Neurotrophin-3 production promotes human neuroblastoma cell survival by inhibiting TrkC-induced apoptosis

Abstract

Tropomyosin-related kinase receptor C (TrkC) is a neurotrophin receptor with tyrosine kinase activity that was expected to be oncogenic. However, it has several characteristics of a tumor suppressor: its expression in tumors has often been associated with good prognosis; and it was recently demonstrated to be a dependence receptor, transducing different positive signals in the presence of ligand but inducing apoptosis in the absence of ligand. Here we show that the TrkC ligand neurotrophin-3 (NT-3) is upregulated in a large fraction of aggressive human neuroblastomas (NBs) and that it blocks TrkC-induced apoptosis of human NB cell lines, consistent with the idea that TrkC is a dependence receptor. Functionally, both siRNA knockdown of NT-3 expression and incubation with a TrkC-specific blocking antibody triggered apoptosis in human NB cell lines. Importantly, disruption of the NT-3 autocrine loop in malignant human neuroblasts triggered in vitro NB cell death and inhibited tumor growth and metastasis in both a chick and a mouse xenograft model. Thus, we believe that our data suggest that NT-3/TrkC disruption is a putative alternative targeted therapeutic strategy for the treatment of NB.

TrkC signaling is activated in adenoid cystic carcinoma and requires NT-3 to stimulate invasive behavior

“…Indeed, autocrine TrkC/NT-3 loops detected recently in neuroblastomas were linked with poor prognosis. 16 Upregulation of Bcl2 along with TrkC in ACC, which is also observed in CYLD-deficient tumors that overexpress TrkC, 50 is an intriguing discovery, given the important role that Bcl2 has in cell survival and, particularly, the resistance to radio-and chemotherapies. 58 High Bcl2 levels that we detected in ACC cells are supported by a study performed on four ACC specimens 59 and may explain the relative resistance of this cancer to cytotoxic therapies, making development of targeted approaches even more justified.…”

“…12 Inactivating mutations in TrkC/NTRK3 have been recently associated with Hirschsprung disease, a developmental disorder characterized by the absence of ganglion cells in the myenteric and submucosal plexuses likely due to neural crest neuroblast migration defects. 13,14 In cancers, where TrkC activities are not fully understood, TrkC prosurvival signaling was found to prevail over apoptotic signaling in the presence of NT-3, 15,16 or when ligand requirement was bypassed by activating mutations 17 or fusions. 18 Potentially activating somatic mutations in the TrkC kinase domain have been reported in breast, lung, colon and pancreatic cancers.…”

“…TrkC signaling varies depending on the availability of its ligand, NT-3. To determine if an autocrine loop between NT-3 and TrkC is active in ACC, as it was demonstrated recently for neuroblastoma, 16 primary tumors (n ¼ 7) and xenografted ACC specimens (n ¼ 11) were analyzed by RT-PCR for NT-3 expression. We detected and verified by sequencing NTF3 (NT-3) expression in both primary and xenografted ACC specimens, suggesting that an autocrine survival pathway may be active in ACC (Figure 2e).…”

MicroRNAs in neuroblastoma differentiation and differentiation therapy

“…These findings altogether support the function of miR-125b in inducing neuronal differentiation. In investigating the mechanism underlying the differentiationinducing function of miR-125b, Laneve et al found that an iso-form of neurotrophin receptor tropomyosin-related kinase C (TrkC), which has been known to play a critical role in neuronal differentiation, was seen significantly repressed in neuroblastoma cells after the ectopic expression of miR125a/b [58][59][60][61] . The study also examined the expression of miR-125b in primary neuroblastoma tumors and found that this miRNA was down-regulated in primary neuroblastoma tumors, supporting its potential role in neuroblastoma tumorigenesis [61] .…”

Detection of aberrant methylated SEPT9 and NTRK3 genes in sporadic colorectal cancer patients as a potential diagnostic biomarker

“…It has been demonstrated previously that NTRKs have oncogenic effects in some cancer types, such as breast cancer and liver cancer (33). Recent studies have demonstrated that NTRK1 and NTRK3 may be dependent receptors, which depend on availability of their ligands to select their specific cell signals; these receptors are defined as having the ability to induce opposite effects in the presence or absence of their ligands (34,35). The availability of the ligand leads to the transduction of a positive cellular survival or differentiation signal, whereas the induction of apoptosis is a result of the absence of ligand (36).…”