Abstract
Medulloblastoma, the most common malignant brain tumor of childhood, has a variable prognosis. Although half of the children and young adults with the disease survive longer than 10 years after diagnosis, the others relapse and die despite identical therapy. We have examined the expression of neurotrophins and their receptors in medulloblastoma samples snap frozen in the operating room to preserve RNA integrity. All tumors (n = 12) were found to express mRNA encoding neurotrophin 3 and its receptor TrkC. The level of trkC expression was highly variable, with a more than 50-fold difference between the highest and lowest values. By Kaplan-Meier analysis, patients with tumors expressing high levels of trkC mRNA had significantly longer intervals without disease progression than those with low levels (log-rank, P = 0.03) and a more favorable overall survival (log-rank, P = 0.05). Thus, trkC expression is a prognostic indicator for patients with medulloblastoma.
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- 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]
- Bartel D. P., Sheng M., Lau L. F., Greenberg M. E. Growth factors and membrane depolarization activate distinct programs of early response gene expression: dissociation of fos and jun induction. Genes Dev. 1989 Mar;3(3):304–313. doi: 10.1101/gad.3.3.304. [DOI] [PubMed] [Google Scholar]
- Berkemeier L. R., Winslow J. W., Kaplan D. R., Nikolics K., Goeddel D. V., Rosenthal A. Neurotrophin-5: a novel neurotrophic factor that activates trk and trkB. Neuron. 1991 Nov;7(5):857–866. doi: 10.1016/0896-6273(91)90287-a. [DOI] [PubMed] [Google Scholar]
- DiCicco-Bloom E., Friedman W. J., Black I. B. NT-3 stimulates sympathetic neuroblast proliferation by promoting precursor survival. Neuron. 1993 Dec;11(6):1101–1111. doi: 10.1016/0896-6273(93)90223-e. [DOI] [PubMed] [Google Scholar]
- Druker B. J., Mamon H. J., Roberts T. M. Oncogenes, growth factors, and signal transduction. N Engl J Med. 1989 Nov 16;321(20):1383–1391. doi: 10.1056/NEJM198911163212007. [DOI] [PubMed] [Google Scholar]
- Ernfors P., Ibáez C. F., Ebendal T., Olson L., Persson H. Molecular cloning and neurotrophic activities of a protein with structural similarities to nerve growth factor: developmental and topographical expression in the brain. Proc Natl Acad Sci U S A. 1990 Jul;87(14):5454–5458. doi: 10.1073/pnas.87.14.5454. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gibbs J. B. Ras C-terminal processing enzymes--new drug targets? Cell. 1991 Apr 5;65(1):1–4. doi: 10.1016/0092-8674(91)90352-y. [DOI] [PubMed] [Google Scholar]
- 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]
- Hempstead B. L., Rabin S. J., Kaplan L., Reid S., Parada L. F., Kaplan D. R. Overexpression of the trk tyrosine kinase rapidly accelerates nerve growth factor-induced differentiation. Neuron. 1992 Nov;9(5):883–896. doi: 10.1016/0896-6273(92)90241-5. [DOI] [PubMed] [Google Scholar]
- Hermanson M., Funa K., Hartman M., Claesson-Welsh L., Heldin C. H., Westermark B., Nistér M. Platelet-derived growth factor and its receptors in human glioma tissue: expression of messenger RNA and protein suggests the presence of autocrine and paracrine loops. Cancer Res. 1992 Jun 1;52(11):3213–3219. [PubMed] [Google Scholar]
- Hohn A., Leibrock J., Bailey K., Barde Y. A. Identification and characterization of a novel member of the nerve growth factor/brain-derived neurotrophic factor family. Nature. 1990 Mar 22;344(6264):339–341. doi: 10.1038/344339a0. [DOI] [PubMed] [Google Scholar]
- Ip N. Y., Ibáez C. F., Nye S. H., McClain J., Jones P. F., Gies D. R., Belluscio L., Le Beau M. M., Espinosa R., 3rd, Squinto S. P. Mammalian neurotrophin-4: structure, chromosomal localization, tissue distribution, and receptor specificity. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):3060–3064. doi: 10.1073/pnas.89.7.3060. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Johnson D., Lanahan A., Buck C. R., Sehgal A., Morgan C., Mercer E., Bothwell M., Chao M. Expression and structure of the human NGF receptor. Cell. 1986 Nov 21;47(4):545–554. doi: 10.1016/0092-8674(86)90619-7. [DOI] [PubMed] [Google Scholar]
- Kadin M. E., Rubinstein L. J., Nelson J. S. Neonatal cerebellar medulloblastoma originating from the fetal external granular layer. J Neuropathol Exp Neurol. 1970 Oct;29(4):583–600. doi: 10.1097/00005072-197010000-00005. [DOI] [PubMed] [Google Scholar]
- Kalcheim C., Carmeli C., Rosenthal A. Neurotrophin 3 is a mitogen for cultured neural crest cells. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1661–1665. doi: 10.1073/pnas.89.5.1661. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kaplan D. R., Martin-Zanca D., Parada L. F. Tyrosine phosphorylation and tyrosine kinase activity of the trk proto-oncogene product induced by NGF. Nature. 1991 Mar 14;350(6314):158–160. doi: 10.1038/350158a0. [DOI] [PubMed] [Google Scholar]
