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PMID: 15652750 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

Role for the epidermal growth factor receptor in neurofibromatosis-related peripheral nerve tumorigenesis.

Cancer cell ·Vol. 7 ·No. 1 ·2005-01-00 ·Pages 65-75

Ling BC, Wu J, Miller SJ, Monk KR, Shamekh R, Rizvi TA, Decourten-Myers G, Vogel KS, DeClue JE, Ratner N

Abstract

Benign neurofibromas and malignant peripheral nerve sheath tumors are serious complications of neurofibromatosis type 1. The epidermal growth factor receptor is not expressed by normal Schwann cells, yet is overexpressed in subpopulations of Nf1 mutant Schwann cells. We evaluated the role of EGFR in Schwann cell tumorigenesis. Expression of EGFR in transgenic mouse Schwann cells elicited features of neurofibromas: Schwann cell hyperplasia, excess collagen, mast cell accumulation, and progressive dissociation of non-myelin-forming Schwann cells from axons. Mating EGFR transgenic mice to Nf1 hemizygotes did not enhance this phenotype. Genetic reduction of EGFR in Nf1(+/-);p53(+/-) mice that develop sarcomas significantly improved survival. Thus, gain- and loss-of-function experiments support the relevance of EGFR to peripheral nerve tumor formation.

MeSH Terms
2',3'-Cyclic-Nucleotide Phosphodiesterases/genetics,metabolism Animals Cells, Cultured ErbB Receptors/genetics,metabolism Fibrosis Humans Mast Cells/metabolism Mice Mice, Inbred C57BL Mice, Transgenic Neoplasms, Nerve Tissue/genetics,metabolism,pathology Neurofibroma/genetics,metabolism,pathology Neurofibromatosis 1/genetics,metabolism,pathology Neurofibromin 1/genetics,metabolism Peripheral Nerves/metabolism,pathology,ultrastructure Schwann Cells/cytology,physiology Signal Transduction/physiology Survival Rate Tumor Suppressor Protein p53/genetics,metabolism
Chemicals
Neurofibromin 1 Tumor Suppressor Protein p53 ErbB Receptors 2',3'-Cyclic-Nucleotide Phosphodiesterases
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Ling Benjamin C
Departments of Cell Biology, Neurobiology, and Anatomy, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
Wu Jianqiang
Miller Shyra J
Monk Kelly R
Shamekh Rania
Rizvi Tilat A
Decourten-Myers Gabrielle
Vogel Kristine S
DeClue Jeffrey E
Ratner Nancy
References (53)
53 references, click to expand
  1. Activation of neu by missense point mutation in the transmembrane domain in schwannomas induced in C3H/HeNCr mice by transplacental exposure to N-nitrosoethylurea.
    J Cancer Res Clin Oncol. 1999 Dec;125(12):653-9 PMID: 10592097
  2. Heterophilic binding of L1 on unmyelinated sensory axons mediates Schwann cell adhesion and is required for axonal survival.
    J Cell Biol. 1999 Sep 6;146(5):1173-84 PMID: 10477768
  3. Mouse tumor model for neurofibromatosis type 1.
    Science. 1999 Dec 10;286(5447):2176-9 PMID: 10591653
  4. Expression of p27(kip) and other cell cycle regulators in malignant peripheral nerve sheath tumors and neurofibromas: the emerging role of p27(kip) in malignant transformation of neurofibromas.
    Am J Pathol. 1999 Dec;155(6):1885-91 PMID: 10595919
  5. Epidermal growth factor receptor expression in neurofibromatosis type 1-related tumors and NF1 animal models.
    J Clin Invest. 2000 May;105(9):1233-41 PMID: 10791998
  6. The EGF receptor provides an essential survival signal for SOS-dependent skin tumor development.
    Cell. 2000 Jul 21;102(2):211-20 PMID: 10943841
  7. Nf1;Trp53 mutant mice develop glioblastoma with evidence of strain-specific effects.
    Nat Genet. 2000 Sep;26(1):109-13 PMID: 10973261
  8. Single cell Ras-GTP analysis reveals altered Ras activity in a subpopulation of neurofibroma Schwann cells but not fibroblasts.
    J Biol Chem. 2000 Sep 29;275(39):30740-5 PMID: 10900196
