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Proc Natl Acad Sci U S A. 2009 Nov 17;106(46):19479-84. doi: 10.1073/pnas.0910398106. Epub 2009 Oct 21.

PTEN dosage is essential for neurofibroma development and malignant transformation.

Author information

1
Department of Molecular and Medical Pharmacology, Institute for Molecular Medicine, University of California, Los Angeles, CA 90095, USA.

Abstract

Patients with neurofibromatosis type 1 (NF1) carry approximately a 10% lifetime risk of developing a malignant peripheral nerve sheath tumor (MPNST). Although the molecular mechanisms underlying NF1 to MPNST malignant transformation remain unclear, alterations of both the RAS/RAF/MAPK and PI3K/AKT/mTOR signaling pathways have been implicated. In a series of genetically engineered murine models, we perturbed RAS/RAF/MAPK or/and PTEN/PI3K/AKT pathway, individually or simultaneously, via conditional activation of K-ras oncogene or deletion of Nf1 or Pten tumor suppressor genes. Only K-Ras activation in combination with a single Pten allele deletion led to 100% penetrable development of NF lesions and subsequent progression to MPNST. Importantly, loss or decrease in PTEN expression was found in all murine MPNSTs and a majority of human NF1-associated MPNST lesions, suggesting that PTEN dosage and its controlled signaling pathways are critical for transformation of NFs to MPNST. Using noninvasive in vivo PET-CT imaging, we demonstrated that FDG can be used to identify the malignant transformation in both murine and human MPNSTs. Our data suggest that combined inhibition of RAS/RAF/MAPK and PTEN/PI3K/AKT pathways may be beneficial for patients with MPNST.

PMID:
19846776
PMCID:
PMC2765459
DOI:
10.1073/pnas.0910398106
[Indexed for MEDLINE]
Free PMC Article

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