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. 1996 Sep;74(5):773–779. doi: 10.1038/bjc.1996.435

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

M Rydén 1, R Sehgal 1, C Dominici 1, F H Schilling 1, C F Ibáñez 1, P Kogner 1
PMCID: PMC2074710  PMID: 8795581

Abstract

Childhood neuroblastoma tumours of the sympathetic nervous system show a remarkable clinical heterogeneity ranging from spontaneous regression to unfavourable outcome despite intensive therapy. Favourable neuroblastomas often express high levels of trkA mRNA, encoding the tyrosine kinase receptor for nerve growth factor. We have investigated mRNA expression for the neurotrophin receptor trkC in 23 primary neuroblastomas using a sensitive RNAase protection assay. TrkC expression was detected in 19 of these tumours at highly variable levels with a 300-fold difference between the highest and lowest values. Significantly higher levels of trkC mRNA were found in tumours from patients with favourable features such as low age (P < 0.012), favourable tumour stage (P < 0.012) and favourable prognosis (P < 0.05). Children with intermediate or high trkC mRNA expression had better prognosis compared with those with low or undetectable levels (83.3% vs 20%, P = 0.005). Further characterisation of trkC mRNA expression by reverse transcriptase-polymerase chain reaction (RT-PCR) showed that mRNA encoding the full-length cytoplasmic tyrosine kinase domain of the receptor was only expressed in a subset of favourable tumours. These data show that favourable neuroblastomas may express the full trkC receptor while advanced tumours, in particular MYCN-amplified neuroblastoma, seem to either express no trkC or truncated trkC receptors of as yet unknown biological function. These data are suggestive of a role for trkC and its preferred ligand neutotrophin-3, NT-3, in neuroblastoma differentiation and/or regression.

