title: Perinatal epidermal growth factor receptor blockade prevents peripheral nerve disruption in a mouse model reminiscent of benign world health organization grade I neurofibroma.
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 (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.
authors.affiliation: Division of Experimental Hematology, Department of Pediatrics, Cincinnati Children's Hospital, OH 45229-7013, USA.
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Wu
authors.forename: Jason T
authors.initials: JT
authors.lastname: Crimmins
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Monk
authors.forename: Jon P
authors.initials: JP
authors.lastname: Williams
authors.forename: Maureen E
authors.initials: ME
authors.lastname: Fitzgerald
authors.forename: Susan
authors.initials: S
authors.lastname: Tedesco
authors.forename: Nancy
authors.initials: N
authors.lastname: Ratner
mesh_terms: D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001369:Axons / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab; D002630:Chemotactic Factors / Q000378:metabolism; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000378:metabolism*; D051525:Fibroblast Growth Factor 9 / Q000502:physiology; D008407:Mast Cells / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009367:Neoplasm Staging; D009455:Neurofibroma / Q000473:pathology* / Q000628:therapy*; D025542:Neurofibromin 1 / Q000235:genetics; D016761:Oncogene Proteins v-fos / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012583:Schwann Cells / Q000378:metabolism / Q000502:physiology*; D014944:World Health Organization
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D002630:Chemotactic Factors; D051525:Fibroblast Growth Factor 9; D025542:Neurofibromin 1; D016761:Oncogene Proteins v-fos; D066246:ErbB Receptors; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D000068818:Cetuximab