Die Expression des Neurotrophin-Rezeptors TrkB beeinflusst die Prognose von Nephroblastomen: Ergebnisse einer Pilotstudie

Zusammenfassung.

Hintergrund: Der Neurotrophin-Rezeptor TrkB spielt eine entscheidende Rolle in der Pathogenese, Biologie und Prognose von Neuroblastomen. Die hohe TrkB-Expression aggressiver Neuroblastome fördert Proliferation und Überleben der Tumorzellen und ist mit einer schlechten Prognose assoziiert. Mittlerweile ist eine Expression von Trk-Rezeptoren auch in extraneuronalen Geweben wie der Niere bekannt. Patienten und Methoden: Um die Rolle des Neurotrophin-Rezeptors TrkB in Nephroblastomen/Wilms-Tumoren (WT) zu studieren, wurde seine mRNA-Expression mittels semiquantitativer RT-PCR in 39 primären WT analysiert und die Expressionshöhe mit klinischen Parametern verglichen. Ergebnisse: Unsere Analyse zeigte eine signifikant schlechtere 5-Jahres-Überlebenswahrscheinlichkeit für WT-Patienten mit hoher Expression eines voll funktionsfähigen TrkB-Rezeptors (TrkBfull) im Vergleich zu Patienten mit niedriger TrkBfull-Expression (70 % versus 100 %, p=0,005). Im Gegensatz dazu hatten WT-Patienten mit hoher mRNA-Expression eines funktionell inaktiven, verkürzten TrkB- Rezeptors (TrkBtrunc) eine signifikant bessere 5-Jahres-Überlebensrate als Patienten mit niedriger Expression von TrkBtrunc (100 % versus 68 %, p=0,003). Das relative Risiko für TrkBfull-Expression blieb signifikant erhöht nach Korrektur für das Tumorstadium. Alle WT mit hoher TrkB-Expression exprimierten auch den spezifischen Liganden Brain-Derived Neurotrophic Factor (BDNF). Schlussfolgerungen: TrkBfull und TrkBtrunc sind wichtige biologische Prognosefaktoren für WT. Ihre Expression sollte prospektiv in größeren Studien erfasst werden und könnte zukünftig eine Rolle bei der risikoadaptierten Stratifikation von WT-Patienten spielen. Die negativen Effekte der TrkB-Signale könnten in WT mit günstigem Verlauf durch eine geringe Anzahl von funktionsfähigen TrkB-Rezeptoren oder einen kompetitiven Effekt des funktionell inaktiven TrkBtrunc-Rezeptors reduziert sein.

Background: The neurotrophin-receptor TrkB plays an important role in pathogenesis, biology and prognosis of neuroblastoma. Expression of TrkB on aggressive neuroblastomas leads to proliferation and survival of the tumor cells and is associated with an unfavorable prognosis. It is now known that Trk receptors are also expressed in extraneural tissues including the kidney. Patients and Methods: To study the role of the neurotrophin-receptor TrkB in nephroblastoma/Wilms' Tumor (WT), we determined TrkB mRNA expression by semiquantitative duplex RT-PCR in 39 primary WT. Comparison of mRNA expression levels with clinical variables was performed using Cox regression analysis. Results: The 5-year overall survival was significantly worse for patients with tumors expressing high levels of a functional TrkB-receptor (TrkBfull) in comparison to patients with low levels of TrkBfull (70 % versus 100 %, p=0.005). Conversely, children with tumors expressing high mRNA levels of a functionally inactive truncated TrkB receptor (TrkBtrunc) had a significantly higher 5-year overall survival rate in comparison to patients with low levels of TrkBtrunc (100 % versus 68 %, p=0.003). The hazard ratios for TrkBfull and TrkBtrunc remained significant after adjusting for tumor stage. All WT with high levels of TrkB also expressed the ligand brain-derived neurotrophic factor (BDNF). Conclusions: Full-length and truncated TrkB appear to be important prognostic factors in WT. Their expression should be assessed prospectively in a larger panel of WT and may have a future role in patient assignment to risk-based treatment strategies. TrkB signaling may be reduced in WT with favorable outcome due to low numbers of TrkB receptors or a competitive effect of functionally inactive TrkBtrunc.

