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¹ Apoptosis, Cancer and Development Laboratory, Equipe labellisée ‘La Ligue’, Centre National de la Recherche Scientifique UMR5238, Université de Lyon, 69008 Lyon, France
² Molecular Interactions and Cancer Centre, National de la Recherche Scientifique UMR 8126 and IFR54, and ³ Oncopediatric Department, Gustave Roussy Institute, 94805 Villejuif Cedex, France
⁴ Department of Pathology, School of Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093
⁵ Division of Biochemistry, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan
⁶ Institut National de la Santé et de la Recherche Médicale U590, Unité d'Oncologie Moléculaire, Université de Lyon, 69008 Lyon, France

CORRESPONDENCE Patrick Mehlen: mehlen{at}lyon.fnclcc.fr

Neuroblastoma (NB), the most frequent solid tumor of early childhood, is diagnosed as a disseminated disease in >60% of cases, and several lines of evidence support the resistance to apoptosis as a prerequisite for NB progression. We show that autocrine production of netrin-1, a multifunctional laminin-related molecule, conveys a selective advantage in tumor growth and dissemination in aggressive NB, as it blocks the proapoptotic activity of the UNC5H netrin-1 dependence receptors. We show that such netrin-1 up-regulation is a potential marker for poor prognosis in stage 4S and, more generally, in NB stage 4 diagnosed infants. Moreover, we propose that interference with the netrin-1 autocrine loop in malignant neuroblasts could represent an alternative therapeutic strategy, as disruption of this loop triggers in vitro NB cell death and inhibits NB metastasis in avian and mouse models.

Abbreviations used: CAM, chorioallantoic membrane; DAPK, DAP kinase; DCC, deleted in colorectal cancer; MNA, MYCN amplification; mRNA, messenger RNA; Myoc, myocardium; NB, neuroblastoma; PTX, primary tumor xenograft; Q-RT-PCR, quantitative RT-PCR; siRNA, small interfering RNA; TUNEL, terminal deoxynucleotidyl transferase–mediated dUTP-biotin nick end labeling.

© 2009 Delloye-Bourgeois et al.
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