Journal Article

The neurotrophin receptor TrkB cooperates with c-Met in enhancing neuroblastoma invasiveness

Monica Hecht, Johannes H. Schulte, Angelika Eggert, Joerg Wilting and Lothar Schweigerer

in Carcinogenesis

Volume 26, issue 12, pages 2105-2115
Published in print December 2005 | ISSN: 0143-3334
Published online July 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi192
The neurotrophin receptor TrkB cooperates with c-Met in enhancing neuroblastoma invasiveness

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Neuroblastoma is the most frequent extracranial solid malignancy of childhood with a high mortality in advanced tumour stages. The hallmark of neuroblastoma is its clinical and biological heterogeneity. The molecular mechanisms leading to favourable or unfavourable tumour behaviour are still speculative. However, amplification of the oncogene MYCN and expression of the neurotrophin receptor TrkB are known to contribute to a highly malignant phenotype. To define the mechanisms through which TrkB may mediate neuroblastoma progression, we stably expressed this receptor in the neuroblastoma cell lines SH-SY5Y and SK-N-AS. The transfectants, but not the controls, had an increased invasive potency both, in vitro and in vivo, as demonstrated by Matrigel-invasion and chorioallantoic membrane assays, respectively. The retinoic acid-induced TrkB expression in parental SH-SY5Y cells was also associated with enhanced cell invasiveness. The TrkB mediated invasiveness involved the upregulation of the hepatocyte growth factor (HGF) and its receptor c-Met, resulting in an autocrine loop. Inhibition of HGF activity by anti-HGF neutralizing antibodies or disabling the function of c-Met by small interfering RNA suppressed the TrkB-induced invasiveness. The enhanced TrkB expression was associated with a significant increase in the secretion of various matrix-degrading proteases. Immunostaining and real-time RT–PCR analysis of tumour specimens demonstrated coordinated expression of TrkB and HGF/c-Met in experimental and primary neuroblastomas. We conclude that TrkB expression in neuroblastoma cells results in an increase in their invasive capability via upregulated expression of HGF/c-Met and enhanced activity of proteolytic networks.

Keywords: BDNF, brain-derived neurotrophic factor; CAM, chorioallantoic membrane; Ct, threshold cycle; HGF, hepatocyte growth factor; IgG, immunoglobulin G; MMP, matrix metalloproteinase; PBS, phosphate-buffered saline; RA, retinoic acid

Journal Article.  6902 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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