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 Article
  • Published:

Epidermal growth factor receptor regulates MET levels and invasiveness through hypoxia-inducible factor-1α in non-small cell lung cancer cells

Oncogene volume 29, pages 2616–2627 (2010)Cite this article

Subjects

Abstract

Recent studies have established that amplification of the MET proto-oncogene can cause resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) cell lines with EGFR-activating mutations. The role of non-amplified MET in EGFR-dependent signaling before TKI resistance, however, is not well understood. Using NSCLC cell lines and transgenic models, we demonstrate here that EGFR activation by either mutation or ligand binding increases MET gene expression and protein levels. Our analysis of 202 NSCLC patient specimens was consistent with these observations: levels of MET were significantly higher in NSCLC with EGFR mutations than in NSCLC with wild-type EGFR. EGFR regulation of MET levels in cell lines occurred through the hypoxia-inducible factor (HIF)-1α pathway in a hypoxia-independent manner. This regulation was lost, however, after MET gene amplification or overexpression of a constitutively active form of HIF-1α. EGFR- and hypoxia-induced invasiveness of NSCLC cells, but not cell survival, were found to be MET dependent. These findings establish that, absent MET amplification, EGFR signaling can regulate MET levels through HIF-1α and that MET is a key downstream mediator of EGFR-induced invasiveness in EGFR-dependent NSCLC cells.

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

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  • Beadsmoore CJ, Screaton NJ . (2003). Classification, staging and prognosis of lung cancer. Eur J Radiol 45: 8–17.

    Article  CAS  PubMed  Google Scholar 

  • Bergstrom JD, Westermark B, Heldin NE . (2000). Epidermal growth factor receptor signaling activates met in human anaplastic thyroid carcinoma cells. Exp Cell Res 259: 293–299.

    Article  CAS  PubMed  Google Scholar 

  • Bredin CG, Liu Z, Klominek J . (2003). Growth factor-enhanced expression and activity of matrix metalloproteases in human non-small cell lung cancer cell lines. Anticancer Res 23: 4877–4884.

    CAS  PubMed  Google Scholar 

  • Ciardiello F, Tortora G . (2008). EGFR antagonists in cancer treatment. N Engl J Med 358: 1160–1174.

    Article  CAS  PubMed  Google Scholar 

  • Cooper CS, Tempest PR, Beckman MP, Heldin CH, Brookes P . (1986). Amplification and overexpression of the met gene in spontaneously transformed NIH3T3 mouse fibroblasts. EMBO J 5: 2623–2628.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cuvier C, Jang A, Hill RP . (1997). Exposure to hypoxia, glucose starvation and acidosis: effect on invasive capacity of murine tumor cells and correlation with cathepsin (L + B) secretion. Clin Exp Metastasis 15: 19–25.

    Article  CAS  PubMed  Google Scholar 

  • Damstrup L, Rude Voldborg B, Spang-Thomsen M, Brunner N, Skovgaard Poulsen H . (1998). In vitro invasion of small-cell lung cancer cell lines correlates with expression of epidermal growth factor receptor. Br J Cancer 78: 631–640.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO et al. (2007). MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316: 1039–1043.

    Article  CAS  PubMed  Google Scholar 

  • Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD et al. (1996). Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 16: 4604–4613.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY et al. (2003). Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected]. J Clin Oncol 21: 2237–2246.

    Article  CAS  PubMed  Google Scholar 

  • Guo A, Villen J, Kornhauser J, Lee KA, Stokes MP, Rikova K et al. (2008). Signaling networks assembled by oncogenic EGFR and c-Met. Proc Natl Acad Sci USA 105: 692–697.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hamada J, Nagayasu H, Takayama M, Kawano T, Hosokawa M, Takeichi N . (1995). Enhanced effect of epidermal growth factor on pulmonary metastasis and in vitro invasion of rat mammary carcinoma cells. Cancer Lett 89: 161–167.

    Article  CAS  PubMed  Google Scholar 

  • Hirami Y, Aoe M, Tsukuda K, Hara F, Otani Y, Koshimune R et al. (2004). Relation of epidermal growth factor receptor, phosphorylated-Akt, and hypoxia-inducible factor-1alpha in non-small cell lung cancers. Cancer Lett 214: 157–164.

