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.

  • Oncogenomics
  • Published:

Modeling of lung cancer by an orthotopically growing H460SM variant cell line reveals novel candidate genes for systemic metastasis

Oncogene volume 23, pages 6316–6324 (2004)Cite this article

Abstract

Endobronchial implantation of NCI-H460 cells into the nude rat generates a primary lung tumor with mediastinal lymph node spread, but rarely systemic metastases. We isolated tumor cells from mediastinal nodes, orthotopically reimplanted the cells into nude rats and repeated this four times to derive a cell line, designated H460SM, that spontaneously metastasizes to bone, kidney, brain, soft tissue and contralateral lung. H460SM cells demonstrated higher invasive activity in vitro than parental NCI-H460 cells. Spectral karyotyping revealed a new inversion within 17q and loss of an extra normal copy of chromosome 14 present in parental NCI-H460 cells. Expression profiling of orthotopic primary tumors revealed differential expression of 360 genes. Of these, 173 were represented in the probe set of a 19.2K OCI cDNA microarray previously used to profile the gene expression of surgically resected lung cancer specimens. We have computationally validated clinical importance of these genes by using in silico analysis of 18 cases of pulmonary adenocarcinoma, which were split into two patient groups with markedly different clinical outcome. The model identifies additional novel candidate genes for the progression of lung cancer to systemic metastases and poor prognosis.

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
Figure 5

Similar content being viewed by others

References

  • Beer DG, Kardia SL, Huang CC, Giordano TJ, Levin AM, Misek DE, Lin L, Chen G, Gharib TG, Thomas DG, Lizyness ML, Kuick R, Hayasaka S, Taylor JM, Iannettoni MD, Orringer MB and Hanash S . (2002). Nat. Med., 8, 816–824.

  • Bhattacharjee A, Richards WG, Staunton J, Li C, Monti S, Vasa P, Ladd C, Beheshti J, Bueno R, Gillette M, Loda M, Weber G, Mark EJ, Lander ES, Wong W, Johnson BE, Golub TR, Sugarbaker DJ and Meyerson M . (2001). Proc. Natl. Acad. Sci. USA, 98, 13790–13795.

  • Carney DN, Gazdar AF, Bepler G, Guccion JG, Marangos PJ, Moody TW, Zweig MH and Minna JD . (1985). Cancer Res., 45, 2913–2923.

  • Fontao L, Favre B, Riou S, Geerts D, Jaunin F, Saurat JH, Green KJ, Sonnenberg A and Borradori L . (2003). Mol. Cell. Biol., 14, 1978–1992.

  • Garber ME, Troyanskaya OG, Schluens K, Petersen S, Thaesler Z, Pacyna-Gengelbach M, van de Rijn M, Rosen GD, Perou CM, Whyte RI, Altman RB, Brown PO, Botstein D and Petersen I . (2001). Proc. Natl. Acad. Sci. USA, 98, 13784–13789.

  • Gayther SA, Batley SJ, Linger L, Bannister A, Thorpe K, Chin S-F, Daigo Y, Russell P, Wilson A, Sowter HM, Delhanty JDA, Ponder BAJ, Kouzarides T and Caldas C . (2000). Nat. Genet., 24, 300–303.

  • Gemma A, Takenaka K, Hosoya Y, Matuda K, Seike M, Kurimoto F, Ono Y, Uematsu K, Takeda Y, Hibino S, Yoshimura A, Shibuya M and Kudoh S . (2001). Eur. J. Cancer, 37, 1554–1561.

  • Gorogh T, Rudert H, Lippert BM, Gottschlich S, Maune S, Heidorn K, Maass J, Hoffmann M, Meyer JE, Rathcke IO, Folz BJ, Hortobagyi T and Werner JA . (1999). Int. J. Cancer, 83, 750–754.

  • Howard RB, Mullen JB, Pagura ME and Johnston MR . (1999). Clin. Exp. Metast., 17, 157–162.

  • Kang Y, Siegel PM, Shu W, Drobnjak M, Kakonen SM, Cordon-Cardo C, Guise TA and Massague J . (2003). Cancer Cell, 3, 537–549.

  • Kashima T, Nakamura K, Kawaguchi J, Takanashi M, Ishida T, Aburatani H, Kudo A, Fukayama M and Grigoriadis AE . (2003). Int. J. Cancer, 104, 147–154.

  • Kozaki K, Koshikawa K, Tatematsu Y, Miyaishi O, Saito H, Hida T, Osada H and Takahashi T . (2001). Oncogene, 20, 4228–4234.

  • Kozaki K, Miyaishi O, Tsukamoto T, Tatematsu Y, Hida T and Takahashi T . (2000). Cancer Res., 60, 2535–2540.

  • Liu J and Johnston MR . (2002). Surg. Oncol., 11, 217–228.

  • Liu M, Parker RM, Darby K, Eyre HJ, Copeland NG, Crawford J, Gilbert DJ, Sutherland GR, Jenkins NA and Herzog H . (1999). Genomics, 55, 296–305.

  • Marinissen MJ and Gutkind JS . (2001). Trends Pharmacol. Sci., 22, 368–376.

  • Mercer KE and Pritchard CA . (2003). Biochim. Biophys. Acta, 1653, 23–40.

