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:

TrkB induces EMT and has a key role in invasion of head and neck squamous cell carcinoma

Oncogene volume 29, pages 2047–2059 (2010)Cite this article

Subjects

Abstract

Head and neck squamous cell carcinoma (HNSCC) remains a significant public health problem, accounting for over 5% of all cancer-related deaths, and these deaths primarily result from metastatic disease. The molecular processes involved in HNSCC pathogenesis and progression are poorly understood, and here we present experimental evidence for a direct role of the cell surface receptor tyrosine kinase, TrkB, in HNSCC tumor progression. Using immunohistochemical analysis and transcriptional profiling of archival HNSCC tumor specimens, we found that TrkB and its secreted ligand, brain-derived neurotrophic factor (BDNF), are expresses in greater than 50% of human HNSCC tumors, but not in normal upper aerodigestive tract (UADT) epithelia. Studies with HNSCC cell lines reveal that in vitro stimulation with BDNF, the ligand for TrkB, upregulates the migration and invasion of HNSCC cells, and both transient and stable suppressions of TrkB result in significant abrogation of constitutive and ligand-mediated migration and invasion. Furthermore, enforced overexpression of TrkB results in altered expression of molecular mediators of epithelial-to-mesenchymal transition (EMT), including downregulation of E-cadherin and upregulation of Twist. Using an in vivo mouse model of HNSCC, we were able to show that downregulation of TrkB suppresses tumor growth. These results directly implicate TrkB in EMT and the invasive behavior of HNSCC, and correlate with the in vivo overexpression of TrkB in human HNSCC. Taken together, these data suggest that the TrkB receptor may be a critical component in the multi-step tumor progression of HNSCC, and may be an attractive target for much needed new therapies for this 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
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  • Arias AM . (2001). Epithelial mesenchymal interactions in cancer and development. Cell 105: 425–431.

    Article  CAS  PubMed  Google Scholar 

  • Armistead P, Salganick J, Roh J, Steinert D, Patel S, Munsell M et al. (2007). Expression of receptor tyrosine kinases and apoptotic molecules in rhabdomyosarcoma. Cancer 110: 2293–2303.

    Article  CAS  PubMed  Google Scholar 

  • Bardelli A, Parsons DW, Silliman N, Ptak J, Szabo S, Saha S et al. (2003). Mutational analysis of the tyrosine kinome in colorectal cancers. Science 300: 949.

    Article  CAS  PubMed  Google Scholar 

  • Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB et al. (2006). Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354: 567–578.

    Article  CAS  PubMed  Google Scholar 

  • Chao MV, Lee FS . (2004). Neurotrophin survival signaling mechanisms. J Alzheimers Dis 6: S7–S11.

    Article  CAS  PubMed  Google Scholar 

  • Cheng GZ, Chan J, Wang Q, Zhang W, Sun CD, Wang L-H . (2007). Twist transcriptionally up-regulates AKT2 in breast cancer cells leading to increased migration, invasion, and resistance to paclitaxel. Cancer Res 67: 1979–1987.

    Article  CAS  PubMed  Google Scholar 

  • Christofori G . (2006). New signals from the invasive front. Nature 441: 444–450.

    Article  CAS  PubMed  Google Scholar 

  • Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K et al. (2008). Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455: 1069–1075.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Douma S, Van Laar T, Zevenhoven J, Meuwissen R, Van Garderen E, Peeper DS . (2004). Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB. Nature 430: 1034–1039.

    Article  CAS  PubMed  Google Scholar 

  • Eggert A, Grotzer MA, Ikegaki N, Liu XG, Evans AE, Brodeur GM . (2002). Expression of the neurotrophin receptor TrkA down-regulates expression and function of angiogenic stimulators in SH-SY5Y neuroblastoma cells. Cancer Res 62: 1802–1808.

    CAS  PubMed  Google Scholar 

  • Eggert A, Grotzer MA, Ikegaki N, Zhao H, Cnaan A, Brodeur GM et al. (2001). Expression of the neurotrophin receptor TrkB is associated with unfavorable outcome in Wilms’ tumor. J Clin Oncol 19: 689–696.

    Article  CAS  PubMed  Google Scholar 

  • Eggert A, Ikegaki N, Liu XG, Brodeur GM . (2000). Prognostic and biological role of neurotrophin-receptor TrkA and TrkB in neuroblastoma. Klin Padiatr 212: 200–205.

    Article  CAS  PubMed  Google Scholar 

  • Geiger TR, Peeper DS . (2007). Critical role for TrkB kinase function in anoikis suppression, tumorigenesis, and metastasis. Cancer Res 67: 6221–6229.

