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Schwann cells secrete factors that impair neuroblastoma growth
Background: Spontaneous maturation of neuroblastomas (NB) occurs in 10 – 15% and results in Schwann cell (SC) stroma-rich tumors, i.e. in ganglioneuroblastomas and ganglioneuromas. Previous studies have demonstrated the SC stroma being of non-neoplastic origin in these non-aggressive NBs. The presence of this specific micro-environment in favorable NBs, the knowledge on neuronal-SC interactions in developmental and patho-physiological processes and preliminary NB-SC in vitro data suggest a tumor-inhibiting effect of the SC. Nevertheless, SC-NB interactions are still poorly understood.
Methods: In vitro co-cultivation and transwell experiments of MYCN amplified and non-amplified NB cell lines together with primary human SCs have been performed. Effects on proliferation and differentiation were measured by FACS and immunocytology. Supernatants from these experiments were analyzed by protein arrays and the RNA from FACS sorted cell types was sequenced. Protein array and RNAseq data-analysis was performed with the Qlucore Omics Explorer.
Results: The co-cultivation experiments confirmed the supposed tumor-inhibiting effect of SCs, reflected by significantly decreased proliferation and increased differentiation as well as apoptosis. Furthermore, transwell experiments showed comparable effects to take place even without direct cell-cell contact. Protein arrays demonstrated differential secretion of 48 proteins in co-cultivation experiments as compared to controls. RNAseq analysis confirmed their upregulation in SCs and respective receptor expression in NB cells.
Conclusion: The in vitro reconstructed SC-NB cell interactions show that the impairment of NB growth is predominantly mediated by secreted SC factors. Candidate factors will be further functionally validated.