Carcinogenesis Advance Access originally published online on July 28, 2005
Carcinogenesis 2005 26(12):2105-2115; doi:10.1093/carcin/bgi192
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Carcinogenesis Vol.26 No.12 © Oxford University Press 2005; all rights reserved.
The neurotrophin receptor TrkB cooperates with c-Met in enhancing neuroblastoma invasiveness
1 Department of Pediatrics, University of Goettingen, Robert-Koch-Strasse 40, D-37075 Goettingen, Germany and 2 University Children's Hospital of Essen, Hufelandstrasse 55, D-45122 Essen, Germany
* To whom correspondence should be addressed at: Department of Oncology and Hematology, University Hospital Charite, Berlin, Schumannstrasse 20/21, D-10117 Berlin, Germany. Tel: +49 30 450513303; Fax: +49 30 450513960; Email: monica.hecht{at}charite.de
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.
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