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:

Transgenic overexpression of IGF-II induces spontaneous lung tumors: a model for human lung adenocarcinoma

Oncogene volume 22, pages 853–857 (2003)Cite this article

Abstract

Elevated levels of insulin-like growth factor (IGF)-II are associated with a poor prognosis in human pulmonary adenocarcinoma; however, a causal role for IGF-II in pulmonary adenocarcinoma has not been demonstrated. Here, we show that transgenic overexpression of IGF-II in lung epithelium induces lung tumors in 69% of mice older than 18 months of age. These tumors displayed morphological characteristics of human pulmonary adenocarcinoma such as their epithelial origin, tubulo-acinar architecture and expression of TTF-1, SP-B and proSP-C. Examination of signaling molecules downstream of the IGF-IR showed the activation of either the Erk1/Erk2 or p38 MAPK pathways, but not both, within the lung tumors. Notably, all lung tumors contained high levels of phosphorylated CREB, suggesting that both the Erk1/Erk2 and p38 MAPK pathways converged on this transcription factor. Moreover, IGF-II induced proliferation and CREB phosphorylation in human lung cancer cell lines, suggesting that IGF-II and CREB also contribute to the growth of human lung tumors. Thus, IGF-II is an important genetic factor in the development of lung tumorigenesis, in which activation of CREB is a ubiquitous event. The MMTV-IGF-II transgenic mice provide a critical model for elucidating the role of IGF-II in this fatal human disease.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  • Abraham E, Arcaroli J and Shenkar R . (2001). J. Immunol., 166, 522–530.

  • Brazil DP and Hemmings BA . (2001). Trends Biochem. Sci., 26, 657–664.

  • Chailley-Heu B, Rambaud C, Barlier-Mur AM, Galateau-Salle F, Perret C, Capron F and Lacaze-Masmonteil T . (2001). J. Pathol., 195, 482–489.

  • Clark JC, Tichelaar JW, Wert SE, Itoh N, Perl AK, Stahlman MT and Whitsett JA . (2001). Am. J. Physiol. Lung Cell Mol. Physiol., 280, L705–L715.

  • Datta SR, Brunet A and Greenberg ME . (1999). Genes Devel., 13, 2905–2927.

  • Di Loreto C, Di Lauro V, Puglisi F, Damante G, Fabbro D and Beltrami CA . (1997). J. Clin. Pathol., 50, 30–32.

  • Fata JE, Leco KJ, Moorehead RA, Martin DC and Khokha R . (1999). Devel. Biol., 211, 238–254.

  • George CL, Fantuzzi G, Bursten S, Leer L and Abraham E . (1999). Am. J. Physiol., 276, L776–L785.

  • Grimberg A and Cohen P . (2000). J. Cell Physiol., 183, 1–9.

  • Harvey MB, Leco KJ, Arcellana-Panlilio MY, Zhang X, Edwards DR and Schultz GA . (1995). Development, 121, 1005–1014.

  • Inderdeo DS, Edwards DR, Han VKM and Khokha R . (1996). Biol. Reprod., 55, 498–508.

  • Jaques G, Rotsch M, Wegmann C, Worsch U, Maasberg M and Havemann K . (1988). Exp. Cell Res., 176, 336–343.

  • Kaiser U, Schardt C, Brandscheidt D, Wollmer E and Havemann K . (1993). J. Cancer Res. Clin. Oncol., 119, 665–668.

  • Kaufmann O and Dietel M . (2000). Histopathology 36, 8–16.

  • Lawlor MA and Alessi DR . (2001). J. Cell Sci., 114, 2903–2910.

  • Lee CT, Wu S, Gabrilovich D, Chen H, Nadaf-Rahrov S, Ciernik IF and Carbone DP . (1996). Cancer Res., 56, 3038–3041.

  • London SJ, Yuan JM, Travlos GS, Gao YT, Wilson RE, Ross RK and Yu MC . (2002). J. Natl. Cancer Inst., 94, 749–754.

  • Lukanova A, Toniolo P, Akhmedkhanov A, Biessy C, Haley NJ, Shore RE, Riboli E, Rinaldi S and Kaaks R . (2001). Int. J. Cancer., 92, 888–892.

  • Mendelson CR . (2000). Annu. Rev. Physiol., 62, 875–915.