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Selected References

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  1. Ambros I. M., Ambros P. F. Schwann cells in neuroblastoma. Eur J Cancer. 1995;31A(4):429–434. doi: 10.1016/0959-8049(95)00051-j. [DOI] [PubMed] [Google Scholar]
  2. Barde Y. A., Edgar D., Thoenen H. Purification of a new neurotrophic factor from mammalian brain. EMBO J. 1982;1(5):549–553. doi: 10.1002/j.1460-2075.1982.tb01207.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bjelfman C., Hedborg F., Johansson I., Nordenskjöld M., Påhlman S. Expression of the neuronal form of pp60c-src in neuroblastoma in relation to clinical stage and prognosis. Cancer Res. 1990 Nov 1;50(21):6908–6914. [PubMed] [Google Scholar]
  4. Borrello M. G., Bongarzone I., Pierotti M. A., Luksch R., Gasparini M., Collini P., Pilotti S., Rizzetti M. G., Mondellini P., De Bernardi B. trk and ret proto-oncogene expression in human neuroblastoma specimens: high frequency of trk expression in non-advanced stages. Int J Cancer. 1993 Jun 19;54(4):540–545. doi: 10.1002/ijc.2910540404. [DOI] [PubMed] [Google Scholar]
  5. Brodeur G. M., Seeger R. C., Schwab M., Varmus H. E., Bishop J. M. Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. Science. 1984 Jun 8;224(4653):1121–1124. doi: 10.1126/science.6719137. [DOI] [PubMed] [Google Scholar]
  6. Brodeur G. M., Sekhon G., Goldstein M. N. Chromosomal aberrations in human neuroblastomas. Cancer. 1977 Nov;40(5):2256–2263. doi: 10.1002/1097-0142(197711)40:5<2256::aid-cncr2820400536>3.0.co;2-1. [DOI] [PubMed] [Google Scholar]
  7. Caron H., Peter M., van Sluis P., Speleman F., de Kraker J., Laureys G., Michon J., Brugières L., Voûte P. A., Westerveld A. Evidence for two tumour suppressor loci on chromosomal bands 1p35-36 involved in neuroblastoma: one probably imprinted, another associated with N-myc amplification. Hum Mol Genet. 1995 Apr;4(4):535–539. doi: 10.1093/hmg/4.4.535. [DOI] [PubMed] [Google Scholar]
  8. Chao M. V., Hempstead B. L. p75 and Trk: a two-receptor system. Trends Neurosci. 1995 Jul;18(7):321–326. [PubMed] [Google Scholar]
  9. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  10. Ernfors P., Lee K. F., Kucera J., Jaenisch R. Lack of neurotrophin-3 leads to deficiencies in the peripheral nervous system and loss of limb proprioceptive afferents. Cell. 1994 May 20;77(4):503–512. doi: 10.1016/0092-8674(94)90213-5. [DOI] [PubMed] [Google Scholar]
  11. Glass D. J., Nye S. H., Hantzopoulos P., Macchi M. J., Squinto S. P., Goldfarb M., Yancopoulos G. D. TrkB mediates BDNF/NT-3-dependent survival and proliferation in fibroblasts lacking the low affinity NGF receptor. Cell. 1991 Jul 26;66(2):405–413. doi: 10.1016/0092-8674(91)90629-d. [DOI] [PubMed] [Google Scholar]
  12. Hoehner J. C., Olsen L., Sandstedt B., Kaplan D. R., Påhlman S. Association of neurotrophin receptor expression and differentiation in human neuroblastoma. Am J Pathol. 1995 Jul;147(1):102–113. [PMC free article] [PubMed] [Google Scholar]
  13. Ibáez C. F. Neurotrophic factors: from structure-function studies to designing effective therapeutics. Trends Biotechnol. 1995 Jun;13(6):217–227. doi: 10.1016/S0167-7799(00)88949-0. [DOI] [PubMed] [Google Scholar]
  14. Kaplan D. R., Matsumoto K., Lucarelli E., Thiele C. J. Induction of TrkB by retinoic acid mediates biologic responsiveness to BDNF and differentiation of human neuroblastoma cells. Eukaryotic Signal Transduction Group. Neuron. 1993 Aug;11(2):321–331. doi: 10.1016/0896-6273(93)90187-v. [DOI] [PubMed] [Google Scholar]
  15. Klein R., Conway D., Parada L. F., Barbacid M. The trkB tyrosine protein kinase gene codes for a second neurogenic receptor that lacks the catalytic kinase domain. Cell. 1990 May 18;61(4):647–656. doi: 10.1016/0092-8674(90)90476-u. [DOI] [PubMed] [Google Scholar]
  16. Klein R., Nanduri V., Jing S. A., Lamballe F., Tapley P., Bryant S., Cordon-Cardo C., Jones K. R., Reichardt L. F., Barbacid M. The trkB tyrosine protein kinase is a receptor for brain-derived neurotrophic factor and neurotrophin-3. Cell. 1991 Jul 26;66(2):395–403. doi: 10.1016/0092-8674(91)90628-c. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kogner P., Barbany G., Björk O., Castello M. A., Donfrancesco A., Falkmer U. G., Hedborg F., Kouvidou H., Persson H., Raschella G. Trk mRNA and low affinity nerve growth factor receptor mRNA expression and triploid DNA content in favorable neuroblastoma tumors. Prog Clin Biol Res. 1994;385:137–145. [PubMed] [Google Scholar]
  18. Kogner P., Barbany G., Dominici C., Castello M. A., Raschellá G., Persson H. Coexpression of messenger RNA for TRK protooncogene and low affinity nerve growth factor receptor in neuroblastoma with favorable prognosis. Cancer Res. 1993 May 1;53(9):2044–2050. [PubMed] [Google Scholar]
  19. Kogner P., Björk O., Theodorsson E. Neuropeptide Y as a marker in pediatric neuroblastoma. Pediatr Pathol. 1990;10(1-2):207–216. doi: 10.3109/15513819009067108. [DOI] [PubMed] [Google Scholar]
  20. Lamballe F., Klein R., Barbacid M. trkC, a new member of the trk family of tyrosine protein kinases, is a receptor for neurotrophin-3. Cell. 1991 Sep 6;66(5):967–979. doi: 10.1016/0092-8674(91)90442-2. [DOI] [PubMed] [Google Scholar]
  21. Leibrock J., Lottspeich F., Hohn A., Hofer M., Hengerer B., Masiakowski P., Thoenen H., Barde Y. A. Molecular cloning and expression of brain-derived neurotrophic factor. Nature. 1989 Sep 14;341(6238):149–152. doi: 10.1038/341149a0. [DOI] [PubMed] [Google Scholar]
