title: Impaired Pten expression in human malignant peripheral nerve sheath tumours.
abstract: Malignant peripheral nerve sheath tumours (MPNST) are aggressive sarcomas that develop in about 10% of patients with the genetic disease neurofibromatosis type 1 (NF1). Molecular alterations contributing to MPNST formation have only partially been resolved. Here we examined the role of Pten, a key regulator of the Pi3k/Akt/mTOR pathway, in human MPNST and benign neurofibromas. Immunohistochemistry showed that Pten expression was significantly lower in MPNST (n=16) than in neurofibromas (n=16) and normal nervous tissue. To elucidate potential mechanisms for Pten down-regulation or Akt/mTOR activation in MPNST we performed further experiments. Mutation analysis revealed absence of somatic mutations in PTEN (n=31) and PIK3CA (n=38). However, we found frequent PTEN promotor methylation in primary MPNST (11/26) and MPNST cell lines (7/8) but not in benign nerve sheath tumours. PTEN methylation was significantly associated with early metastasis. Moreover, we detected an inverse correlation of Pten-regulating miR-21 and Pten protein levels in MPNST cell lines. The examination of NF1-/- and NF1+/+Schwann cells and fibroblasts showed that Pten expression is not regulated by NF1. To determine the significance of Pten status for treatment with the mTOR inhibitor rapamycin we treated 5 MPNST cell lines with rapamycin. All cell lines were sensitive to rapamycin without a significant correlation to Pten levels. When rapamycin was combined with simvastatin a synergistic anti-proliferative effect was achieved. Taken together we show frequent loss/reduction of Pten expression in MPNST and provide evidence for the involvement of multiple Pten regulating mechanisms.
authors.affiliation: Department of Neuropathology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Bradtmöller
authors.forename: Christian
authors.initials: C
authors.lastname: Hartmann
authors.forename: Jan
authors.initials: J
authors.lastname: Zietsch
authors.forename: Sebastian
authors.initials: S
authors.lastname: Jäschke
authors.forename: Victor-F
authors.initials: VF
authors.lastname: Mautner
authors.forename: Andreas
authors.initials: A
authors.lastname: Kurtz
authors.forename: Su-Jin
authors.initials: SJ
authors.lastname: Park
authors.forename: Michael
authors.initials: M
authors.lastname: Baier
authors.forename: Anja
authors.initials: A
authors.lastname: Harder
authors.forename: David
authors.initials: D
authors.lastname: Reuss
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.forename: Frank L
authors.initials: FL
authors.lastname: Heppner
authors.forename: Nikola
authors.initials: N
authors.lastname: Holtkamp
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D018317:Nerve Sheath Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009455:Neurofibroma / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D025542:Neurofibromin 1 / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology
chemical_list: D025542:Neurofibromin 1; D019821:Simvastatin; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D020123:Sirolimus