  • Miura K, Bowman ED, Simon R, Peng AC, Robles AI, Jones RT, Katagiri T, He P, Mizukami H, Charboneau L, Kikuchi T, Liotta LA, Nakamura Y and Harris CC . (2002). Cancer Res., 62, 3244–3250.

  • Nakamura H, Saji H, Ogata A, Hosaka M, Hagiwara M, Saijo T, Kawasaki N and Kato H . (2003). Cancer, 97, 2798–2805.

  • Rhee J, Mahfooz NS, Arregui C, Lilien J, Balsamo J and VanBerkum MF . (2002). Nat. Cell Biol., 4, 798–805.

  • Saiga T, Ohbayashi T, Tabuchi K and Midorikawa O . (1987). In vitro Cell Dev. Biol., 23, 850–854.

  • Sattler M and Salgia R . (2003). Semin. Oncol., 30, 57–71.

  • Shaw LM, Rabinovitz I, Wang HH, Toker A and Mercurio AM . (1997). Cell, 91, 949–960.

  • Shindo-Okada N, Takeuchi K and Nagamachi Y . (2001). Jpn. J. Cancer Res., 92, 174–183.

  • Shindo-Okada N, Takeuchi K, Han BS and Nagamachi Y . (2002). Jpn. J. Cancer Res., 93, 50–60.

  • Sultan M, Wigle DA, Cumbaa CA, Maziarz M, Glasgow J, Tsao MS and Jurisica I . (2002). Bioinformatics, 18, S111–S119.

  • Tsao MS, Liu N, Chen JR, Pappas J, Ho J, To C, Viallet J, Park M and Zhu H . (1998). Lung Cancer, 20, 1–16.

  • Van 't Veer LJ, Dai H, van de Vijer MJ, He YD, Hart AA, Mao M, Peterse HL, van der Kooy K, Marton MJ, Witteveen AT, Schreiber GJ, Kerkhoven RM, Roberts C, Linsley PS, Bernards R and Friend SH . (2002). Nature, 415, 530–536.

  • Wang KK, Liu N, Radulovich N, Wigle DA, Johnston MR, Shepherd FA, Minden MD and Tsao MS . (2002). Oncogene, 21, 7598–7604.

  • Wigle DA, Jurisica I, Radulovich N, Pintilie M, Rossant J, Liu N, Lu C, Woodgett J, Seiden I, Johnston M, Keshavjee S, Darling G, Winton T, Breitkreutz BJ, Jorgenson P, Tyers M, Shepherd FA and Tsao MS . (2002). Cancer Res., 62, 3005–3008.

  • Wigle DA, Tsao M and Jurisica I . (2004). Genome Biol., 5, 309.

Download references

Acknowledgements

This work is supported by grants from the Canadian Cancer Society (NCIC Grant #012150), National Science and Engineering Research Council (RGPIN 203833-02) and the Institute for Robotics and Intelligence Systems. Dr Blackhall was supported by an unrestricted educational fellowship from Aventis Pharma Inc. (Laval, Quebec, Canada). Dr Tsao is the M Qasim Choksi Chair in Lung Cancer Translational Research. We are grateful to Dr Frances Shepherd for her continuing support in this project. We also thank Dr Squire and the Oncologic Molecular Micro-imaging Clinical Research Program at OCI/PMH for assistance in the SKY analysis on the cell lines. We thank Dr David A Adler (University of Washington) for permitting the use of karyotype ideogram for constructing Figure 3C.

Author information

Author notes

  1. Fiona Blackhall and Isolde Seiden-Long: These authors contributed equally this work

Authors and Affiliations

  1. Division of Thoracic Surgery, University Health Network, Princess Margaret Hospital and Ontario Cancer Institute, M5G 2M9, Ontario, Canada

    Jiang Liu, Dennis Wigle & Michael R Johnston

  2. Division of Cellular Molecular Biology, University Health Network, Princess Margaret Hospital and Ontario Cancer Institute, M5G 2M9, Ontario, Canada

    Fiona Blackhall, Isolde Seiden-Long, Ni Liu, Nikolina Radulovich & Ming-Sound Tsao

  3. Division of Cancer Informatics, University Health Network, Princess Margaret Hospital and Ontario Cancer Institute, M5G 2M9, Ontario, Canada

    Igor Jurisica & Muhajid Sultan

  4. Hospital for Sick Children Research Institute; University of Toronto,

    Roya Navab & Jim Hu

  5. University of Toronto, Toronto, M5G 2M9, Ontario, Canada

    Roya Navab & Jim Hu

  6. Department of Pathology, University Health Network, Princess Margaret Hospital and Ontario Cancer Institute, M5G 2M9, Ontario, Canada

    Ming-Sound Tsao

Authors
  1. Jiang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fiona Blackhall
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Isolde Seiden-Long
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Igor Jurisica
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Roya Navab
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ni Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nikolina Radulovich
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dennis Wigle
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Muhajid Sultan
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jim Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ming-Sound Tsao
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Michael R Johnston
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael R Johnston.

Additional information

Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, J., Blackhall, F., Seiden-Long, I. et al. Modeling of lung cancer by an orthotopically growing H460SM variant cell line reveals novel candidate genes for systemic metastasis. Oncogene 23, 6316–6324 (2004). https://doi.org/10.1038/sj.onc.1207795

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207795

Keywords

This article is cited by

Search

Advanced search

Quick links