Characterization of Neurofibromas of the Skin and Spinal Roots in a Mouse Model
Annual rept. 1 Jul 2007-1 Jul 2008
PENNSYLVANIA UNIV PHILADELPHIA
Pagination or Media Count:
Benign neurofibromas and malignant peripheral nerve sheath tumors MPNSTs contribute to the majority of morbidity and mortality associated with NF1. The proposed studies are attempting to provide insights into one of the fundamental questions in neurofibroma biology whether bi-allelic NF1 inactivation is necessary for neurofibroma formation. The objectives of this proposal are to use a newly established mouse model to 1 identify and characterize neurofibromas that are exclusively or predominantly comprised of NF1- cells designated NF1- neurofibromas hereafter in the skin and spinal roots and 2 determine whether in this model, neurofibromas in the skin are similar to human dermal neurofibromas and thus are fundamentally different from the plexiform neurofibromas found in spinal roots. Previous studies of human tumors suggest that dermal and plexiform neurofibromas have fundamental differences in their dependence on the NF1 hetereozygous environment and have different malignant transformation potentials. We have made substantial progress in the first three years of the award. For Task 1, we demonstrated that bi-allelic inactivation of Nf1 in neural crest stem cells is required for neurofibroma formation. These results resulted in publication of 3 manuscripts in 2008 see appendices. For Task 2, we have determined that the Nf1 heterozygous environment promotes neurofibroma progression, but is not required for tumor initiation. For Task 3, we demonstrate that the Nf1 heterozygous environment is not required for malignant transformation of neurofibroma. We have established a novel mouse model for MPNST, in which neurofibroma arises first followed by MPNST formation a process that closely resembles the progressive nature of human MPNST. We are currently working on a manuscript to publish these results.
- Medicine and Medical Research