TRKc apoptosis in absence of ligand - Positive possibly Possible Neural differentiation ### [The RUNX Family Defines Trk Phenotype and Aggressiveness of Human Neuroblastoma through Regulation of p53 and MYCN | Cells 2023](https://pmc.ncbi.nlm.nih.gov/articles/PMC9954111/) > Intriguingly, primary neuroblastoma cells with high TrkA expression display differentiation with neurite outgrowth in the presence of NGF but undergo apoptosis in the absence of NGF, giving insight into the mechanisms underlying spontaneous regression of neuroblastomas [14]. This suggests that ligand deprivation could trigger spontaneous regression of neuroblastomas, phenocopying the developmental process in sympathoadrenal cells. Furthermore, TrkA-induced apoptosis of neuroblastoma cells is mediated, at least in part, through p53 function [27]. > > Even when patients achieve remission after this intensive multi-model treatment, relapse rates remain high likely due to persistent chemotherapy-resistant minimal residual disease (MRD) [16 17](https://www.cancertreatmentreviews.com/article/S0305-7372\(23\)00093-2/fulltext). The anti-GD2 and isotretinoin maintenance therapy is aimed at eradicating or differentiating any MRD. Isotretinoin is a retinoid that regulates cell proliferation and development and has been demonstrated to induce differentiation and inhibit uncontrolled proliferation of neuroblastoma cells [18](https://www.cancertreatmentreviews.com/article/S0305-7372\(23\)00093-2/fulltext). The combination of anti-GD2 and isotretinoin has shown significant improvements in overall survival and event-free survival [14](https://www.cancertreatmentreviews.com/article/S0305-7372\(23\)00093-2/fulltext). > > As a second approach, we used a blocking TrkC antibody described before (14) to prevent NT-3 from binding to endogenous TrkC. As shown in Figure Figure2,2,  D and E, and Supplemental Figure 2D, the addition of anti-TrkC  triggered CLB-Ge2 and CLB-VolMo apoptotic cell death, as measured by  caspase-3 activity assay (Figure 2D) and TUNEL staining (Figure (Figure2E  and Supplemental Figure 2D). This effect was specific for NT-3/TrkC  inhibition, since the anti-TrkC antibody had no effect on IMR32 cells.  Similar CLB-Ge2 cell death induction was observed when, instead of using  a blocking TrkC antibody, a recombinant ectodomain of TrkC was used to  trap NT-3 (Supplemental Figure 2E).          > > To determine whether the NB cell death associated with  inhibition of the TrkC/NT-3 interaction can be extended to fresh tumors,  a surgical biopsy from a tumor and the corresponding bone marrow was  semi-dissociated and further incubated with the anti-TrkC antibody. This  primary tumor and the disseminated neoplasia expressed both NT-3 and  TrkC (Supplemental Figure 2F), and an increased cell death, measured by  caspase activation, was detected in response to the anti-TrkC antibody  (Figure2F). > > ![[Pasted image 20250701170656.png]]