Abstract
Expression of Trk receptors is an important prognostic factor in neuroblastoma (NB) and other cancers. TrkB and its ligand brain-derived neurotrophic factor (BDNF) are preferentially expressed in NB with poor prognosis, conferring invasive and metastatic potential to the tumor cells as well as enhancing therapy resistance. Galectin-1 (Gal-1) has emerged as an interesting cancer target, as it is involved in modulating cell proliferation, cell death and cell migration, all of which are linked to cancer initiation and progression. We previously identified Gal-1 mRNA to be upregulated in patients with aggressive, relapsing NB and found that Gal-1 protein was upregulated in human SY5Y NB cells on activation of ectopically expressed TrkB (SY5Y-TrkB), but not TrkA (SY5Y-TrkA). Here, we report that Gal-1 mRNA levels positively correlated with TrkB expression and anticorrelated with TrkA expression in a cohort of 102 primary NB. Immunohistochemical analyses of 92 primary NB specimens revealed high Gal-1 expression in stromal septae and in neuroblasts. BDNF-mediated activation of TrkB enhanced invasiveness and migration in vitro, which could be impaired by transient transfection using Gal-1-specific siRNA or a neutralizing antibody directed against Gal-1. The addition of recombinant Gal-1 (rGal-1) in the absence of BDNF partially restored migration and invasive capacity. Using the Trk inhibitor K252a, we could show that the upregulation of Gal-1 protein strictly depended on activated TrkB. Our data suggest that targeting Gal-1 might be a promising strategy for the treatment of aggressive NB.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Belanis L, Plowman SJ, Rotblat B, Hancock JF, Kloog Y . (2008). Galectin-1 is a novel structural component and a major regulator of h-ras nanoclusters. Mol Biol Cell 19: 1404–1414.
Chiang WF, Liu SY, Fang LY, Lin CN, Wu MH, Chen YC et al. (2008). Overexpression of galectin-1 at the tumor invasion front is associated with poor prognosis in early-stage oral squamous cell carcinoma. Oral Oncol 44: 325–334.
Cimmino F, Spano D, Capasso M, Zambrano N, Russo R, Zollo M et al. (2007). Comparative proteomic expression profile in all-trans retinoic acid differentiated neuroblastoma cell line. J Proteome Res 6: 2550–2564.
Eggert A, Grotzer MA, Zuzak TJ, Wiewrodt BR, Ho R, Ikegaki N et al. (2001). Resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in neuroblastoma cells correlates with a loss of caspase-8 expression. Cancer Res 61: 1314–1319.
Hanahan D, Weinberg RA . (2000). The hallmarks of cancer. Cell 100: 57–70.
He J, Baum LG . (2004). Presentation of galectin-1 by extracellular matrix triggers T cell death. J Biol Chem 279: 4705–4712.
Hecht M, Papoutsi M, Tran HD, Wilting J, Schweigerer L . (2004). Hepatocyte growth factor/c-Met signaling promotes the progression of experimental human neuroblastomas. Cancer Res 64: 6109–6118.
Hecht M, Schulte JH, Eggert A, Wilting J, Schweigerer L . (2005). The neurotrophin receptor TrkB cooperates with c-Met in enhancing neuroblastoma invasiveness. Carcinogenesis 26: 2105–2115.
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.
Hughes RC . (2001). Galectins as modulators of cell adhesion. Biochimie 83: 667–676.
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.
Jung EJ, Moon HG, Cho BI, Jeong CY, Joo YT, Lee YJ et al. (2007). Galectin-1 expression in cancer-associated stromal cells correlates tumor invasiveness and tumor progression in breast cancer. Int J Cancer 120: 2331–2338.
Juszczynski P, Ouyang J, Monti S, Rodig SJ, Takeyama K, Abramson J et al. (2007). The AP1-dependent secretion of galectin-1 by Reed Sternberg cells fosters immune privilege in classical Hodgkin lymphoma. Proc Natl Acad Sci USA 104: 13134–13139.
Le Mercier M, Mathieu V, Haibe-Kains B, Bontempi G, Mijatovic T, Decaestecker C et al. (2008). Knocking down galectin 1 in human hs683 glioblastoma cells impairs both angiogenesis and endoplasmic reticulum stress responses. J Neuropathol Exp Neurol 67: 456–469.
Liu FT, Rabinovich GA . (2005). Galectins as modulators of tumour progression. Nat Rev Cancer 5: 29–41.
Lucarelli E, Kaplan D, Thiele CJ . (1997). Activation of trk-A but not trk-B signal transduction pathway inhibits growth of neuroblastoma cells. Eur J Cancer 33: 2068–2070.
Mathieu V, Le Mercier M, De Neve N, Sauvage S, Gras T, Roland I et al. (2007). Galectin-1 knockdown increases sensitivity to temozolomide in a B16F10 mouse metastatic melanoma model. J Invest Dermatol 127: 2399–2410.
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.
Nakagawara A, Arima-Nakagawara M, Scavarda NJ, Azar CG, Cantor AB, Brodeur GM . (1993). Association between high levels of expression of the Trk gene and favorable outcome in human neuroblastomas. N Engl J Med 328: 847–854.
Nakagawara A, Azar CG, Scavarda NJ, Brodeur GM . (1994). Expression and function of Trk-B and BDNF in human neuroblastomas. Mol Cell Biol 14: 759–767.
