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.
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Authors | Maren Bradtmöller, Christian Hartmann, Jan Zietsch, Sebastian Jäschke, Victor-F Mautner, Andreas Kurtz, Su-Jin Park, Michael Baier, Anja Harder, David Reuss, Andreas von Deimling, Frank L Heppner, Nikola Holtkamp |
Journal | PloS one
(PLoS One)
Vol. 7
Issue 11
Pg. e47595
( 2012)
ISSN: 1932-6203 [Electronic] United States |
PMID | 23139750
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Neurofibromin 1
- Simvastatin
- Ribosomal Protein S6 Kinases, 70-kDa
- PTEN Phosphohydrolase
- PTEN protein, human
- Sirolimus
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Topics |
- Animals
- Blotting, Western
- Cell Line, Tumor
- Drug Synergism
- Fibroblasts
(drug effects, metabolism, pathology)
- Gene Expression Regulation, Neoplastic
(drug effects)
- Humans
- Mice
- Nerve Sheath Neoplasms
(enzymology, genetics, pathology)
- Neurofibroma
(enzymology, genetics, pathology)
- Neurofibromin 1
(metabolism)
- PTEN Phosphohydrolase
(genetics, metabolism)
- Ribosomal Protein S6 Kinases, 70-kDa
(metabolism)
- Simvastatin
(pharmacology)
- Sirolimus
(pharmacology)
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