Hepatocyte growth factor/c-Met signaling promotes the progression of experimental human neuroblastomas.

作者: Monica Hecht , Maria Papoutsi , Hoa Dinh Tran , Joerg Wilting , Lothar Schweigerer

DOI: 10.1158/0008-5472.CAN-04-1014

关键词:

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

参考文章(53)
Paolo Comoglio, Silvia Giordano, Maria Flavia Di Renzo, C Rosa, Cs Cooper, Rp Narsimhan, Biosynthesis of the protein encoded by the c-met proto-oncogene. Oncogene. ,vol. 4, pp. 1383- 1388 ,(1989)
K. Nakajima, Y. Yamanaka, K. Nakae, H. Kojima, M. Ichiba, N. Kiuchi, T. Kitaoka, T. Fukada, M. Hibi, T. Hirano, A central role for Stat3 in IL‐6‐induced regulation of growth and differentiation in M1 leukemia cells. The EMBO Journal. ,vol. 15, pp. 3651- 3658 ,(1996) , 10.1002/J.1460-2075.1996.TB00734.X
A. Graziani, D. Gramaglia, L.C. Cantley, P.M. Comoglio, The tyrosine-phosphorylated hepatocyte growth factor/scatter factor receptor associates with phosphatidylinositol 3-kinase. Journal of Biological Chemistry. ,vol. 266, pp. 22087- 22090 ,(1991) , 10.1016/S0021-9258(18)54536-1
M.S. Pepper, K Matsumoto, T Nakamura, L Orci, R Montesano, Hepatocyte growth factor increases urokinase-type plasminogen activator (u-PA) and u-PA receptor expression in Madin-Darby canine kidney epithelial cells. Journal of Biological Chemistry. ,vol. 267, pp. 20493- 20496 ,(1992) , 10.1016/S0021-9258(19)88729-X
A B Tuck, A Boag, B E Elliott, E E Sterns, M Park, Coexpression of hepatocyte growth factor and receptor (Met) in human breast carcinoma. American Journal of Pathology. ,vol. 148, pp. 225- 232 ,(1996)
Carla Boccaccio, Margherita Andò, Luca Tamagnone, Alberto Bardelli, Paolo Michieli, Carlo Battistini, Paolo M. Comoglio, Induction of epithelial tubules by growth factor HGF depends on the STAT pathway Nature. ,vol. 391, pp. 285- 288 ,(1998) , 10.1038/34657
H K Kleinman, A Albini, G R Martin, S A Aaronson, Y Iwamoto, R N McEwan, J M Kozlowski, A Rapid in Vitro Assay for Quantitating the Invasive Potential of Tumor Cells Cancer Research. ,vol. 47, pp. 3239- 3245 ,(1987)
Monica Stefan, Alexandra Koch, Annalisa Mancini, Andrea Mohr, K. Michael Weidner, Heiner Niemann, Teruko Tamura, Src homology 2-containing inositol 5-phosphatase 1 binds to the multifunctional docking site of c-Met and potentiates hepatocyte growth factor-induced branching tubulogenesis. Journal of Biological Chemistry. ,vol. 276, pp. 3017- 3023 ,(2001) , 10.1074/JBC.M009333200
P. Boros, C.M. Miller, Hepatocyte growth factor: a multifunctional cytokine. The Lancet. ,vol. 345, pp. 293- 295 ,(1995) , 10.1016/S0140-6736(95)90279-1
Liang Jin, Alexander Fuchs, Stuart J. Schnitt, Yan Yao, Ansamma Joseph, Katrin Lamszus, Morag Park, Itzhak D. Goldberg, Eliot M. Rosen, Expression of scatter factor and c‐met receptor in benign and malignant breast tissue Cancer. ,vol. 79, pp. 749- 760 ,(1997) , 10.1002/(SICI)1097-0142(19970215)79:4<749::AID-CNCR12>3.0.CO;2-#