Carcinogenesis Advance Access published online on July 28, 2005
Carcinogenesis, doi:10.1093/carcin/bgi192
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1 Department of Pediatrics, University of Goettingen, Robert-Koch-Str. 40, D-37075 Goettingen, Germany
* To whom correspondence should be addressed. 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 neutralising 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.
Received February 15, 2005
Revised July 11, 2005
Accepted July 22, 2005
CANCER BIOLOGY
The neurotrophin receptor TrkB cooperates with c-Met in enhancing neuroblastoma invasiveness
2 University Children's Hospital of Essen, Hufelandstr. 55, D-45122 Essen, Germany
Monica Hecht, E-mail: monica.hecht{at}charite.de
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