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.
Highlights
Malignant peripheral nerve sheath tumours (MPNST) are aggressive soft tissue sarcomas that develop with an incidence of 1:100.000
We demonstrate that Pten expression in MPNST is significantly lower than in neurofibroma indicating that its down-regulation could contribute to malignant progression
Because Pten is a key regulator of the Akt/mTOR pathway, the Pten status may impact the therapeutic success of mTOR inhibiting drugs
Summary
Malignant peripheral nerve sheath tumours (MPNST) are aggressive soft tissue sarcomas that develop with an incidence of 1:100.000. Rare in the general population MPNST develop frequently in patients with the genetic disorder neurofibromatosis type 1 (NF1), which occurs with an incidence of 1:3500 [1]. The life-time risk of developing MPNST is estimated to be 8–13% [2] for NF1 patients, who account for about 50% of all MPNST. MPNST generally arise from plexiform neurofibromas (pNF) in NF1 patients and constitute the major cause for reduced life expectancy with only 21% of patients surviving longer than 5 years after diagnosis. During the course of malignant progression, further alterations are acquired in TSG and oncogenes like TP53, CDKN2A, EGFR, and PDGFRA [3,4,5,6,7]. Sporadic and NF1-associated MPNST share many similarities in their molecular pathogenesis, Ras mutations are linked to sporadic
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