The evolution and multi-molecular properties of NF1 cutaneous neurofibromas originating from C-fiber sensory endings and terminal Schwann cells at normal sites of sensory terminations in the skin.

Frank L Rice,Marilyn Dockum,Michael P Jankowski,Steven L Carroll,Vincent M Riccardi,James R Storey,Sara J C Gosline,James P Wymer,Jianqiang Wu,Salvo La Rosa,George Houk,Phillip J Albrecht,Justin Guinney,Nancy Ratner,Claudia Sommer

doi:10.1371/journal.pone.0216527

Abstract

In addition to large plexiform neurofibromas (pNF), NF1 patients are frequently disfigured by cutaneous neurofibromas (cNF) and are often afflicted with chronic pain and itch even from seemingly normal skin areas. Both pNFs and cNF consist primarily of benign hyperproliferating nonmyelinating Schwann cells (nSC). While pNF clearly arise within deep nerves and plexuses, the role of cutaneous innervation in the origin of cNF and in chronic itch and pain is unknown. First, we conducted a comprehensive, multi-molecular, immunofluorescence (IF) analyses on 3mm punch biopsies from three separate locations in normal appearing, cNF-free skin in 19 NF1 patients and skin of 16 normal subjects. At least one biopsy in 17 NF1 patients had previously undescribed micro-lesions consisting of a small, dense cluster of nonpeptidergic C-fiber endings and the affiliated nSC consistently adjoining adnexal structures—dermal papillae, hair follicles, sweat glands, sweat ducts, and arterioles—where C-fiber endings normally terminate. Similar micro-lesions were detected in hind paw skin of mice with conditionally-induced SC Nf1-/- mutations. Hypothesizing that these microlesions were pre-cNF origins of cNF, we subsequently analyzed numerous overt, small cNF (s-cNF, 3–6 mm) and discovered that each had an adnexal structure at the epicenter of vastly increased nonpeptidergic C-fiber terminals, accompanied by excessive nSC. The IF and functional genomics assays indicated that neurturin (NTRN) and artemin (ARTN) signaling through cRET kinase and GFRα2 and GFRα3 co-receptors on the aberrant C-fiber endings and nSC may mutually promote the onset of pre-cNF and their evolution to s-cNF. Moreover, TrpA1 and TrpV1 receptors may, respectively, mediate symptoms of chronic itch and pain. These newly discovered molecular characteristics might be targeted to suppress the development of cNF and to treat chronic itch and pain symptoms in NF1 patients.

Highlights

Multiple cutaneous neurofibromas are characteristic of neurofibromatosis type 1 (NF1) patients who have an autosomal dominant loss-of-function mutation of an NF1 allele. cNF are visibly protruding masses in the skin composed of a complex mixture of hyperproliferating Schwann cells (SC), nonmyelinating SC, intermingled with fibroblasts, vasculature, macrophages, mast cells and other cellular components [1,2,3,4,5]
A total of 45 microlesions were detected among all the biopsies from NF1 patients, with some biopsies containing more than one microlesion, each involving its own adnexa (Fig 1)
Our results indicate that NTRN and ATRN signaling interactions between the C fiber terminals and their terminal SC, as well as autocrine/paracrine signaling among the SC, contribute to the initiation of precursors to cNF (pre-cNF) and subsequent evolution into overt cNF

Summary

Introduction

Multiple cutaneous neurofibromas (cNF) are characteristic of neurofibromatosis type 1 (NF1) patients who have an autosomal dominant loss-of-function mutation of an NF1 allele. cNF are visibly protruding masses in the skin composed of a complex mixture of hyperproliferating Schwann cells (SC), nonmyelinating SC (nSC), intermingled with fibroblasts, vasculature, macrophages, mast cells and other cellular components [1,2,3,4,5]. CNF are visibly protruding masses in the skin composed of a complex mixture of hyperproliferating Schwann cells (SC), nonmyelinating SC (nSC), intermingled with fibroblasts, vasculature, macrophages, mast cells and other cellular components [1,2,3,4,5]. This composition is similar to another hallmark of NF1, which are the expansive growths within large nerves and plexuses referred to as plexiform neurofibromas (pNF). Whereas pNF clearly originate within nerves and plexuses, the origin of cNF remains uncertain in relation to cutaneous innervation [1, 8, 9]

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Discussion

Conclusion