  22. Martin-Zanca D., Oskam R., Mitra G., Copeland T., Barbacid M. Molecular and biochemical characterization of the human trk proto-oncogene. Mol Cell Biol. 1989 Jan;9(1):24–33. doi: 10.1128/mcb.9.1.24. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Martinsson T., Sjöberg R. M., Hedborg F., Kogner P. Deletion of chromosome 1p loci and microsatellite instability in neuroblastomas analyzed with short-tandem repeat polymorphisms. Cancer Res. 1995 Dec 1;55(23):5681–5686. [PubMed] [Google Scholar]
  24. Matsumoto K., Wada R. K., Yamashiro J. M., Kaplan D. R., Thiele C. J. Expression of brain-derived neurotrophic factor and p145TrkB affects survival, differentiation, and invasiveness of human neuroblastoma cells. Cancer Res. 1995 Apr 15;55(8):1798–1806. [PubMed] [Google Scholar]
  25. Matsushima H., Bogenmann E. Expression of trkA cDNA in neuroblastomas mediates differentiation in vitro and in vivo. Mol Cell Biol. 1993 Dec;13(12):7447–7456. doi: 10.1128/mcb.13.12.7447. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Middlemas D. S., Lindberg R. A., Hunter T. trkB, a neural receptor protein-tyrosine kinase: evidence for a full-length and two truncated receptors. Mol Cell Biol. 1991 Jan;11(1):143–153. doi: 10.1128/mcb.11.1.143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Nakagawara A., Arima-Nakagawara M., Scavarda N. J., Azar C. G., Cantor A. B., Brodeur G. M. Association between high levels of expression of the TRK gene and favorable outcome in human neuroblastoma. N Engl J Med. 1993 Mar 25;328(12):847–854. doi: 10.1056/NEJM199303253281205. [DOI] [PubMed] [Google Scholar]
  28. Nakagawara A., Azar C. G., Scavarda N. J., Brodeur G. M. Expression and function of TRK-B and BDNF in human neuroblastomas. Mol Cell Biol. 1994 Jan;14(1):759–767. doi: 10.1128/mcb.14.1.759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Poluha W., Poluha D. K., Ross A. H. TrkA neurogenic receptor regulates differentiation of neuroblastoma cells. Oncogene. 1995 Jan 5;10(1):185–189. [PubMed] [Google Scholar]
  30. Schwab M., Alitalo K., Klempnauer K. H., Varmus H. E., Bishop J. M., Gilbert F., Brodeur G., Goldstein M., Trent J. Amplified DNA with limited homology to myc cellular oncogene is shared by human neuroblastoma cell lines and a neuroblastoma tumour. Nature. 1983 Sep 15;305(5931):245–248. doi: 10.1038/305245a0. [DOI] [PubMed] [Google Scholar]
  31. Seeger R. C., Brodeur G. M., Sather H., Dalton A., Siegel S. E., Wong K. Y., Hammond D. Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. N Engl J Med. 1985 Oct 31;313(18):1111–1116. doi: 10.1056/NEJM198510313131802. [DOI] [PubMed] [Google Scholar]
  32. Segal R. A., Goumnerova L. C., Kwon Y. K., Stiles C. D., Pomeroy S. L. Expression of the neurotrophin receptor TrkC is linked to a favorable outcome in medulloblastoma. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12867–12871. doi: 10.1073/pnas.91.26.12867. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Shelton D. L., Sutherland J., Gripp J., Camerato T., Armanini M. P., Phillips H. S., Carroll K., Spencer S. D., Levinson A. D. Human trks: molecular cloning, tissue distribution, and expression of extracellular domain immunoadhesins. J Neurosci. 1995 Jan;15(1 Pt 2):477–491. doi: 10.1523/JNEUROSCI.15-01-00477.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Suzuki T., Bogenmann E., Shimada H., Stram D., Seeger R. C. Lack of high-affinity nerve growth factor receptors in aggressive neuroblastomas. J Natl Cancer Inst. 1993 Mar 3;85(5):377–384. doi: 10.1093/jnci/85.5.377. [DOI] [PubMed] [Google Scholar]
  35. Tanaka T., Slamon D. J., Shimada H., Shimoda H., Fujisawa T., Ida N., Seeger R. C. A significant association of Ha-ras p21 in neuroblastoma cells with patient prognosis. A retrospective study of 103 cases. Cancer. 1991 Sep 15;68(6):1296–1302. doi: 10.1002/1097-0142(19910915)68:6<1296::aid-cncr2820680619>3.0.co;2-z. [DOI] [PubMed] [Google Scholar]
  36. Trupp M., Rydén M., Jörnvall H., Funakoshi H., Timmusk T., Arenas E., Ibáez C. F. Peripheral expression and biological activities of GDNF, a new neurotrophic factor for avian and mammalian peripheral neurons. J Cell Biol. 1995 Jul;130(1):137–148. doi: 10.1083/jcb.130.1.137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Tsoulfas P., Soppet D., Escandon E., Tessarollo L., Mendoza-Ramirez J. L., Rosenthal A., Nikolics K., Parada L. F. The rat trkC locus encodes multiple neurogenic receptors that exhibit differential response to neurotrophin-3 in PC12 cells. Neuron. 1993 May;10(5):975–990. doi: 10.1016/0896-6273(93)90212-a. [DOI] [PubMed] [Google Scholar]
  38. Valenzuela D. M., Maisonpierre P. C., Glass D. J., Rojas E., Nuñez L., Kong Y., Gies D. R., Stitt T. N., Ip N. Y., Yancopoulos G. D. Alternative forms of rat TrkC with different functional capabilities. Neuron. 1993 May;10(5):963–974. doi: 10.1016/0896-6273(93)90211-9. [DOI] [PubMed] [Google Scholar]
  39. White P. S., Maris J. M., Beltinger C., Sulman E., Marshall H. N., Fujimori M., Kaufman B. A., Biegel J. A., Allen C., Hilliard C. A region of consistent deletion in neuroblastoma maps within human chromosome 1p36.2-36.3. Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5520–5524. doi: 10.1073/pnas.92.12.5520. [DOI] [PMC free article] [PubMed] [Google Scholar]

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