trk and ret proto‐oncogene expression in human neuroblastoma specimens: High frequency of trk expression in non‐advanced stages

Abstract

Forty-three fresh tumor specimens of human neuroblastoma belonging to different clinical stages were analyzed for the expression of 2 proto-oncogenes: trk, which encodes a tyrosine-kinase receptor for nerve growth factor (NGF) and ret, another receptor-type tyrosine kinase whose ligand is unknown. The mRNA expression of the trk gene was detected in 67.4% of cases, with increased frequency in I, II and IVs Evans' stages and in patients with favorable prognosis according to the Shimada classification. Moreover, trk expression inversely correlated with Nmyc-gene amplification. ret mRNA was found in 36.8% of cases and equally distributed in the different stages. In addition, ngfR (low-affinity NGF receptor)-gene expression was present in 9 out of 25 cases. The simultaneous presence of mRNA related to both forms of the NGF receptor, while not proving the presence of a functional receptor, indicates the existence of a sub-set of neuroblastoma cells potentially responsive to NGF.

Expression of mRNA for the neurotrophin receptor trkC in neuroblastomas with favourable tumour stage and good prognosis

“…Combining our own present and previous results (Kogner et al, 1993) with those from other groups (Borello et al, 1993;Kaplan et al, 1993;Matsumoto et al, 1995;Nakagawara et al, 1994;Suzuki et al, 1993) a specific pattern of neurotrophin receptor expression in various neuroblastoma tumours emerges. Favourable neuroblastoma tumours express trkA together with p75LNGFR and sometimes full-length trkC, but only truncated trkB.…”

An Autocrine Loop Involving Ret and Glial Cell–Derived Neurotrophic Factor Mediates Retinoic Acid–Induced Neuroblastoma Cell Differentiation

“…As mentioned above, although Ret has been consistently found expressed in neuroblastoma tumor specimens and in most neuroblastoma-derived cell lines, no clear evidence has been reported that may support its involvement in neuroblastoma pathogenesis, and its expression does not correlate with disease aggressiveness (10,11). On the other hand, in primary cultures, GDNF and neurturin cooperate with RA to induce neurite outgrowth and GDNF induces neuronal differentiation in lowgrade but not in high-grade neuroblastoma cells (12,13).…”

NGF activation of TrkA decreases N-myc expression via MAPK path leading to a decrease in neuroblastoma cell number

“…Several characteristics have been identified that predict the outcome of NB patients. In patients with a good prognosis, tumors occur in infants (o1 year), are aneuploid, lack loss of heterozygosity (LOH) at 1p or N-myc amplification and express relatively high levels of TrkA mRNA (Borello et al, 1993;Kogner et al, 1993;Nakagawara et al, 1993;Suzuki et al, 1993). Indicators of poor prognosis include clinical presentation in older children (41 year) of tumors that are diploid, contain LOH at lp and amplification of the N-myc proto-oncogene.…”