    Article  CAS  PubMed  Google Scholar 

  • Han G, Lu SL, Li AG, He W, Corless CL, Kulesz-Martin M et al. (2005). Distinct mechanisms of TGF-beta1-mediated epithelial-to-mesenchymal transition and metastasis during skin carcinogenesis. J Clin Invest 115: 1714–1723.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ho R, Eggert A, Hishiki T, Minturn JE, Ikegaki N, Foster P et al. (2002). Resistance to chemotherapy mediated by TrkB in neuroblastomas. Cancer Res 62: 6462–6466.

    CAS  PubMed  Google Scholar 

  • Hoot KE, Lighthall J, Han G, Lu SL, Li A, Ju W et al. (2008). Keratinocyte-specific Smad2 ablation results in increased epithelial–mesenchymal transition during skin cancer formation and progression. J Clin Invest 118: 2722–2732.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Huang EJ, Reichardt LF . (2003). Trk receptors: roles in neuronal signal transduction. Annu Rev Biochem 72: 609–642.

    Article  CAS  PubMed  Google Scholar 

  • Jaboin J, Kim CJ, Kaplan DR, Thiele CJ . (2002). Brain-derived neurotrophic factor activation of TrkB protects neuroblastoma cells from chemotherapy-induced apoptosis via phosphatidylinositol 3′-kinase pathway. Cancer Res 62: 6756–6763.

    CAS  PubMed  Google Scholar 

  • Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ . (2007). Cancer Statistics, 2007. CA Cancer J Clin 57: 43–66.

    Article  PubMed  Google Scholar 

  • Karamouzis MV, Grandis JR, Argiris A . (2007). Therapies directed against epidermal growth factor receptor in aerodigestive carcinomas. JAMA 298: 70–82.

    Article  CAS  PubMed  Google Scholar 

  • Ketterer K, Rao S, Friess H, Weiss J, Buchler MW, Korc M . (2003). Reverse transcription-PCR analysis of laser-captured cells points to potential paracrine and autocrine actions of neurotrophins in pancreatic cancer. Clin Cancer Res 9: 5127–5136.

    CAS  PubMed  Google Scholar 

  • Klein R, Lamballe F, Bryant S, Barbacid M . (1992). The trkB tyrosine protein kinase is a receptor for neurotrophin-4. Neuron 8: 947–956.

    Article  CAS  PubMed  Google Scholar 

  • Kupferman ME, Jayakumar A, Zhou G, Xie T, Dakak-Yazici Y, Zhao M et al. (2009). Therapeutic suppression of constitutive and inducible JAK/STAT activation in head and neck squamous cell carcinoma. J Exp Ther Oncol 8: 117–127.

    CAS  PubMed  Google Scholar 

  • Kupferman ME, Myers JN . (2006). Molecular biology of oral cavity squamous cell carcinoma. Otolaryngol Clin North Am 39: 229–247.

    Article  PubMed  Google Scholar 

  • Li Z, Zhang J, Liu Z, Woo CW, Thiele CJ . (2007). Downregulation of Bim by brain-derived neurotrophic factor activation of TrkB protects neuroblastoma cells from paclitaxel but not etoposide or cisplatin-induced cell death. Cell Death Differ 14: 318–326.

    Article  PubMed  Google Scholar 

  • Liang C-C, Park AY, Guan J-L . (2007). In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro. Nat Protoc 2: 329–333.

    Article  CAS  PubMed  Google Scholar 

  • Lu C-H, Wyszomierski SL, Tseng L-M, Sun M-H, Lan K-H, Neal CL et al. (2007). Preclinical testing of clinically applicable strategies for overcoming trastuzumab resistance caused by PTEN deficiency. Clin Cancer Res 13: 5883–5888.

    Article  CAS  PubMed  Google Scholar 

  • Luikart BW, Zhang W, Wayman GA, Kwon CH, Westbrook GL, Parada LF . (2008). Neurotrophin-dependent dendritic filopodial motility: a convergence on PI3K signaling. J Neurosci 28: 7006–7012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martens LK, Kirschner KM, Warnecke C, Scholz H . (2007). Hypoxia-inducible factor-1 (HIF-1) is a transcriptional activator of the TrkB neurotrophin receptor gene. J Biol Chem 282: 14379–14388.

    Article  CAS  PubMed  Google Scholar 

  • Matsumoto K, Wada RK, Yamashiro JM, Kaplan DR, Thiele CJ . (1995). Expression of brain-derived neurotrophic factor and p145TrkB affects survival, differentiation, and invasiveness of human neuroblastoma cells. Cancer Res 55: 1798–1806.

