title: Vascular endothelial growth factor, basic fibroblast growth factor and epithelial growth factor receptor in peripheral nerve sheath tumors of neurofibromatosis type 1.
abstract: OBJECTIVE
  Neurofibromas, benign tumors of the nerve sheaths, are the hallmark of neurofibromatosis type 1 (NF1), an autosomal-dominant inherited tumor predisposition syndrome. Malignant tumors arising from nerve sheath cells are an important factor influencing the life expectancy of NF1 patients. Expression of growth factors and growth factor receptors play a key role in the development of tumors. Therapy of peripheral nerve sheath (PNS) tumors is predominantly surgical. The outcome in malignant entities of NF1-affected patients remains poor, despite many efforts to implement pharmacological therapy into the treatment modalities. Growth of peripheral nerve sheath tumors is finely-adjusted by growth factors and PNS tumors express growth factor receptors. However, quantification of receptor expression and comparison to the expression of other related factors are not available. The aim of the present study was to determine growth factor expression relevant for growth control in neurofibromas of NF1.
  
  
  METHODS
  Fifty-eight dermal, dermal/diffuse and plexiform neurofibromas and malignant peripheral nerve sheath tumors (MPNST) of NF1-affected patients were analyzed immunohistochemically for the expression of growth factors relevant for angiogenesis: vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and epithelial growth factor receptor (EGFR). The vessel density was also determined quantitatively by light microscopy.
  
  
  RESULTS
  Plexiform neurofibroma revealed a higher expression level for VEGF compared to dermal/diffuse neurofibroma. However, statistical significant differences for VEGF expression and of all other proteins investigated were found in comparison to MPNST only. EGFR expression was remarkably high in NF1 patients in their first decade of life. However, this result has to be interpreted with caution in view of the high number of young patients with MPNST in this age group. Vessel density correlated with tumor type. Vessel density increased significantly comparing benign nerve sheath tumors and MPNST (p<0.05).
  
  
  CONCLUSIONS
  This study revealed the presence of factors and receptors involved in angiogenesis as a prerequisite for tumor development and maintenance of PNS in NF1. These factors are highly expressed in all tumors of this study. This study reveals these relevant factors in nerve sheath tumors and also described the significant increase of vessel density in MPNST compared to benign counterparts. Anti-angiogenic drugs are presently investigated for application in NF1 tumor treatment, in particular for patients with a surgically-intractable high tumor burden. Drugs capable of blocking the EGFR receptor-mediated pathway are promising tools within the pharmacological repertoires to treat these patients.
authors.affiliation: Department of Oral and Craniomaxillofacial Surgery, Eppendorf University Hospital, University of Hamburg, Hamburg, Germany r.friedrich@uke.de.
authors.forename: Reinhard E
authors.initials: RE
authors.lastname: Friedrich
authors.affiliation: Institute of Neuropathology, Eppendorf University Hospital, University of Hamburg, Hamburg, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Beer
authors.affiliation: Institute of Neuropathology, Eppendorf University Hospital, University of Hamburg, Hamburg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Glatzel
authors.affiliation: Institute of Neuropathology, Eppendorf University Hospital, University of Hamburg, Hamburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hagel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000378:metabolism; D009456:Neurofibromatosis 1 / Q000378:metabolism*; D010524:Peripheral Nervous System Neoplasms / Q000098:blood supply / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D055815:Young Adult
chemical_list: C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: Epidermal growth factor receptor; basic fibroblastic growth factor; malignant peripheral nerve sheath tumor; neurofibromatosis type 1; vascular endothelial growth factor; vessel density