Expression of trkB in human neuroblastoma in relation to MYCN expression and retinoic acid treatment.
Expression of full-length trkB can be found in some highly malignant neuroblastoma tumors with an amplified MYCN gene. This contrasts sympathetic neuroblasts, from which neuroblastomas are thought to arise, which neither express trkB nor are dependent on the p145(trkB) ligands, brain-derived neurotrophic factor (BDNF) or neurotrophin-4/5, for their normal development. In this study we show that trkB was expressed in two out of five neuroblastoma tumors with amplified MYCN, while no trkB expression was observed when the MYCN gene was overexpressed in a non-MYCN-amplified neuroblastoma cell line. This shows that MYCN overexpression per se is not sufficient to induce trkB expression. trkB expression and BDNF responsiveness in neuroblastoma cells can be induced by all-trans-retinoic acid (RA). When SH-SY5Y cells were stimulated with a combination of RA and BDNF, norepinephrine and tyrosine hydroxylase levels were unaltered, showing that the cells did not change toward a more catecholaminergic sympathetic phenotype. However, expression of growth-associated protein 43, indicative of a neuronal phenotype, was elevated. Vesicular acetylcholine transporter, choline acetyl transferase, and neuropeptide tyrosine mRNA levels also increased in RA-BDNF-treated cells, which could suggest that these cells develop into a sympathetic cholinergic phenotype. In addition, treatment with RA-induced expression of the platelet-derived growth factor receptor-alpha. As previously shown for BDNF, platelet-derived growth factor stimulated growth of the RA-treated cells, findings that could have clinical relevance. If these receptors mediate a mitogenic signal in vivo also, this might limit the effect of RA treatment on neuroblastoma patients.
Edsjö
Anders
A
Department of Laboratory Medicine, Lund University, University Hospital MAS, Malmö, Sweden.
Lavenius
Erik
E
Nilsson
Helén
H
Hoehner
Jeff C
JC
Simonsson
Per
P
Culp
Lloyd A
LA
Martinsson
Tommy
T
Larsson
Christer
C
Påhlman
Sven
S
D001483:Base Sequence; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D017931:DNA Primers; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D009447:Neuroblastoma / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D020813:Receptor, trkB / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D019208:Brain-Derived Neurotrophic Factor; D017931:DNA Primers; D016271:Proto-Oncogene Proteins c-myc; D014212:Tretinoin; D020813:Receptor, trkB