  • Minuto F, Del Monte P, Barreca A, Alama A, Cariola G and Giordano G . (1988). Cancer Res., 48, 3716–3719.

  • Minuto F, Del Monte P, Barreca A, Fortini P, Cariola G, Catrambone G and Giordano G . (1986). Cancer Res., 46, 985–988.

  • Moorehead RA, Fata JE, Johnson MB and Khokha R . (2001). Cell Death Differ., 8, 16–29.

  • Nakanishi Y, Mulshine JL, Kasprzyk PG, Natale RB, Maneckjee R, Avis I, Treston AM, Gazdar AF, Minna JD and Cuttitta F . (1988). J. Clin. Invest., 82, 354–359.

  • Nguyen LQ, Kopp P, Martinson F, Stanfield K, Roth SI and Jameson JL . (2000). Mol. Endocrinol., 14, 1448–1461.

  • Ordonez NG . (2000). Am. J. Surg. Pathol., 24, 1217–1223.

  • Rehm S, Ward JM and Sass B . (1994). Tumours of the Lungs: Pathology of Tumours in Laboratory Animals, Vol. II – Tumours of the Mouse. Turusov VS, Mohr U (eds). International Agency for Research on Cancer: Lyon, France, pp. 325–355.

    Google Scholar 

  • Rotsch M, Maasberg M, Erbil C, Jaques G, Worsch U and Havemann K . (1992). J. Cancer Res. Clin. Oncol., 118, 502–508.

  • Rudolph D, Tafuri A, Gass P, Hammerling GJ, Arnold B and Schutz G . (1998). Proc. Natl. Acad. Sci. USA, 95, 4481–4486.

  • Samet JM, Graves LM, Quay J, Dailey LA, Devlin RB, Ghio AJ, Wu W, Bromberg PA and Reed W . (1998). Am. J. Physiol., 275, L551–L558.

  • Schardt C, Rotsch M, Erbil C, Goke R, Richter G and Havemann K . (1993). Exp. Cell Res., 204, 22–29.

  • Scheid MP and Woodgett JR . (2001). Nat. Rev. Mol. Cell Biol., 2, 760–768.

  • Schneider MR, Lahm H, Wu M, Hoeflich A and Wolf E . (2000). FASEB J., 14, 629–640.

  • Shenkar R and Abraham E . (1999). J. Immunol., 163, 954–962.

  • Shenkar R, Yum HK, Arcaroli J, Kupfner J and Abraham E . (2001). Am. J. Physiol. Lung Cell Mol. Physiol., 281, L418–L426.

  • Takanami I, Imamuma T, Hashizume T, Kikuchi K, Yamamoto Y, Yamamoto T and Kodaira S . (1996). J. Surg. Oncol., 61, 205–208.

  • Toretsky JA and Helman LJ . (1996). J. Endocrinol., 149, 367–372.

  • Wetterau LA, Moore MG, Lee KW, Shim ML and Cohen P . (1999). Mol. Genet. Metab., 68, 161–181.

  • Yan C and Whitsett JA . (1997). J. Biol. Chem., 272, 17327–17332.

  • Yu H, Spitz MR, Mistry J, Gu J, Hong WK and Wu X . (1999). J. Natl. Cancer Inst., 91, 151–156.

  • Zia F, Jacobs S, Kull Jr F, Cuttitta F, Mulshine JL and Moody TW . (1996). J. Cell Biochem. Suppl., 24, 269–275.

Download references

Author information

Author notes

  1. Roger A Moorehead & R Mitchell Baldwin

    Present address: Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada, N1G 2W1

  2. Roger A Moorehead and Otto H Sanchez: These authors contributed equally to this manuscript

Authors and Affiliations

  1. Ontario Cancer Institute, University of Toronto, Toronto, M5G 2M9, Ontario, Canada

    Roger A Moorehead, Otto H Sanchez, R Mitchell Baldwin & Rama Khokha

Authors
  1. Roger A Moorehead
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Otto H Sanchez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R Mitchell Baldwin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rama Khokha
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rama Khokha.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Moorehead, R., Sanchez, O., Baldwin, R. et al. Transgenic overexpression of IGF-II induces spontaneous lung tumors: a model for human lung adenocarcinoma. Oncogene 22, 853–857 (2003). https://doi.org/10.1038/sj.onc.1206188

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1206188

Keywords

This article is cited by

Search

Advanced search

Quick links