This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hecht, M. Articles by Schweigerer, L. Search for Related Content PubMed PubMed Citation Articles by Hecht, M. Articles by Schweigerer, L.

Hepatocyte Growth Factor/c-Met Signaling Promotes the Progression of Experimental Human Neuroblastomas

Abteilung Pädiatrie I, Zentrum für Kinderheilkunde und Jugendmedizin, Universitätsklinikum Göttingen, Göttingen, Germany

Neuroblastoma is the most frequent solid childhood malignancy. Despite aggressive therapy, mortality is high due to rapid tumor progression to advanced stages. The molecules and mechanisms underlying poor prognosis are not well understood. Here, we report that cultured human neuroblastoma cells express the hepatocyte growth factor (HGF) and its receptor c-Met. Binding of HGF to c-Met triggers receptor autophosphorylation, indicating functional relevance of this interaction. HGF activates several downstream effectors of c-Met such as the mitogen-activated protein kinases extracellular signal-regulated kinase 1/extracellular signal-regulated kinase 2 and phospholipase C-, whereas signal transducer and activator of transcription 3 is constitutively activated in neuroblastoma cells expressing c-Met. In addition, HGF is able to stimulate expression and proteolytic activity of matrix metalloproteinase-2 and tissue-type plasminogen activator in neuroblastoma cells, thereby promoting degradation of extracellular matrix components. We show that HGF stimulates invasion of neuroblastoma cells in vitro and in vivo, and it promotes the formation of angiogenic neuroblastomas in vivo. These processes can be blocked by specific inhibitors of the mitogen-activated protein kinase cascade, by inhibitors of phospholipase C-, and also by the expression of a dominant negative signal transducer and activator of transcription 3 mutant. Our data provide the first evidence that the HGF/c-Met pathway is essential for invasiveness and malignant progression of human neuroblastomas. They further suggest that specific inhibitors of this pathway may be suitable as therapeutic agents to improve clinical outcome of neuroblastomas.

This article has been cited by other articles:

				J. Becker, B. Erdlenbruch, I. Noskova, A. Schramm, M. Aumailley, D. F. Schorderet, and L. Schweigerer Keratoepithelin suppresses the progression of experimental human neuroblastomas. Cancer Res., May 15, 2006; 66(10): 5314 - 5321. [Abstract] [Full Text] [PDF]

				M. Hecht, J. H. Schulte, A. Eggert, J. Wilting, and L. Schweigerer The neurotrophin receptor TrkB cooperates with c-Met in enhancing neuroblastoma invasiveness Carcinogenesis, December 1, 2005; 26(12): 2105 - 2115. [Abstract] [Full Text] [PDF]

				R. Abounader and J. Laterra Scatter factor/hepatocyte growth factor in brain tumor growth and angiogenesis Neuro-oncol, October 1, 2005; 7(4): 436 - 451. [Abstract] [PDF]

				M. Hagedorn, S. Javerzat, D. Gilges, A. Meyre, B. de Lafarge, A. Eichmann, and A. Bikfalvi Accessing key steps of human tumor progression in vivo by using an avian embryo model PNAS, February 1, 2005; 102(5): 1643 - 1648. [Abstract] [Full Text] [PDF]