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1: Am J Pathol. 2006 May;168(5):1686-96.

Perinatal epidermal growth factor receptor blockade prevents peripheral nerve
disruption in a mouse model reminiscent of benign world health organization grade
I neurofibroma.

Wu J, Crimmins JT, Monk KR, Williams JP, Fitzgerald ME, Tedesco S, Ratner N.

Division of Experimental Hematology, Department of Pediatrics, Cincinnati
Children's Hospital, OH 45229-7013, USA.

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 (EGFR). 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 (IMC-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 neurotrophic factor,
monocyte chemoattractant protein-1, and transforming growth factor-beta1, 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 prolifera-tion in perinatal mutant
nerve, so CNPase-hEGFR Schwann cell numbers correlate with the cetuximab effect. 
A >250-fold enlarged population of EGFR(+)/p75(+) cells 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 neurofibroma formation.

PMID: 16651634 [PubMed - indexed for MEDLINE]

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