Conditional deletion of Pten tumor suppressor gene and activation of K-Ras oncogene result in the development of Neurofibromatoses

3863

Neurofibromatoses (NFs) are a set of inherited disorders designated as Neurofibromatosis Type 1 (NF1), Neurofibromatosis Type 2 (NF2), and Schwannomatosis, that result in a variety of tumors in the central and peripheral nervous systems (CNS and PNS). NF1 and NF2 are caused by mutations in the neurofibromin (Nf1) or neurofibromin-2 (Nf2, or merlin) gene, respectively, which act as negative regulators of RAS activity. Nf1^+/-, Nf2^+/-, and conditional knockout lines for either gene fail to recapitulate the full disease spectrum observed in humans. To address the involvement of other signaling pathways with those controlled by NF1 and NF2, we utilized Cre-Lox technology to perturb RAS/RAF/MAPK and PI3K/AKT/mTOR, two of the major signaling pathways involved in tumorigenesis of the nerve system, individually and in combination. The resulting mouse model accurately reflects the human clinical symptoms associated with NF1, NF2, and Schwannomatosis. Pathologically, neoplastic nervous system manifestations of NF1 include: 1) malignant peripheral nerve sheath tumors, 2) neurofibromas, 3) optic nerve gliomas and 4) malignant gliomas. Neoplastic manifestations of NF2 include 1) acoustic schwannomas and 2) meningiomas, with 3) malignant astrocytoma and oligodendroglioma. Manifestations of Schwannomatosis are multiple schwannomas. In addition, key mediators of the AKT and RAS signaling pathways (P-AKT, P-mTOR, P-S6, P-ERK) are shown to be chronically phosphorylated within these tumors, indicating that the neoplasms not only reflect the morphology of the human tumors, but also recapitulate the molecular phenotype. Thus, the model reflects key features associated with both NF1 and NF2 pathology. We are currently testing various imaging modalities to monitor tumor progression and regression in response to therapeutics in living animals.

C.G. is a predoctoral trainee supported by USHHS Ruth L. Kirschstein Institutional National Research Service Award # T32 CA09056.