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:

Immortalization and transformation of primary human airway epithelial cells by gene transfer

Oncogene volume 21, pages 4577–4586 (2002)Cite this article

Abstract

One critical step in the development of a cancerous cell is its acquisition of an unlimited replicative lifespan, the process termed immortalization. Experimental model systems designed to study cellular transformation ex vivo have relied to date on the in vitro selection of a subpopulation of cells that have become immortalized through treatment with chemical or physical mutagens and the selection of rare clonal variants. In this study, we describe the direct immortalization of primary human airway epithelial cells through the successive introduction of the Simian Virus 40 Early Region and the telomerase catalytic subunit hTERT. Cells immortalized in this way are now responsive to malignant transformation by an introduced H-ras or K-ras oncogene. These immortalized human airway epithelial cells, which have been created through the stepwise introduction of genetic alterations, provide a novel experimental model system with which to study further the biology of the airway epithelial cell and to dissect the molecular basis of lung cancer pathogenesis.

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
Figure 4

Similar content being viewed by others

References

  • Barcellos-Hoff MH, Ravani SA . 2000 Cancer Res. 60: 1254–1260

  • Bernacki SH, Nelson AL, Abdullah L, Sheehan JK, Harris A, William Davis C, Randell SH . 1999 Am. J. Respir. Cell. Mol. Biol. 20: 595–604

  • Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, Harley CB, Shay JW, Lichtsteiner S, Wright WE . 1998 Science 279: 349–352

  • Counter CM, Hahn WC, Wei W, Caddle SD, Beijersbergen RL, Lansdorp PM, Sedivy JM, Weinberg RA . 1998 Proc. Natl. Acad. Sci. USA 95: 14723–14728

  • Dickson MA, Hahn WC, Ino Y, Ronfard V, Wu JY, Weinberg RA, Louis DN, Li FP, Rheinwald JG . 2000 Mol. Cell. Biol. 20: 1436–1447

  • Elenbaas B, Spirio L, Koerner F, Fleming MD, Zimonjic DB, Donaher JL, Popescu NC, Hahn WC, Weinberg RA . 2001 Genes Dev. 15: 50–65

  • Elenbaas B, Weinberg RA . 2001 Exp. Cell Res. 264: 169–184

  • Finney RE, Bishop JM . 1993 Science 260: 1524–1527

  • Hahn WC, Counter CM, Lundberg AS, Beijersbergen RL, Brooks MW, Weinberg RA . 1999 Nature 400: 464–468

  • Hahn WC, Dessain SK, Brooks MW, King JE, Elenbaas B, Sabatini DM, DeCaprio JA, Weinberg RA . 2002 Mol. Cell. Biol. 22: 2111–2123

  • Halvorsen TL, Leibowitz G, Levine F . 1999 Mol. Cell. Biol. 19: 1864–1870

  • Harper JR, Roop DR, Yuspa SH . 1986 Mol. Cell. Biol. 6: 3144–3149

  • Hayflick L, Moorhead PS . 1961 Exp. Cell Res. 25: 585–621

  • Jat PS, Cepko CL, Mulligan RC, Sharp PA . 1986 Mol. Cell. Biol. 6: 1204–1217

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

  • Kiyono T, Foster SA, Koop JI, McDougall JK, Galloway DA, Klingelhutz AJ . 1998 Nature 396: 84–88

  • Kreda SM, Gynn MC, Fenstermacher DA, Boucher RC, Gabriel SE . 2001 Am. J. Respir. Cell. Mol. Biol. 24: 224–234

  • Lechner JF, Haugen A, Autrup H, McClendon IA, Trump BF, Harris CC . 1981 Cancer Res. 41: 2294–2304

  • Lechner JF, Haugen A, McClendon IA, Pettis EW . 1982 In Vitro 18: 633–642

  • Lustig AJ . 1999 Proc. Natl. Acad. Sci. USA 96: 3339–3341

  • McCoy MS, Bargmann CI, Weinberg RA . 1984 Mol. Cell. Biol. 4: 1577–1582

  • Mercer RR, Russell ML, Roggli VL, Crapo JD . 1994 Am. J. Respir. Cell. Mol. Biol. 10: 613–624

  • Morgenstern JP, Land H . 1990 Nucleic Acids Res. 18: 1068–

  • Newbold RF, Overell RW . 1983 Nature 304: 648–651

  • Olumi AF, Grossfeld GD, Hayward SW, Carroll PR, Tlsty TD, Cunha GR . 1999 Cancer Res. 59: 5002–5011

  • Ramirez RD, Morales CP, Herbert BS, Rohde JM, Passons C, Shay JW, Wright WE . 2001 Genes Dev. 15: 398–403