    CAS  PubMed  Google Scholar 

  • Miknyoczki SJ, Lang D, Huang L, Klein-Szanto AJ, Dionne CA, Ruggeri BA . (1999). Neurotrophins and Trk receptors in human pancreatic ductal adenocarcinoma: expression patterns and effects on in vitro invasive behavior. Int J Cancer 81: 417–427.

    Article  CAS  PubMed  Google Scholar 

  • Nakamura K, Martin KC, Jackson JK, Beppu K, Woo CW, Thiele CJ . (2006). Brain-derived neurotrophic factor activation of TrkB induces vascular endothelial growth factor expression via hypoxia-inducible factor-1alpha in neuroblastoma cells. Cancer Res 66: 4249–4255.

    Article  CAS  PubMed  Google Scholar 

  • Nakashima T, Pak SC, Silverman GA, Spring PM, Frederick MJ, Clayman GL . (2000). Genomic cloning, mapping, structure and promoter analysis of HEADPIN, a serpin which is down-regulated in head and neck cancer cells. Biochim Biophys Acta 1492: 441–446.

    Article  CAS  PubMed  Google Scholar 

  • O'Donnell RK, Kupferman M, Wei SJ, Singhal S, Weber R, O′Malley B et al. (2005). Gene expression signature predicts lymphatic metastasis in squamous cell carcinoma of the oral cavity. Oncogene 24: 1244–1251.

    Article  CAS  PubMed  Google Scholar 

  • Parkin DM, Bray F, Ferlay J, Pisani P . (2005). Global Cancer Statistics, 2002. CA Cancer J Clin 55: 74–108.

    Article  PubMed  Google Scholar 

  • Pearse RN, Swendeman SL, Li Y, Rafii D, Hempstead BL . (2005). A neurotrophin axis in myeloma: TrkB and BDNF promote tumor-cell survival. Blood 105: 4429–4436.

    Article  CAS  PubMed  Google Scholar 

  • Smit MA, Geiger TR, Song J-Y, Gitelman I, Peeper DS . (2009). A Twist–Snail axis critical for TrkB-induced EMT-like transformation, anoikis resistance and metastasis. Mol Cell Biol 29: 3722–3737.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thiery JP . (2002). Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer 2: 442–454.

    Article  CAS  PubMed  Google Scholar 

  • Yang MH, Chang SY, Chiou SH, Liu CJ, Chi CW, Chen PM et al. (2006). Overexpression of NBS1 induces epithelial-mesenchymal transition and co-expression of NBS1 and Snail predicts metastasis of head and neck cancer. Oncogene 26: 1459–1467.

    Article  PubMed  Google Scholar 

  • Yigitbasi OG, Younes MN, Doan D, Jasser SA, Schiff BA, Bucana CD et al. (2004). Tumor cell and endothelial cell therapy of oral cancer by dual tyrosine kinase receptor blockade. Cancer Res 64: 7977–7984.

    Article  CAS  PubMed  Google Scholar 

  • Zhou G, Xie TX, Zhao M, Jasser SA, Younes MN, Sano D et al. (2008). Reciprocal negative regulation between S100A7/psoriasin and beta-catenin signaling plays an important role in tumor progression of squamous cell carcinoma of oral cavity. Oncogene 27: 3527–3538.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank S Jasser, MS, for technical assistance, T Astin for administrative assistance and X Wu, PhD, for critical review of the paper. This study was supported by the following funding sources: American Head and Neck Society; Young Investigator Award (MEK); Head and Neck SPORE Program-Career Development Award, MDACC (MEK); and the MD Anderson Cancer Center Physician-Scientist Program (MEK). NIH Cancer Center Support Grant CA16672 (MDACC) and Grant K08 DE019185 from the NIDCR (MEK).

Author information

Authors and Affiliations

  1. Department of Head and Neck Surgery, Houston, TX, USA

    M E Kupferman, T Jiffar, T Yilmaz, G Zhou, T Xie, F C Holsinger & J N Myers

  2. Department of Pathology, Houston, TX, USA

    A El-Naggar

  3. Department of Biostatistics, Houston, TX, USA

    L Feng

  4. Department of Bioinformatics, Houston, TX, USA

    J Wang

  5. Department of Molecular and Cellular Oncology, Houston, TX, USA

    D Yu

Authors
  1. M E Kupferman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T Jiffar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A El-Naggar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T Yilmaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. L Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. F C Holsinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. D Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. J N Myers
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M E Kupferman.

Additional information

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

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kupferman, M., Jiffar, T., El-Naggar, A. et al. TrkB induces EMT and has a key role in invasion of head and neck squamous cell carcinoma. Oncogene 29, 2047–2059 (2010). https://doi.org/10.1038/onc.2009.486

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2009.486

Keywords

This article is cited by

Search

Advanced search

Quick links