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.

Resection of Plexiform Neurofibromas in Children With Neurofibromatosis Type 1

“…Moreover, PNF are associated with a significant increase in vascularity, which in turn could enhance the excessive development of body segments involved. 19,20 The main goal of surgical resection of those lesions is to restore function, relieve pain, and improve cosmesis.…”

Neurofibromatosis with unilateral lower limb gigantism

“…There are numerous hypotheses that attempt to explain the abnormal growth of body segments associated with the disease, particularly in the presence of plexiform neurofibromas. Receptors of several hormones and growth factors, including GH and EGF, have been discovered in these neoplasms [7,10]. These could influence the growth and possibly the malignant degeneration of neurofibromas [7,10], but it is not clear how neurofibromas may exert a direct paracrine effect on the surrounding tissues.…”

“…Receptors of several hormones and growth factors, including GH and EGF, have been discovered in these neoplasms [7,10]. These could influence the growth and possibly the malignant degeneration of neurofibromas [7,10], but it is not clear how neurofibromas may exert a direct paracrine effect on the surrounding tissues. Plexiform neurofibromas are associated with a significant increase in vascularity [8], which in turn could enhance the excessive development of body segments involved as in the case here described.…”

“…In one pediatric series, complete resections were followed by recurrence in 20% of cases, and incomplete resections relapsed in up to 45% [8]. Other therapeutic modalities, including antihistamines, differentiating or anti-angiogenic drugs, anti-cancer agents, or radiation therapy were ineffective [7]. We present the case of a 3-year-male child, suffering from genetically documented NF1, who presented with a lower limb discrepancy of about 5 cm (Fig.…”

“…In spite of their presence in large numbers, localized neurofibromas rarely, if ever, become malignant [5]. The lifetime risk for NF1 patients of developing a malignant peripheral nerve sheath tumor, mainly from within plexiform neurofibromas, is 8-13% [6,7]. Cutaneous neurofibromas arise in close association with small nerve branches, whereas diffuse plexiform neurofibromas often extend deeply along nerves and involve all levels of skin, fascia, muscle, bone, and even viscera.…”