TY - JOUR
T1 - Perinatal epidermal growth factor receptor blockade prevents peripheral nerve disruption in a mouse model reminiscent of benign World Health Organization grade I neurofibroma
AU - Wu, Jianqiang
AU - Crimmins, Jason T.
AU - Monk, Kelly R.
AU - Williams, Jon P.
AU - Fitzgerald, Maureen E.
AU - Tedesco, Susan
AU - Ratner, Nancy
N1 - Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2006/5
Y1 - 2006/5
N2 - 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.
AB - 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.
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U2 - 10.2353/ajpath.2006.050859
DO - 10.2353/ajpath.2006.050859
M3 - Article
C2 - 16651634
AN - SCOPUS:33646522740
SN - 0002-9440
VL - 168
SP - 1686
EP - 1696
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 5
ER -