  • Reddel RR, Ke Y, Gerwin BI, McMenamin MG, Lechner JF, Su RT, Brash DE, Park JB, Rhim JS, Harris CC . 1988a Cancer Res. 48: 1904–1909

  • Reddel RR, Ke Y, Kaighn ME, Malan-Shibley L, Lechner JF, Rhim JS, Harris CC . 1988b Oncogene Res. 3: 401–408

  • Rhim JS, Jay G, Arnstein P, Price FM, Sanford KK, Aaronson SA . 1985 Science 227: 1250–1252

  • Rich JN, Guo C, McLendon RE, Bigner DD, Wang XF, Counter CM . 2001 Cancer Res. 61: 3556–3560

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

  • Rodriguez-Puebla ML, LaCava M, Bolontrade MF, Russell J, Conti CJ . 1999 Mol. Carcinog. 26: 150–156

  • Sager R . 1991 Environ. Health Perspect. 93: 59–62

  • Sedivy JM . 1998 Proc. Natl. Acad. Sci. USA 95: 9078–9081

  • Sherr CJ, DePinho RA . 2000 Cell 102: 407–410

  • Stewart N, Bacchetti S . 1991 Virology 180: 49–57

  • Stoner GD, Katoh Y, Foidart JM, Myers GA, Harris CC . 1980 Methods Cell Biol. 21A: 15–35

  • Thomas M, Yang L, Hornsby PJ . 2000 Nat. Biotechnol. 18: 39–42

  • Vaziri H, Benchimol S . 1998 Curr. Biol. 8: 279–282

  • Wei W, Sedivy JM . 1999 Exp. Cell Res. 253: 519–522

  • Wright WE, Shay JW . 1992 Exp. Gerontol. 27: 383–389

  • Yoakum GH, Lechner JF, Gabrielson EW, Korba BE, Malan-Shibley L, Willey JC, Valerio MG, Shamsuddin AM, Trump BF, Harris CC . 1985 Science 227: 1174–1179

  • Yu J, Boyapati A, Rundell K . 2001 Virology 290: 192–198

  • Zhu J, Wang H, Bishop JM, Blackburn EH . 1999 Proc. Natl. Acad. Sci. USA 96: 3723–3728

Download references

Acknowledgements

We thank the members of the Weinberg, Randell, and Hahn laboratories for helpful comments. This work was supported in part by grants from the US National Cancer Institute (AS Lundberg, WC Hahn, and RA Weinberg), NHLBI (SH Randell), the Doris Duke Charitable Foundation (WC Hahn), the American Cancer Institute (SA Stewart) and the G Harold and Leila Y Mathers Charitable Foundation (RA Weinberg). AS Lundberg, WC Hahn, and SA Stewart were Margaret and Herman Sokol Fellows. RA Weinberg is an American Cancer Society Research Professor and the Daniel K Ludwig Cancer Research Professor.

Author information

Author notes

  1. Ante S Lundberg

    Present address: Genzyme Corporation, Cambridge, 02139, Massachusetts, MA, USA

  2. Brian Elenbaas

    Present address: Biogen, Inc., Cambridge, 02142, Massachusetts, MA, USA

Authors and Affiliations

  1. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, 02142, Massachusetts, MA, USA

    Ante S Lundberg, Sheila A Stewart, Brian Elenbaas, Kimberly A Hartwell, Mary W Brooks, Robert A Weinberg & William C Hahn

  2. Cystic Fibrosis/Pulmonary Research and Treatment Center, The University of North Carolina at Chapel Hill, Chapel Hill, 27599, North Carolina, NC, USA

    Scott H Randell, John C Olsen & Scott W Miller

  3. Department of Adult Oncology, and Department of Medicine, Dana-Farber Cancer Institute, Brigham and Women's Hospital, 44 Binney St., Boston, 02115, Massachusetts, MA, USA

    Ante S Lundberg & William C Hahn

  4. Department of Medicine, Harvard Medical School, Boston, 02115, Massachusetts, MA, USA

    Ante S Lundberg & William C Hahn

  5. Department of Pathology, Children's Hospital and Harvard Medical School, Boston, 02115, Massachusetts, MA, USA

    Mark D Fleming

  6. Department of Biology, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, MA, USA

    Kimberly A Hartwell & Robert A Weinberg

Authors
  1. Ante S Lundberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Scott H Randell
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sheila A Stewart
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Brian Elenbaas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kimberly A Hartwell
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mary W Brooks
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mark D Fleming
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. John C Olsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Scott W Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Robert A Weinberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. William C Hahn
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Scott H Randell or William C Hahn.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lundberg, A., Randell, S., Stewart, S. et al. Immortalization and transformation of primary human airway epithelial cells by gene transfer. Oncogene 21, 4577–4586 (2002). https://doi.org/10.1038/sj.onc.1205550

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205550

Keywords

This article is cited by

Search

Advanced search

Quick links