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 neu roblastomas (NB). Observations from several independent studies suggest tha t high expression of TrkA is present in NE with favorable biological featur es and highly correlated with patient survival, whereas TrkB is mainly expr essed on unfavorable, aggressive NE with MYCN-amplification. To determine e xpression of Trk receptors and ligands in primary NE, we developed a reliab le semiquantitative duplex RT-PCR protocol, that requires only 1 mu g RNA p er tumor sample. Activation of TrkA by its ligand nerve growth factor (NGF) initiates a cascade of signaling events and promotes neuronal differentiat ion in vitro. Activation of TrkB by its ligand brain derived neurotrophic f actor (BDNF) has been associated with proliferation and survival of NE cell s. To study Trk signal transduction pathways and their biological effects i n NE, we stably expressed TrkA and TrkB cDNA in the human NE cell line SH-S Y5Y. Introduction of TrkA and TrkB restored responsiveness of SH-SY5Y cells to the ligands NGF and BDNF, respectively, and resulted in morphological d ifferentiation. Expression of TrkA resulted in growth inhibition of the tra nsfectants compared to parental cells, whereas TrkB transfectants demonstra ted an increased proliferation rate. Further insight into the differences o f 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 s hould be performed for German neuroblastoma patients.