- Keles G. E., Berger M. S., Schofield D., Bothwell M. Nerve growth factor receptor expression in medulloblastomas and the potential role of nerve growth factor as a differentiating agent in medulloblastoma cell lines. Neurosurgery. 1993 Feb;32(2):274–280. doi: 10.1227/00006123-199302000-00017. [DOI] [PubMed] [Google Scholar]
- Keles G. E., Berger M. S., Schofield D., Bothwell M. Nerve growth factor receptor expression in medulloblastomas and the potential role of nerve growth factor as a differentiating agent in medulloblastoma cell lines. Neurosurgery. 1993 Feb;32(2):274–280. doi: 10.1227/00006123-199302000-00017. [DOI] [PubMed] [Google Scholar]
- 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]
- Klein R., Jing S. Q., Nanduri V., O'Rourke E., Barbacid M. The trk proto-oncogene encodes a receptor for nerve growth factor. Cell. 1991 Apr 5;65(1):189–197. doi: 10.1016/0092-8674(91)90419-y. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- 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]
- Maisonpierre P. C., Belluscio L., Squinto S., Ip N. Y., Furth M. E., Lindsay R. M., Yancopoulos G. D. Neurotrophin-3: a neurotrophic factor related to NGF and BDNF. Science. 1990 Mar 23;247(4949 Pt 1):1446–1451. doi: 10.1126/science.247.4949.1446. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- Pleasure S. J., Reddy U. R., Venkatakrishnan G., Roy A. K., Chen J., Ross A. H., Trojanowski J. Q., Pleasure D. E., Lee V. M. Introduction of nerve growth factor (NGF) receptors into a medulloblastoma cell line results in expression of high- and low-affinity NGF receptors but not NGF-mediated differentiation. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8496–8500. doi: 10.1073/pnas.87.21.8496. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Radeke M. J., Misko T. P., Hsu C., Herzenberg L. A., Shooter E. M. Gene transfer and molecular cloning of the rat nerve growth factor receptor. Nature. 1987 Feb 12;325(6105):593–597. doi: 10.1038/325593a0. [DOI] [PubMed] [Google Scholar]
- Rodriguez-Tébar A., Dechant G., Barde Y. A. Binding of brain-derived neurotrophic factor to the nerve growth factor receptor. Neuron. 1990 Apr;4(4):487–492. doi: 10.1016/0896-6273(90)90107-q. [DOI] [PubMed] [Google Scholar]
- Rodríguez-Tébar A., Dechant G., Götz R., Barde Y. A. Binding of neurotrophin-3 to its neuronal receptors and interactions with nerve growth factor and brain-derived neurotrophic factor. EMBO J. 1992 Mar;11(3):917–922. doi: 10.1002/j.1460-2075.1992.tb05130.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rorke L. B. The cerebellar medulloblastoma and its relationship to primitive neuroectodermal tumors. J Neuropathol Exp Neurol. 1983 Jan;42(1):1–15. [PubMed] [Google Scholar]
- Rosenthal A., Goeddel D. V., Nguyen T., Lewis M., Shih A., Laramee G. R., Nikolics K., Winslow J. W. Primary structure and biological activity of a novel human neurotrophic factor. Neuron. 1990 May;4(5):767–773. doi: 10.1016/0896-6273(90)90203-r. [DOI] [PubMed] [Google Scholar]
- Segal R. A., Takahashi H., McKay R. D. Changes in neurotrophin responsiveness during the development of cerebellar granule neurons. Neuron. 1992 Dec;9(6):1041–1052. doi: 10.1016/0896-6273(92)90064-k. [DOI] [PubMed] [Google Scholar]
- Shamah S. M., Stiles C. D., Guha A. Dominant-negative mutants of platelet-derived growth factor revert the transformed phenotype of human astrocytoma cells. Mol Cell Biol. 1993 Dec;13(12):7203–7212. doi: 10.1128/mcb.13.12.7203. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Tessarollo L., Tsoulfas P., Martin-Zanca D., Gilbert D. J., Jenkins N. A., Copeland N. G., Parada L. F. trkC, a receptor for neurotrophin-3, is widely expressed in the developing nervous system and in non-neuronal tissues. Development. 1993 Jun;118(2):463–475. doi: 10.1242/dev.118.2.463. [DOI] [PubMed] [Google Scholar]
- Tohyama T., Lee V. M., Rorke L. B., Marvin M., McKay R. D., Trojanowski J. Q. Monoclonal antibodies to a rat nestin fusion protein recognize a 220-kDa polypeptide in subsets of fetal and adult human central nervous system neurons and in primitive neuroectodermal tumor cells. Am J Pathol. 1993 Jul;143(1):258–268. [PMC free article] [PubMed] [Google Scholar]
- Trojanowski J. Q., Tohyama T., Lee V. M. Medulloblastomas and related primitive neuroectodermal brain tumors of childhood recapitulate molecular milestones in the maturation of neuroblasts. Mol Chem Neuropathol. 1992 Oct;17(2):121–135. doi: 10.1007/BF03159987. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]