期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 106, 期 46, 页码 19479-19484出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0910398106
关键词
in vivo PET imaging; peripheral nerve sheath tumor; tumor suppressor
资金
- USHHS Ruth L. Kirschstein Institutional National Research Service Award [T32 CA09056]
- National Cancer Institute (NCI) [P50 (P50 CA086306)]
- Miriam and Sheldon Adelson Program
- National Institutes of Health [NS057624, NS50151, P50NS052606]
- Brain Tumor Funders' Collaborative
- University of California
- Los Angeles' Jonsson Comprehensive Cancer Center Foundation
- American Cancer Society
- Brain Tumor Society Award
- Henry Singleton Brain Cancer Research Program
- James S. McDonnell Foundation
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.
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