    Article  CAS  PubMed  Google Scholar 

  • Hu CJ, Wang LY, Chodosh LA, Keith B, Simon MC . (2003). Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Mol Cell Biol 23: 9361–9374.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang PH, Mukasa A, Bonavia R, Flynn RA, Brewer ZE, Cavenee WK et al. (2007). Quantitative analysis of EGFRvIII cellular signaling networks reveals a combinatorial therapeutic strategy for glioblastoma. Proc Natl Acad Sci USA 104: 12867–12872.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ichimura E, Maeshima A, Nakajima T, Nakamura T . (1996). Expression of c-met/HGF receptor in human non-small cell lung carcinomas in vitro and in vivo and its prognostic significance. Jpn J Cancer Res 87: 1063–1069.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ide T, Kitajima Y, Miyoshi A, Ohtsuka T, Mitsuno M, Ohtaka K et al. (2006). Tumor-stromal cell interaction under hypoxia increases the invasiveness of pancreatic cancer cells through the hepatocyte growth factor/c-Met pathway. Int J Cancer 119: 2750–2759.

    Article  CAS  PubMed  Google Scholar 

  • Janne PA, Engelman JA, Johnson BE . (2005). Epidermal growth factor receptor mutations in non-small-cell lung cancer: implications for treatment and tumor biology. J Clin Oncol 23: 3227–3234.

    Article  CAS  PubMed  Google Scholar 

  • Ji H, Li D, Chen L, Shimamura T, Kobayashi S, McNamara K et al. (2006). The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies. Cancer Cell 9: 485–495.

    Article  CAS  PubMed  Google Scholar 

  • Jo M, Stolz DB, Esplen JE, Dorko K, Michalopoulos GK, Strom SC . (2000). Cross-talk between epidermal growth factor receptor and c-Met signal pathways in transformed cells. J Biol Chem 275: 8806–8811.

    Article  CAS  PubMed  Google Scholar 

  • Johnson L, Mercer K, Greenbaum D, Bronson RT, Crowley D, Tuveson DA et al. (2001). Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 410: 1111–1116.

    Article  CAS  PubMed  Google Scholar 

  • Kim WY, Safran M, Buckley MR, Ebert BL, Glickman J, Bosenberg M et al. (2006). Failure to prolyl hydroxylate hypoxia-inducible factor alpha phenocopies VHL inactivation in vivo. EMBO J 25: 4650–4662.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kris MG, Natale RB, Herbst RS, Lynch Jr TJ, Prager D, Belani CP et al. (2003). Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 290: 2149–2158.

    Article  CAS  PubMed  Google Scholar 

  • Li C, Hung Wong W . (2001). Model-based analysis of oligonucleotide arrays: model validation, design issues and standard error application. Genome Biol 2: RESEARCH0032.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lin M, Wei LJ, Sellers WR, Lieberfarb M, Wong WH, Li C . (2004). dChipSNP: significance curve and clustering of SNP-array-based loss-of-heterozygosity data. Bioinformatics 20: 1233–1240.

    Article  CAS  PubMed  Google Scholar 

  • Liu C, Tsao MS . (1993). In vitro and in vivo expressions of transforming growth factor-alpha and tyrosine kinase receptors in human non-small-cell lung carcinomas. Am J Pathol 142: 1155–1162.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lutterbach B, Zeng Q, Davis LJ, Hatch H, Hang G, Kohl NE et al. (2007). Lung cancer cell lines harboring MET gene amplification are dependent on Met for growth and survival. Cancer Res 67: 2081–2088.

    Article  CAS  PubMed  Google Scholar 

  • Luwor RB, Lu Y, Li X, Mendelsohn J, Fan Z . (2005). The antiepidermal growth factor receptor monoclonal antibody cetuximab/C225 reduces hypoxia-inducible factor-1 alpha, leading to transcriptional inhibition of vascular endothelial growth factor expression. Oncogene 24: 4433–4441.

    Article  CAS  PubMed  Google Scholar 

  • Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW et al. (2004). Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350: 2129–2139.

    Article  CAS  PubMed  Google Scholar 

  • Masson N, Willam C, Maxwell PH, Pugh CW, Ratcliffe PJ . (2001). Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation. EMBO J 20: 5197–5206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nakamura Y, Niki T, Goto A, Morikawa T, Miyazawa K, Nakajima J et al. (2007). c-Met activation in lung adenocarcinoma tissues: An immunohistochemical analysis. Cancer Sci 98: 1006–1013.

    Article  CAS  PubMed  Google Scholar 

  • NCBI-GEO (2007). http://www.ncbi.nlm.nih.gov/geo/.

  • Olivero M, Rizzo M, Madeddu R, Casadio C, Pennacchietti S, Nicotra MR et al. (1996). Overexpression and activation of hepatocyte growth factor/scatter factor in human non-small-cell lung carcinomas. Br J Cancer 74: 1862–1868.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S et al. (2004). EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304: 1497–1500.

