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.
Delloye-Bourgeois
Céline
C
Centre National de la Recherche Scientifique UMR, Université de Lyon, France.
Fitamant
Julien
J
Paradisi
Andrea
A
Cappellen
David
D
Douc-Rasy
Setha
S
Raquin
Marie-Anne
MA
Stupack
Dwayne
D
Nakagawara
Akira
A
Rousseau
Raphaël
R
Combaret
Valérie
V
Puisieux
Alain
A
Valteau-Couanet
Dominique
D
Bénard
Jean
J
Bernet
Agnès
A
Mehlen
Patrick
P
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