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 R. Monk^*, Jon P. Williams^*, Maureen E. Fitzgerald, Susan Tedesco and Nancy Ratner^*

From the Division of Experimental Hematology, Department of Pediatrics,^* Cincinnati Children’s Hospital, and the Departments of Cell Biology, Neurobiology, and Anatomy, and Anesthesia, University of Cincinnati College of Medicine, Cincinnati, Ohio

Benign peripheral nerve tumors called neurofibromas are a majorsource of morbidity for patients with neurofibromatosis type1. Some neurofibroma Schwann cells aberrantly express the epidermalgrowth factor receptor (EGFR). In a mouse model in which theCNPase promoter drives expression of human EGFR in Schwann cells,nerves develop hypertrophy, mast cell accumulation, collagendeposition, disruption of axon-glial interactions, characteristicsof neurofibroma and are hypoalgesic. Administration of the EGFRantagonist cetuximab (IMC-C225) for 2 weeks beginning at birthin CNPase-hEGFR mice normalized all pathologies at 3 monthsof age as evaluated by hotplate testing or histology and byelectron microscopy. Mast cell chemoattractants brain-derivedneurotrophic factor, monocyte chemoattractant protein-1, andtransforming growth factor-ß1, which may account formast cell accumulation and fibrosis, were reduced by cetuximab.Later treatment was much less effective. A birth to 2-week pulseof cetuximab blocked hEGFR phosphorylation and Schwann cellprolifera-tion in perinatal mutant nerve, so CNPase-hEGFR Schwanncell numbers correlate with the cetuximab effect. A >250-foldenlarged population of EGFR⁺/p75⁺ cells was detected in newbornNf1^+/– mouse nerves. These results suggest the existenceof an EGFR⁺ cell enriched in the perinatal period capable ofdriving complex changes characteristic of neurofibroma formation.