    Article  CAS  PubMed  Google Scholar 

  • Pai R, Nakamura T, Moon WS, Tarnawski AS . (2003). Prostaglandins promote colon cancer cell invasion; signaling by cross-talk between two distinct growth factor receptors. FASEB J 17: 1640–1647.

    Article  CAS  PubMed  Google Scholar 

  • Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I et al. (2004). EGF receptor gene mutations are common in lung cancers from ‘never smokers’ and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA 101: 13306–13311.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pao W, Miller VA . (2005). Epidermal growth factor receptor mutations, small-molecule kinase inhibitors, and non-small-cell lung cancer: current knowledge and future directions. J Clin Oncol 23: 2556–2568.

    Article  CAS  PubMed  Google Scholar 

  • Park M, Dean M, Kaul K, Braun MJ, Gonda MA, Vande Woude G . (1987). Sequence of MET protooncogene cDNA has features characteristic of the tyrosine kinase family of growth-factor receptors. Proc Natl Acad Sci USA 84: 6379–6383.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peng XH, Karna P, Cao Z, Jiang BH, Zhou M, Yang L . (2006). Cross-talk between epidermal growth factor receptor and hypoxia-inducible factor-1alpha signal pathways increases resistance to apoptosis by up-regulating survivin gene expression. J Biol Chem 281: 25903–25914.

    Article  CAS  PubMed  Google Scholar 

  • Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM . (2003). Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 3: 347–361.

    Article  PubMed  Google Scholar 

  • Peruzzi B, Bottaro DP . (2006). Targeting the c-Met signaling pathway in cancer. Clin Cancer Res 12: 3657–3660.

    Article  CAS  PubMed  Google Scholar 

  • Phillips RJ, Mestas J, Gharaee-Kermani M, Burdick MD, Sica A, Belperio JA et al (2005). Epidermal growth factor and hypoxia-induced expression of CXC chemokine receptor 4 on non-small cell lung cancer cells is regulated by the phosphatidylinositol 3-kinase/PTEN/AKT/mammalian target of rapamycin signaling pathway and activation of hypoxia inducible factor-1alpha. J Biol Chem 280: 22473–22481.

    Article  CAS  PubMed  Google Scholar 

  • Pore N, Jiang Z, Gupta A, Cerniglia G, Kao GD, Maity A . (2006). EGFR tyrosine kinase inhibitors decrease VEGF expression by both hypoxia-inducible factor (HIF)-1-independent and HIF-1-dependent mechanisms. Cancer Res 66: 3197–3204.

    Article  CAS  PubMed  Google Scholar 

  • Qiao H, Hung W, Tremblay E, Wojcik J, Gui J, Ho J et al. (2002). Constitutive activation of met kinase in non-small-cell lung carcinomas correlates with anchorage-independent cell survival. J Cell Biochem 86: 665–677.

    Article  CAS  PubMed  Google Scholar 

  • Rosario M, Birchmeier W . (2003). How to make tubes: signaling by the Met receptor tyrosine kinase. Trends Cell Biol 13: 328–335.

    Article  CAS  PubMed  Google Scholar 

  • Scheving LA, Stevenson MC, Taylormoore JM, Traxler P, Russell WE . (2002). Integral role of the EGF receptor in HGF-mediated hepatocyte proliferation. Biochem Biophys Res Commun 290: 197–203.

    Article  CAS  PubMed  Google Scholar 

  • Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S et al. (2005). Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353: 123–132.

    Article  CAS  PubMed  Google Scholar 

  • Shimamura T, Lowell AM, Engelman JA, Shapiro GI . (2005). Epidermal growth factor receptors harboring kinase domain mutations associate with the heat shock protein 90 chaperone and are destabilized following exposure to geldanamycins. Cancer Res 65: 6401–6408.

    Article  CAS  PubMed  Google Scholar 

  • Shimazaki K, Yoshida K, Hirose Y, Ishimori H, Katayama M, Kawase T . (2003). Cytokines regulate c-Met expression in cultured astrocytes. Brain Res 962: 105–110.

    Article  CAS  PubMed  Google Scholar 

  • Siegfried JM, Weissfeld LA, Luketich JD, Weyant RJ, Gubish CT, Landreneau RJ . (1998). The clinical significance of hepatocyte growth factor for non-small cell lung cancer. Ann Thorac Surg 66: 1915–1918.

    Article  CAS  PubMed  Google Scholar 

  • Smolen GA, Sordella R, Muir B, Mohapatra G, Barmettler A, Archibald H et al. (2006). Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752. Proc Natl Acad Sci USA 103: 2316–2321.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stabile LP, Lyker JS, Huang L, Siegfried JM . (2004). Inhibition of human non-small cell lung tumors by a c-Met antisense/U6 expression plasmid strategy. Gene Ther 11: 325–335.