  9. Neuregulin, a factor with many functions in the life of a schwann cell.
    Bioessays. 2000 Nov;22(11):987-96 PMID: 11056475
  10. The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification.
    Endocr Relat Cancer. 2001 Mar;8(1):11-31 PMID: 11350724
  11. The human mast cell: functions in physiology and disease.
    Front Biosci. 2001 Sep 1;6:D1109-27 PMID: 11532608
  12. The EGFR family and its ligands in human cancer. signalling mechanisms and therapeutic opportunities.
    Eur J Cancer. 2001 Sep;37 Suppl 4:S3-8 PMID: 11597398
  13. Importance of epidermal growth factor receptor signaling in establishment of adenomas and maintenance of carcinomas during intestinal tumorigenesis.
    Proc Natl Acad Sci U S A. 2002 Feb 5;99(3):1521-6 PMID: 11818567
  14. ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial.
    J Clin Oncol. 2002 May 1;20(9):2240-50 PMID: 11980995
  15. Neurofibromas in NF1: Schwann cell origin and role of tumor environment.
    Science. 2002 May 3;296(5569):920-2 PMID: 11988578
  16. Malignant peripheral nerve sheath tumours in neurofibromatosis 1.
    J Med Genet. 2002 May;39(5):311-4 PMID: 12011145
  17. Differential NF1, p16, and EGFR patterns by interphase cytogenetics (FISH) in malignant peripheral nerve sheath tumor (MPNST) and morphologically similar spindle cell neoplasms.
    J Neuropathol Exp Neurol. 2002 Aug;61(8):702-9 PMID: 12152785
  18. Epidermal growth factor receptor signaling pathways are associated with tumorigenesis in the Nf1:p53 mouse tumor model.
    Cancer Res. 2002 Aug 1;62(15):4507-13 PMID: 12154062
  19. Nf1 has an essential role in endothelial cells.
    Nat Genet. 2003 Jan;33(1):75-9 PMID: 12469121
  20. Brain lipid binding protein in axon-Schwann cell interactions and peripheral nerve tumorigenesis.
    Mol Cell Biol. 2003 Mar;23(6):2213-24 PMID: 12612091
  21. Hypertrophic neuropathies and malignant peripheral nerve sheath tumors in transgenic mice overexpressing glial growth factor beta3 in myelinating Schwann cells.
    J Neurosci. 2003 Aug 13;23(19):7269-80 PMID: 12917360
  22. Disruption of ErbB receptor signaling in adult non-myelinating Schwann cells causes progressive sensory loss.
    Nat Neurosci. 2003 Nov;6(11):1186-93 PMID: 14555954
  23. Neurofibromin-deficient Schwann cells secrete a potent migratory stimulus for Nf1+/- mast cells.
    J Clin Invest. 2003 Dec;112(12):1851-61 PMID: 14679180
  24. Protein kinase inhibitors: insights into drug design from structure.
    Science. 2004 Mar 19;303(5665):1800-5 PMID: 15031492
  25. Comparative pathology of nerve sheath tumors in mouse models and humans.
    Cancer Res. 2004 May 15;64(10):3718-24 PMID: 15150133
  26. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer.
    N Engl J Med. 2004 Jul 22;351(4):337-45 PMID: 15269313
  27. Transplacental and neonatal induction of neurogenic tumors in mice: comparison with related species and with human pediatric neoplasms.
    Natl Cancer Inst Monogr. 1979 May;(51):219-26 PMID: 384262
  28. The activity of 2',3'-cyclic nucleotide 3'-phosphodiesterase in rat tissues.
    J Neurochem. 1981 Sep;37(3):677-80 PMID: 6268752
  29. Schwann cell proliferation in the postnatal mouse: timing and topography.
    Exp Neurol. 1981 Oct;74(1):170-86 PMID: 7286116
  30. Epidermal-growth-factor-dependent transformation by a human EGF receptor proto-oncogene.
    Science. 1987 Dec 4;238(4832):1408-10 PMID: 3500513
  31. Mast cell and lymphoreticular infiltrates in neurofibromas. Comparison with nerve sheath tumors.
    Arch Pathol Lab Med. 1989 Nov;113(11):1263-70 PMID: 2479359
  32. The neurofibromatosis type 1 gene encodes a protein related to GAP.
    Cell. 1990 Aug 10;62(3):599-608 PMID: 2116237
  33. Angiogenic and invasive properties of neurofibroma Schwann cells.
