.
Hursting SD, Perkins SN, Donehower LA and Davis BJ . (2001). Toxicol. Pathol., 29, 137–141.
Husgafvel-Pursiainen K, Hackman P, Ridanpaa M, Anttila S, Karjalainen A, Partanen T, Taikina-Aho O, Heikkila L and Vainio H . (1993). Int. J. Cancer, 53, 250–256.
Hwang SJ, Cheng LS, Lozano G, Amos CI, Gu X and Strong LC . (2003). Hum. Genet., 113, 238–243.
Kamb A, Shattuck-Eidens D, Eeles R, Liu Q, Gruis NA, Ding W, Hussey C, Tran T, Miki Y, Weaver-Feldhaus J, McClure M, Aitken JF, Anderson DE, Bergman W, Frants R, Goldgar DE, Green A, MacLennan R, Martin NG, Meyer LJ, Youl P, Zone JJ, Skolnick MH and Cannon-Albright LA . (1994). Nat. Genet., 8, 23–26.
Kinoshita I, Dosaka-Akita H, Mishina T, Akie K, Nishi M, Hiroumi H, Hommura F and Kawakami Y . (1996). Cancer Res., 56, 5557–5562.
Levine AJ . (1997). Cell, 88, 323–331.
Marchetti A, Buttitta F, Pellegrini S, Campani D, Diella F, Cecchetti D, Callahan R and Bistocchi M . (1993). Cancer Res., 53, 4665–4669.
Matzinger SA, Crist KA, Stoner GD, Anderson MW, Pereira MA, Steele VE, Kelloff GJ, Lubet RA and You M . (1995). Carcinogenesis, 16, 2487–2492.
Merlo A, Herman JG, Mao L, Lee DJ, Gabrielson E, Burger PC, Baylin SB and Sidransky D . (1995). Nat. Med., 1, 686–692.
Minna JD . (1993). Chest, 103, 449S–456S.
Rodenhuis S and Slebos RJ . (1990). Am. Rev. Respir. Dis., 142, S27–S30.
Rodenhuis S and Slebos RJ . (1992). Cancer Res., 52, 2665s–2669s.
Rodenhuis S, Slebos RJ, Boot AJ, Evers SG, Mooi WJ, Wagenaar SS, van Bodegom PC and Bos JL . (1988). Cancer Res., 48, 5738–5741.
Ronai ZA, Gradia S, Peterson LA and Hecht SS . (1993). Carcinogenesis, 14, 2419–2422.
Serrano M, Hannon GJ and Beach D . (1993). Nature, 366, 704–707.
Shapiro GI, Park JE, Edwards CD, Mao L, Merlo A, Sidransky D, Ewen ME and Rollins BJ . (1995). Cancer Res., 55, 6200–6209.
Slebos RJ, Hruban RH, Dalesio O, Mooi WJ, Offerhaus GJ and Rodenhuis S . (1991). J. Natl. Cancer Inst., 83, 1024–1027.
Sozzi G, Miozzo M, Donghi R, Pilotti S, Cariani CT, Pastorino U, Della Porta G and Pierotti MA . (1992). Cancer Res., 52, 6079–6082.
Takahashi T, Suzuki H, Hida T, Sekido Y, Ariyoshi Y and Ueda R . (1991). Oncogene, 6, 1775–1778.
Teague SV, Pinkerton KE, Goldsmith M, Gebremichael A, Chang S, Jenkins RA and Moneyhum JH . (1994). Inhal. Toxicol., 6, 79–93.
Top B, Mooi WJ, Klaver SG, Boerrigter L, Wisman P, Elbers HR, Visser S and Rodenhuis S . (1995). Int. J. Cancer, 64, 83–91.
Wang XW and Harris CC . (1997). J. Cell. Physiol., 173, 247–255.
Wang Y, Zhang Z, Kastens E, Lubet RA and You Y . (2003). Cancer Res., 63, 4389–4395.
Wiethege T, Voss B and Müller KM . (1995). J. Cancer Res. Clin. Oncol., 121, 371–377.
Witschi H, Esperitu I, Dance ST and Miller MS . (2002). Toxicol. Sci., 68, 322–330.
Witschi H, Oreffo VI and Pinkerton KE . (1995). Fund. Appl. Toxicol., 26, 32–40.
Witschi HP . (2000). Exp. Lung Res., 26, 743–755.
You M and Bergman G . (1998). Hematol. Oncol. Clin. N. Am., 12, 1037–1053.
You M, Candrian U, Maronpot RR, Stoner GD and Anderson MW . (1989). Proc. Natl. Acad. Sci. USA, 86, 3070–3074.
You M, Wang Y, Stoner G, You L, Maronpot R, Reynolds SH and Anderson M . (1992). Proc. Natl. Acad. Sci. USA, 89, 5804–5808.
Zhang Z, Futamura M, Vikis HG, Wang M, Li J, Wang Y, Guan K-L and You M . (2003). Proc. Natl. Acad. Sci. USA, 100, 12642–12647.
Zhang Z, Li J, Lantry LE, Wang Y, Wiseman RW, Lubet RA and You M . (2002). Cancer Res., 62, 3024–3029.
Zhang Z, Liu Q, Lantry LE, Wang Y, Kelloff GJ, Anderson MW, Wiseman RW, Lubet RA and You M . (2000). Cancer Res., 60, 901–907.
Zhang Z, Wang Y, Vikis HG, Johnson L, Liu G, Li J, Anderson MW, Sills RC, Hong HL, Devereux TR, Jacks T, Guan KL and You M . (2001). Nat. Genet., 29, 25–33.
Acknowledgements
We are grateful to Dr Roger W Wiseman for providing the original UL53-3 mice, Dr Ronald A DePinho for the original Ink4a/Arf−/− mice, and Dr Tyler Jacks for the original K-ras+/− mice. We thank Dr Daolong Wang for the statistical analysis; and Jin Fang and Elizabeth Kastens for technical support. This work was supported by NIH Grants R01CA58554 and N01CN-35117.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Wang, Y., Zhang, Z., Lubet, R. et al. Tobacco smoke-induced lung tumorigenesis in mutant A/J mice with alterations in K-ras, p53, or Ink4a/Arf. Oncogene 24, 3042–3049 (2005). https://doi.org/10.1038/sj.onc.1208390
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1208390
