Nerve growth factor (
NGF), essential for differentiation and survival of sympathetic neurons is suggested to play a role in differentiation or regression of
neuroblastoma. Expression of
mRNA for the trk protooncogene, encoding a
tyrosine kinase receptor essential for functional
NGF signal transduction, and
mRNA for the low affinity
NGF receptor (LNGFR) was examined in 45
neuroblastomas and 3 benign
ganglioneuromas using Northern blot analysis. Expression of trk
mRNA and LNGFR
mRNA correlated with young age, favorable clinical stages, and absence of N-myc amplification. All children (n = 19) with
neuroblastomas coexpressing
mRNA for trk and LNGFR are alive 8-84 months from diagnosis, regardless of age and stage. In contrast, no child (n = 15) with
tumor lacking trk
mRNA is alive without disease. Three subsets of patients were distinguished, one favorable (trk+, LNGFR+, n = 19, 100% survival probability), one intermediate (trk+, LNGFR-, n = 11, 62.3% survival probability), and one unfavorable (trk-, LNGFR +/-, n = 15, 0% survival probability, P < 0.001). In widespread
neuroblastoma stage IVS prone to
spontaneous regression, three
tumors coexpressing trk and LNGFR mRNAs regressed after no or minimal
therapy while the remaining
tumor expressing trk but not LNGFR
mRNA progressed to a fatal outcome. It is concluded that
neuroblastomas coexpressing
mRNA for both
NGF receptor subtypes are favorable
tumors likely to differentiate or regress spontaneously or respond to conventional
therapy. It is further hypothesized that loss of functional
NGF receptors is an important step in
tumorigenesis of undifferentiated malignant childhood
neuroblastoma. For these unfavorable
tumors current
therapy remains futile and first-line
innovative therapy is justified.