title: EGFR-Stat3 signalling in nerve glial cells modifies neurofibroma initiation.
abstract: Neurofibromatosis type 1 (NF1) is an inherited disease in which affected patients are predisposed to develop benign Schwann cell (SC) tumours called neurofibromas. In the mouse, loss of Nf1 in the SC lineage causes neurofibroma formation. The tyrosine kinase receptor EGFR is expressed in Schwann cell precursors (SCP), which have been implicated in plexiform neurofibroma initiation. To test if EGFR activity affects neurofibroma initiation, size, and/or number, we studied mice expressing human EGFR in SCs and SCP in the context of mice that form neurofibromas. Neurofibroma number increased in homozygous CNP-hEGFR mice versus heterozygous littermates, and neurofibroma number and size increased when CNP-hEGFR was crossed to Nf1fl/fl;DhhCre mice. Conversely, diminished EGFR signalling in Nf1fl/fl;DhhCre;Wa2/+ mice decreased neurofibroma number. In vivo transplantation verified the correlation between EGFR activity and neurofibroma formation. Mechanistically, expression of CNP-hEGFR increased SCP/neurofibroma-initiating cell self-renewal, a surrogate for tumour initiation, and activated P-Stat3. Further, Il-6 reinforced Jak2/Stat3 activation in SCPs and SCs. These gain- and loss-of function assays show that levels of tyrosine kinase expression in SCPs modify neurofibroma initiation.
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Research Foundation, Cincinnati Children's Hospital, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: J
authors.initials: J
authors.lastname: Wu
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Research Foundation, Cincinnati Children's Hospital, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: W
authors.initials: W
authors.lastname: Liu
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Research Foundation, Cincinnati Children's Hospital, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Williams
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Research Foundation, Cincinnati Children's Hospital, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: N
authors.initials: N
authors.lastname: Ratner
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006720:Homozygote; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009455:Neurofibroma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D025542:Neurofibromin 1 / Q000235:genetics; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D047368:Tumor Burden
chemical_list: D015850:Interleukin-6; D025542:Neurofibromin 1; D050796:STAT3 Transcription Factor; D066246:ErbB Receptors; D053614:Janus Kinase 2