Impaired Pten expression in human malignant peripheral nerve sheath tumours.
Standard
Impaired Pten expression in human malignant peripheral nerve sheath tumours. / Bradtmöller, Maren; Hartmann, Christian; Zietsch, Jan; Jäschke, Sebastian; Mautner, Viktor Felix; Kurtz, Andreas; Park, Su-Jin; Baier, Michael; Harder, Anja; Reuss, David; von Deimling, Andreas; Heppner, Frank L; Holtkamp, Nikola.
In: PLOS ONE, Vol. 7, No. 11, 11, 2012, p. 47595.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Impaired Pten expression in human malignant peripheral nerve sheath tumours.
AU - Bradtmöller, Maren
AU - Hartmann, Christian
AU - Zietsch, Jan
AU - Jäschke, Sebastian
AU - Mautner, Viktor Felix
AU - Kurtz, Andreas
AU - Park, Su-Jin
AU - Baier, Michael
AU - Harder, Anja
AU - Reuss, David
AU - von Deimling, Andreas
AU - Heppner, Frank L
AU - Holtkamp, Nikola
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - Animals
KW - Humans
KW - Mice
KW - Cell Line, Tumor
KW - Blotting, Western
KW - Drug Synergism
KW - Gene Expression Regulation, Neoplastic/drug effects
KW - Simvastatin/pharmacology
KW - Fibroblasts/drug effects/metabolism/pathology
KW - Nerve Sheath Neoplasms/enzymology/genetics/pathology
KW - Neurofibroma/enzymology/genetics/pathology
KW - Neurofibromin 1/metabolism
KW - PTEN Phosphohydrolase/genetics/metabolism
KW - Ribosomal Protein S6 Kinases, 70-kDa/metabolism
KW - Sirolimus/pharmacology
KW - Animals
KW - Humans
KW - Mice
KW - Cell Line, Tumor
KW - Blotting, Western
KW - Drug Synergism
KW - Gene Expression Regulation, Neoplastic/drug effects
KW - Simvastatin/pharmacology
KW - Fibroblasts/drug effects/metabolism/pathology
KW - Nerve Sheath Neoplasms/enzymology/genetics/pathology
KW - Neurofibroma/enzymology/genetics/pathology
KW - Neurofibromin 1/metabolism
KW - PTEN Phosphohydrolase/genetics/metabolism
KW - Ribosomal Protein S6 Kinases, 70-kDa/metabolism
KW - Sirolimus/pharmacology
U2 - 10.1371/journal.pone.0047595
DO - 10.1371/journal.pone.0047595
M3 - SCORING: Journal article
VL - 7
SP - 47595
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 11
M1 - 11
ER -