    J Cell Biol. 1990 Aug;111(2):645-53 PMID: 1696266
  34. S100 is preferentially distributed in myelin-forming Schwann cells.
    J Neurocytol. 1990 Jun;19(3):432-42 PMID: 2391542
  35. Three markers of adult non-myelin-forming Schwann cells, 217c(Ran-1), A5E3 and GFAP: development and regulation by neuron-Schwann cell interactions.
    Development. 1990 May;109(1):91-103 PMID: 2209471
  36. A de novo Alu insertion results in neurofibromatosis type 1.
    Nature. 1991 Oct 31;353(6347):864-6 PMID: 1719426
  37. Somatic deletion of the neurofibromatosis type 1 gene in a neurofibrosarcoma supports a tumour suppressor gene hypothesis.
    Nat Genet. 1993 Feb;3(2):122-6 PMID: 8499945
  38. The mouse waved-2 phenotype results from a point mutation in the EGF receptor tyrosine kinase.
    Genes Dev. 1994 Feb 15;8(4):399-413 PMID: 8125255
  39. Tumour predisposition in mice heterozygous for a targeted mutation in Nf1.
    Nat Genet. 1994 Jul;7(3):353-61 PMID: 7920653
  40. Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues.
    Genes Dev. 1994 May 1;8(9):1019-29 PMID: 7926784
  41. The influence of heregulins on human Schwann cell proliferation.
    J Neurosci. 1995 Feb;15(2):1329-40 PMID: 7869101
  42. Axon-induced mitogenesis of human Schwann cells involves heregulin and p185erbB2.
    Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1431-5 PMID: 7877996
  43. Schwann cells from neurofibromin deficient mice exhibit activation of p21ras, inhibition of cell proliferation and morphological changes.
    Oncogene. 1995 Jul 20;11(2):325-35 PMID: 7624147
  44. Structural analysis of p185c-neu and epidermal growth factor receptor tyrosine kinases: oligomerization of kinase domains.
    Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6252-7 PMID: 8692801
  45. Identification of NF1 mutations in both alleles of a dermal neurofibroma.
    Nat Genet. 1996 Sep;14(1):110-2 PMID: 8782831
  46. Axonal interactions regulate Schwann cell apoptosis in developing peripheral nerve: neuregulin receptors and the role of neuregulins.
    J Neurosci. 1996 Oct 1;16(19):6107-18 PMID: 8815893
  47. Type 1 neurofibromatosis: a descriptive analysis of the disorder in 1,728 patients.
    Am J Med Genet. 1997 May 16;70(2):138-43 PMID: 9128932
  48. Confirmation of a double-hit model for the NF1 gene in benign neurofibromas.
    Am J Hum Genet. 1997 Sep;61(3):512-9 PMID: 9326316
  49. Four-kilobase sequence of the mouse CNP gene directs spatial and temporal expression of lacZ in transgenic mice.
    J Neurosci Res. 1998 Aug 15;53(4):393-404 PMID: 9710259
  50. Expression of Kit in neurofibromin-deficient human Schwann cells: role in Schwann cell hyperplasia associated with type 1 neurofibromatosis.
    Oncogene. 1998 Aug 13;17(6):795-800 PMID: 9715282
  51. Identification and characterization of early glial progenitors using a transgenic selection strategy.
    J Neurosci. 1999 Jan 15;19(2):759-74 PMID: 9880596
  52. Neurofibromatosis type 1 peripheral nerve tumors: aberrant activation of the Ras pathway.
    Surg Neurol. 1999 Feb;51(2):211-8 PMID: 10029430
  53. Mouse models of tumor development in neurofibromatosis type 1.
    Science. 1999 Dec 10;286(5447):2172-6 PMID: 10591652
Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1535-6108
DOI
10.1016/j.ccr.2004.10.016
Published
2005-01-00
Pages
65-75
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC2854500
Subset
IM
Grants
NINDS NIH HHS · R01 NS028840 · United States
NINDS NIH HHS · R01 NS028840-09 · United States
NCI NIH HHS · T32 CA059268 · United States
NINDS NIH HHS · NS28840 · United States
External Links
PubMed source DOI: 10.1016/j.ccr.2004.10.016 PMC Full Text View journal details
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