Neurotrophin receptor expression in human primary retinoblastomas and retinoblastoma cell lines.
BACKGROUND
Neurotrophin receptor signaling regulates proliferation, differentiation and death of neuronal cells. Expression of Trk receptors has been implicated in the pathogenesis and prognosis of embryonal tumors, including neuroblastoma, nephroblastoma, and medulloblastoma.


METHODS
We analyzed TrkA, TrkB, TrkC, and p75 expression using semi-quantitative RT-PCR in 23 retinoblastomas and 8 retinoblastoma cell lines. Comparison of mRNA expression with clinical variables as well as the proliferation (PI) and apoptotic index (AI) of the tumor, was performed by Pearson correlation analysis and two-sample t-test.


RESULTS
Almost all tumor samples and cell lines demonstrated high expression of all Trk receptors. Expression of TrkB and its ligand, BDNF, was most pronounced, suggesting TrkB to be the major Trk receptor involved in retinoblastoma biology. In contrast, p75 expression was substantially reduced in a subset of tumors and cell lines, in particular compared to its expression in normal retina. Tumors with infiltrative growth demonstrated significantly lower relative levels of TrkC expression than localized tumors (P = 0.004). High expression of TrkA was associated with a higher AI (P = 0.04), and high expression of TrkC was associated with a younger age of the patients (P = 0.03). Inhibition of Trk signaling by K252a resulted in marked growth inhibition of retinoblastoma cells in vitro.


CONCLUSIONS
Our findings suggest a role for neurotrophin signaling in the biology of retinoblastoma. General Trk inhibitors are effective in decreasing growth rates of retinoblastoma cells in vitro, and should be evaluated in in vivo studies.
Stephan
Harald
H
Department of Pediatric Hematology, Oncology and Endocrinology, University Hospital of Essen, Essen, Germany.
Zakrzewski
Johannes L
JL
Bölöni
Réka
R
Grasemann
Corinna
C
Lohmann
Dietmar R
DR
Eggert
Angelika
A
D000367:Age Factors; D017209:Apoptosis / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D020932:Nerve Growth Factor / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020800:Receptor, Nerve Growth Factor / Q000096:biosynthesis / Q000235:genetics; D020917:Receptor, trkA / Q000096:biosynthesis / Q000235:genetics; D020813:Receptor, trkB / Q000096:biosynthesis / Q000235:genetics; D020812:Receptor, trkC / Q000096:biosynthesis / Q000235:genetics; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D012175:Retinoblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D012333:RNA, Messenger; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D020813:Receptor, trkB; D020812:Receptor, trkC