Perinatal epidermal growth factor receptor blockade prevents peripheral nerve disruption in a mouse model reminiscent of benign World Health Organization grade I neurofibroma

Jianqiang Wu, Jason T. Crimmins, Kelly Monk, Jon P. Williams, Maureen E. Fitzgerald, Susan Tedesco, Nancy Ratner

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Benign peripheral nerve tumors called neurofibromas are a major source of morbidity for patients with neurofibromatosis type 1. Some neurofibroma Schwann cells aberrantly express the epidermal growth factor receptor (MGFR). In a mouse model in which the CNPase promoter drives expression of human EGFR in Schwann cells, nerves develop hypertrophy, mast cell accumulation, collagen deposition, disruption of axon-glial interactions, characteristics of neurofibroma and are hypoalgesic. Administration of the EGFR antagonist cetuximab (EMC-C225) for 2 weeks beginning at birth in CNPase-hEGFR mice normalized all pathologies at 3 months of age as evaluated by hotplate testing or histology and by electron microscopy. Mast cell chemoattractants brain-derived neurotropbic factor, monocyte chemoattractant protein-1, and transforming growth factor-β1 which may account for mast cell accumulation and fibrosis, were reduced by cetuximab. Later treatment was much less effective. A birth to 2-week pulse of cetuximab blocked hEGFR phosphorylation and Schwann cell proliferation in perinatal mutant nerve, so CNPase-hEGFR Schwann cell numbers correlate with the cetuximab effect. A >250-fold enlarged population of EGFR+Vp75+ eels was detected in newborn Nf1+/- mouse nerves. These results suggest the existence of an EGFR+ cell enriched in the perinatal period capable of driving complex changes characteristic of neurofibroina formation.

Original languageEnglish (US)
Pages (from-to)1686-1696
Number of pages11
JournalAmerican Journal of Pathology
Volume168
Issue number5
DOIs
StatePublished - Jan 1 2006
Externally publishedYes

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Neurofibroma
2',3'-Cyclic-Nucleotide Phosphodiesterases
Peripheral Nerves
Epidermal Growth Factor Receptor
Schwann Cells
Mast Cells
Peripheral Nervous System Neoplasms
Parturition
Eels
Neurofibromatosis 1
Chemokine CCL2
Chemotactic Factors
Transforming Growth Factors
Neuroglia
Hypertrophy
Axons
Histology
Electron Microscopy
Fibrosis
Collagen

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Perinatal epidermal growth factor receptor blockade prevents peripheral nerve disruption in a mouse model reminiscent of benign World Health Organization grade I neurofibroma. / Wu, Jianqiang; Crimmins, Jason T.; Monk, Kelly; Williams, Jon P.; Fitzgerald, Maureen E.; Tedesco, Susan; Ratner, Nancy.

In: American Journal of Pathology, Vol. 168, No. 5, 01.01.2006, p. 1686-1696.

Research output: Contribution to journalArticle

Wu, Jianqiang ; Crimmins, Jason T. ; Monk, Kelly ; Williams, Jon P. ; Fitzgerald, Maureen E. ; Tedesco, Susan ; Ratner, Nancy. / Perinatal epidermal growth factor receptor blockade prevents peripheral nerve disruption in a mouse model reminiscent of benign World Health Organization grade I neurofibroma. In: American Journal of Pathology. 2006 ; Vol. 168, No. 5. pp. 1686-1696.
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