title: EGFR-STAT3 signaling promotes formation of malignant peripheral nerve sheath tumors.
abstract: Malignant peripheral nerve sheath tumors (MPNSTs) develop sporadically or in the context of neurofibromatosis type 1. Epidermal growth factor receptor (EGFR) overexpression has been implicated in MPNST formation, but its precise role and relevant signaling pathways remain unknown. We found that EGFR overexpression promotes mouse neurofibroma transformation to aggressive MPNST (GEM-PNST). Immunohistochemistry demonstrated phosphorylated STAT3 (Tyr705) in both human MPNST and mouse GEM-PNST. A specific JAK2/STAT3 inhibitor FLLL32 delayed MPNST formation in an MPNST xenograft nude mouse model. STAT3 knockdown by shRNA prevented MPNST formation in vivo. Finally, reducing EGFR activity strongly reduced pSTAT3 in vivo. Thus, an EGFR-STAT3 pathway is necessary for MPNST transformation and establishment of MPNST xenografts growth but not for tumor maintenance. Efficacy of the FLLL32 pharmacological inhibitor in delaying MPNST growth suggests that combination therapies targeting JAK/STAT3 might be useful therapeutics.
authors: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Research Foundation, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors: J
authors: J
authors: Wu
authors: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Research Foundation, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors: D M
authors: DM
authors: Patmore
authors: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Research Foundation, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors: E
authors: E
authors: Jousma
authors: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Research Foundation, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors: D W
authors: DW
authors: Eaves
authors: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Research Foundation, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors: K
authors: K
authors: Breving
authors: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Research Foundation, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors: A V
authors: AV
authors: Patel
authors: Ohio State University, College of Pharmacy, Columbus, OH, USA.
authors: E B
authors: EB
authors: Schwartz
authors: Ohio State University, College of Pharmacy, Columbus, OH, USA.
authors: J R
authors: JR
authors: Fuchs
authors: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Research Foundation, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors: T P
authors: TP
authors: Cripe
authors: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors: A O
authors: AO
authors: Stemmer-Rachamimov
authors: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Research Foundation, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors: N
authors: N
authors: Ratner
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003474:Curcumin / Q000031:analogs & derivatives / Q000494:pharmacology; D066246:ErbB Receptors / Q000502:physiology*; D016514:Genes, Neurofibromatosis 1; D006801:Humans; D053614:Janus Kinase 2 / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018317:Nerve Sheath Neoplasms / Q000209:etiology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D012509:Sarcoma / Q000209:etiology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C548902:FLLL 32; D050796:STAT3 Transcription Factor; D066246:ErbB Receptors; D053614:Janus Kinase 2; D003474:Curcumin