    Article  CAS  PubMed  Google Scholar 

  • Swinson DE, Jones JL, Cox G, Richardson D, Harris AL, O′Byrne KJ . (2004). Hypoxia-inducible factor-1 alpha in non small cell lung cancer: relation to growth factor, protease and apoptosis pathways. Int J Cancer 111: 43–50.

    Article  CAS  PubMed  Google Scholar 

  • Swinson DE, O'Byrne KJ . (2006). Interactions between hypoxia and epidermal growth factor receptor in non-small-cell lung cancer. Clin Lung Cancer 7: 250–256.

    Article  CAS  PubMed  Google Scholar 

  • Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J et al. (2005). Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 366: 1527–1537.

    Article  CAS  PubMed  Google Scholar 

  • Weinberger PM, Yu Z, Kowalski D, Joe J, Manger P, Psyrri A et al. (2005). Differential expression of epidermal growth factor receptor, c-Met, and HER2/neu in chordoma compared with 17 other malignancies. Arch Otolaryngol Head Neck Surg 131: 707–711.

    Article  PubMed  Google Scholar 

  • Yang Y, Wislez M, Fujimoto N, Prudkin L, Izzo JG, Uno F et al. (2008). A selective small molecule inhibitor of c-Met, PHA-665752, reverses lung premalignancy induced by mutant K-ras. Mol Cancer Ther 7: 952–960.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yi S, Chen JR, Viallet J, Schwall RH, Nakamura T, Tsao MS . (1998). Paracrine effects of hepatocyte growth factor/scatter factor on non-small-cell lung carcinoma cell lines. Br J Cancer 77: 2162–2170.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao X, Weir BA, LaFramboise T, Lin M, Beroukhim R, Garraway L et al. (2005). Homozygous deletions and chromosome amplifications in human lung carcinomas revealed by single nucleotide polymorphism array analysis. Cancer Res 65: 5561–5570.

    Article  CAS  PubMed  Google Scholar 

  • Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C, Georgescu MM et al. (2000). Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res 60: 1541–1545.

    CAS  PubMed  Google Scholar 

  • Zhou BB, Peyton M, He B, Liu C, Girard L, Caudler E et al. (2006). Targeting ADAM-mediated ligand cleavage to inhibit HER3 and EGFR pathways in non-small cell lung cancer. Cancer Cell 10: 39–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Drs Mien-Chie Hung, Scott Lippman, and Kian Ang for their critical review, Dr Jeffrey Engelman for the EGFR-transfected NIH 3T3 cell lines, and Joseph Munch for editorial assistance. Supported in part by the NIH Lung Cancer SPORE grant P50 CA70907, NIH Grant P01 CA06294, Department of Defense Grant W81XWH-07-1-0306 01, awards from the Metastasis Foundation, the Physician-Scientist Program, and the American Society for Clinical Oncology Career Development Award (JVH). JVH is a Damon Runyon-Lilly Clinical Investigator supported in part by the Damon Runyon Cancer Research Foundation (CI 24-04).

Author information

Author notes

  1. L Xu and M B Nilsson: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    L Xu, M B Nilsson, P Saintigny, T Cascone, M H Herynk, P G Nikolinakos, Y Yang, F M Johnson, J M Kurie & J V Heymach

  2. Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Z Du, I I Wistuba & J V Heymach

  3. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    L Prudkin & I I Wistuba

  4. Department of Biostatistics and Applied Mathematics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    D Liu & J J Lee

  5. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    K-K Wong

  6. Department of Pharmacology, Hamon Center for Therapeutic Oncology Research, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX, USA

    L Girard, A F Gazdar & J D Minna

  7. Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA

    J D Minna

Authors
  1. L Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M B Nilsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P Saintigny
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T Cascone
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M H Herynk
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Z Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. P G Nikolinakos
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Y Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. L Prudkin
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. D Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. J J Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. F M Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. K-K Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. L Girard
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. A F Gazdar
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. J D Minna
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. J M Kurie
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. I I Wistuba
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. J V Heymach
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J V Heymach.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Xu, L., Nilsson, M., Saintigny, P. et al. Epidermal growth factor receptor regulates MET levels and invasiveness through hypoxia-inducible factor-1α in non-small cell lung cancer cells. Oncogene 29, 2616–2627 (2010). https://doi.org/10.1038/onc.2010.16

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2010.16

Keywords

This article is cited by

Search

Advanced search

Quick links