Netrin-1 acts as a survival factor for aggressive neuroblastoma.
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.
Centre National de la Recherche Scientifique UMR, Université de Lyon, France.
Céline
C
Delloye-Bourgeois
Julien
J
Fitamant
Andrea
A
Paradisi
David
D
Cappellen
Setha
S
Douc-Rasy
Marie-Anne
MA
Raquin
Dwayne
D
Stupack
Akira
A
Nakagawara
Raphaël
R
Rousseau
Valérie
V
Combaret
Alain
A
Puisieux
Dominique
D
Valteau-Couanet
Jean
J
Bénard
Agnès
A
Bernet
Patrick
P
Mehlen
D016923:Cell Death; D045744:Cell Line, Tumor; D002470:Cell Survival; D018572:Disease-Free Survival; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D009367:Neoplasm Staging; D009414:Nerve Growth Factors / Q000235:genetics*; D000075388:Netrin-1; D009447:Neuroblastoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D011379:Prognosis; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017741:Survivors; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D015854:Up-Regulation
C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1