Nephroblastom - Wilms-Tumor - Trk-Rezeptoren - Neurotrophine

Nephroblastoma - Wilms' Tumor - Trk-receptors - Neurotrophins

Literatur

• 01 Nakagawara  A, Arima-Nakagawara  M, Scavarda  N J et al. Association between high levels of expression of the Trk gene and favorable outcome in human neuroblastomas.  N Engl J Med. 1993;  328 847-854
• 02 Nakagawara  A, Azar  C G, Scavarda  N J et al. Expression and function of Trk-B and BDNF in human neuroblastomas.  Mol Cell Biol. 1994;  14 759-767
• 03 Grotzer  M A, Janss  A J, Fung  K-M et al. TrkC expression predicts good clinical outcome in primitive neuroectodermal brain tumors.  J Clin Oncol. 2000;  18 1027-1035
• 04 Kaplan  D R, Miller  F D. Signal transduction by the neurotrophin receptors.  Curr Opin in Cell Biology. 1997;  9 213-221
• 05 Eggert  A, Ikegak  N, Liu  X-G, Brodeur  G M. Prognostic and biological role of neurotrophin-receptor TrkA and TrkB in neuroblastoma.  Klin Pädiatr. 2000;  212 200-205
• 06 Klein  R, Conway  D, Parada  L et al. The trkB tyrosine kinase gene codes for a second neurogenic receptor that lacks the catalytic kinase domain.  Cell. 1990;  61 647-656
• 07 Donovan  M J, Hempstead  B, Huber  L J et al. Identification of the neurotrophin receptors p75 and trk in a series of Wilms' Tumors.  Am J Pathol. 1994;  145 792-800
• 08 Thomson  T, Pellicer  A, Greene  L A. Functional receptors for nerve growth factor on Ewing's sarcoma and Wilms tumor cells.  J Cell Physiol. 1989;  141 60-64
• 09 Beckwith  J B, Palmer  N F. Histopathology and prognosis of Wilm's tumor: results from the First National Wilms Tumor Study.  Cancer. 1978;  41 1937-1948
• 10 Prowse  O A, Reddy  P P, Barrieras  D et al. Pediatric genitourinary tumors.  Current Opinion in Oncology. 1998;  10 253-260
• 11 Bonadio  J F, Storer  B, Norkool  P et al. Anaplastic Wilms' Tumor: clinical and pathological studies.  J Clin Oncol. 1985;  3 513
• 12 Green  D M, Breslow  N E, Beckwith  J B et al. Comparison between single dose and divided-dose administration of dactinomycin and doxorubicin for patients with Wilms' tumor: a report from the National Wilms' Tumor Study Group.  J Clin Oncol. 1998;  16 237-245
• 13 Green  D M, Breslow  N E, Beckwith  J B et al. Effect of duration of treatment on treatment outcome and cost of treatment for Wilms' tumor: a report from the National Wilms' Tumor Study Group.  J Clin Oncol. 1998;  16 3744-3751
• 14 Eggert  A, Brodeur  G M, Ikegaki  N. A relative quantitative RT-PCR protocol for TrkB expression in neuroblastoma using GAPD as an internal control.  Biotechniques. 2000;  28 681-691
• 15 Grundy  P E, Telzerow  P E, Breslow  N et al. Loss of heterozygosity for chromosomes 16q and 1p in Wilms' tumors predicts an adverse outcome.  Cancer Res. 1994;  54 2331-2333
• 16 Beckwith  J B, Zuppan  C E, Browning  N G et al. Histological analysis of aggressiveness and responsiveness in Wilms' tumor.  Med Ped Oncol. 1996;  27 442-447
• 17 Matsumoto  K, Wada  R K, Yamashiro  J M et al. Expression of brain-derived neurotrophic factor and p145TrkB affects survival, differentiation, and invasiveness of human neuroblastoma cells.  Cancer Res. 1995;  55 1798-1806
• 18 Middlemas  D S, Kihl  B K, Zhou  J et al. Brain-derived neurotrophic factor promotes survival and chemoprotection of human neuroblastoma cells.  J Biol Chem. 1999;  274 16451-16460
• 19 Scala  S, Wosikowski  K, Giannakakou  P et al. Brain-derived neurotrophic factor protects neuroblastoma cells from vinblastine toxicity.  Cancer Res. 1996;  56 3737-3742
• 20 Tessarollo  L, Tsoulfas  P, Martin-Zanca  D et al. TrkC, a receptor for neurotrophin-3, is widely expressed in the developing nervous system and in non-neuronal tissues.  Development. 1993;  118 463-475
• 21 Ueno  H, Colbert  H, Escobedo  J et al. Inhibition of PDGF B signal transduction by coexpression of a truncated receptor.  Science. 1991;  252 844-848
• 22 Durbeej  M, Soderstrom  S, Ebendal  T et al. Differential expression of neurotrophin receptors during renal development.  Development. 1993;  119 977-989