PTEN dosage is essential for neurofibroma development and malignant transformation.
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.
Department of Molecular and Medical Pharmacology, Institute for Molecular Medicine, University of California, Los Angeles, CA 90095, USA.
Caroline
C
Gregorian
Jonathan
J
Nakashima
Sarah M
SM
Dry
P Leia
PL
Nghiemphu
Kate Barzan
KB
Smith
Yan
Y
Ao
Julie
J
Dang
Gregory
G
Lawson
Ingo K
IK
Mellinghoff
Paul S
PS
Mischel
Michael
M
Phelps
Luis F
LF
Parada
Xin
X
Liu
Michael V
MV
Sofroniew
Fritz C
FC
Eilber
Hong
H
Wu
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D019788:Fluorodeoxyglucose F18; D018628:Gene Dosage; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009455:Neurofibroma / Q000235:genetics* / Q000473:pathology*; D015689:Oncogene Protein p21(ras) / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D049268:Positron-Emission Tomography; D048490:raf Kinases / Q000378:metabolism
D019788:Fluorodeoxyglucose F18; D048490:raf Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D015689:Oncogene Protein p21(ras)