Prognostic and biological role of neurotrophin-receptor TrkA and TrkB in neuroblastoma

Expression of different neurotrophin receptors of the tyrosine kinase (Trk) family plays an important role in the biology and clinical behavior of neuroblastomas (NB). Observations from several independent studies suggest that high expression of TrkA is present in NE with favorable biological features and highly correlated with patient survival, whereas TrkB is mainly expressed on unfavorable, aggressive NE with MYCN-amplification. To determine expression of Trk receptors and ligands in primary NE, we developed a reliable semiquantitative duplex RT-PCR protocol, that requires only 1 mu g RNA per tumor sample. Activation of TrkA by its ligand nerve growth factor (NGF) initiates a cascade of signaling events and promotes neuronal differentiation in vitro. Activation of TrkB by its ligand brain derived neurotrophic factor (BDNF) has been associated with proliferation and survival of NE cells. To study Trk signal transduction pathways and their biological effects in NE, we stably expressed TrkA and TrkB cDNA in the human NE cell line SH-SY5Y. Introduction of TrkA and TrkB restored responsiveness of SH-SY5Y cells to the ligands NGF and BDNF, respectively, and resulted in morphological differentiation. Expression of TrkA resulted in growth inhibition of the transfectants compared to parental cells, whereas TrkB transfectants demonstrated an increased proliferation rate. Further insight into the differences of TrkA and TrkB signaling may suggest new options for the treatment of NE. As expression of TrkA is a strong prognostic factor especially in MYCN non-amplified NE, a prospective study of Trk receptor expression using RT-PCR should be performed for German neuroblastoma patients.