期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2009
卷号：106
期号：46
页码：19479-19484
DOI：10.1073/pnas.0910398106
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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.
关键词：in vivo PET imaging ; peripheral nerve sheath tumor ; tumor suppressor