Paz A, Haklai R, Elad-Sfadia G, Ballan E, Kloog Y . (2001). Galectin-1 binds oncogenic H-Ras to mediate Ras membrane anchorage and cell transformation. Oncogene 20: 7486–7493.
Rabinovich GA . (2005). Galectin-1 as a potential cancer target. Br J Cancer 92: 1188–1192.
Rodig SJ, Ouyang J, Juszczynski P, Currie T, Law K, Neuberg DS et al. (2008). AP1-dependent galectin-1 expression delineates classical hodgkin and anaplastic large cell lymphomas from other lymphoid malignancies with shared molecular features. Clin Cancer Res 14: 3338–3344.
Rubinstein N, Alvarez M, Zwirner NW, Toscano MA, Ilarregui JM, Bravo A et al. (2004). Targeted inhibition of galectin-1 gene expression in tumor cells results in heightened T cell-mediated rejection; A potential mechanism of tumor-immune privilege. Cancer Cell 5: 241–251.
Salatino M, Croci DO, Bianco GA, Ilarregui JM, Toscano MA, Rabinovich GA . (2008). Galectin-1 as a potential therapeutic target in autoimmune disorders and cancer. Expert Opin Biol Ther 8: 45–57.
Schramm A, Schulte JH, Astrahantseff K, Apostolov O, Limpt V, Sieverts H et al. (2005a). Biological effects of TrkA and TrkB receptor signaling in neuroblastoma. Cancer Lett 228: 143–153.
Schramm A, Schulte JH, Klein-Hitpass L, Havers W, Sieverts H, Berwanger B et al. (2005b). Prediction of clinical outcome and biological characterization of neuroblastoma by expression profiling. Oncogene 24: 7902–7912.
Schulte JH, Kirfel J, Lim S, Schramm A, Friedrichs N, Deubzer HE et al. (2008a). Transcription factor AP2alpha (TFAP2a) regulates differentiation and proliferation of neuroblastoma cells. Cancer Lett 271: 56–63.
Schulte JH, Lim S, Schramm A, Friedrichs N, Ora I, Pajtler K et al. (2009). The LSD1 histone demethylase is strongly expressed in poorly differentiated neuroblastoma: implications for therapy. Cancer Res 69: 2065–2071.
Schulte JH, Schramm A, Klein-Hitpass L, Klenk M, Wessels H, Hauffa BP et al. (2005). Microarray analysis reveals differential gene expression patterns and regulation of single target genes contributing to the opposing phenotype of TrkA- and TrkB-expressing neuroblastomas. Oncogene 24: 165–177.
Sitek B, Apostolov O, Stuhler K, Pfeiffer K, Meyer HE, Eggert A et al. (2005). Identification of dynamic proteome changes upon ligand activation of Trk-receptors using two-dimensional fluorescence difference gel electrophoresis and mass spectrometry. Mol Cell Proteomics 4: 291–299.
Stephan H, Zakrzewski JL, Boloni R, Grasemann C, Lohmann DR, Eggert A . (2008). Neurotrophin receptor expression in human primary retinoblastomas and retinoblastoma cell lines. Pediatr Blood Cancer 50: 218–222.
Tapley P, Lamballe F, Barbacid M . (1992). K252a is a selective inhibitor of the tyrosine protein kinase activity of the trk family of oncogenes and neurotrophin receptors. Oncogene 7: 371–381.
Teitz T, Wei T, Valentine MB, Vanin EF, Grenet J, Valentine VA et al. (2000). Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN. Nat Med 6: 529–535.
Thijssen VL, Poirier F, Baum LG, Griffioen AW . (2007). Galectins in the tumor endothelium: opportunities for combined cancer therapy. Blood 110: 2819–2827.
Thijssen VL, Postel R, Brandwijk RJ, Dings RP, Nesmelova I, Satijn S et al. (2006). Galectin-1 is essential in tumor angiogenesis and is a target for antiangiogenesis therapy. Proc Natl Acad Sci USA 103: 15975–15980.
Yamashiro DJ, Liu X-G, Lee CP, Nakagawara A, Ikegaki N, McGregor LM et al. (1997). Expression and function of TrkC in favourable human neuroblastomas. Eur J of Cancer 33: 2054–2057.
Acknowledgements
This study was supported by the 6th framework program of the European Union, Grant no. 037260 (EET-Pipeline).
Author information
Authors and Affiliations
Corresponding author
Additional information
Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)
Supplementary information
Rights and permissions
About this article
Cite this article
Cimmino, F., Schulte, J., Zollo, M. et al. Galectin-1 is a major effector of TrkB-mediated neuroblastoma aggressiveness. Oncogene 28, 2015–2023 (2009). https://doi.org/10.1038/onc.2009.70
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2009.70
Keywords
This article is cited by
-
Arsenic trioxide induces cell cycle arrest and affects Trk receptor expression in human neuroblastoma SK-N-SH cells
Biological Research (2018)
-
Protein glycosylation in cancers and its potential therapeutic applications in neuroblastoma
Journal of Hematology & Oncology (2016)
-
PI3K and MAPK pathways mediate the BDNF/TrkB-increased metastasis in neuroblastoma
Tumor Biology (2016)
-
RETRACTED ARTICLE: Analysis of serum levels and tissue expression of galectin-1 and galectin-3 as noninvasive biomarkers in osteosarcoma patients
Tumor Biology (2016)
-
Galectin-1 is associated with poor prognosis in patients with cutaneous head and neck cancer with perineural spread
Cancer Immunology, Immunotherapy (2016)