Tumorigenic properties of neurofibromin-deficient neurofibroma schwann cells

Dermal and plexiform neurofibromas are peripheral nerve sheath tumors that arise frequently in neurofibromatosis type 1. The goal of the present study was to examine the tumorigenic properties of neurofibromin-deficient human Schwann cells (SCs) that were found to represent a subset of SCs present i n approximately half of the total neurofibromas examined. Highly enriched S C cultures were established from 10 dermal and eight plexiform neurofibroma s by selective subculture using glial growth factor-2 and laminin. These cu ltures had low tumorigenic potential in classical in vitro assays yet sever al unique preneoplastic properties were frequently observed, including dela yed senescence, a lack of density-limited growth, and a strong propensity t o spontaneously form proliferative cell aggregates rich in extracellular ma trix. Western blot analysis failed to detect full-length neurofibromin in a ny of the neurofibroma SC cultures, indicating that neurofibromin-deficient SCs had a substantial growth advantage. Immunohistochemical staining of th e originating tumors showed the majority were comprised principally of neur ofibromin-negative SCs,whereas the remainder contained both neurofibromin-n egative and neurofibromin-positive SCs, Lastly, engraftment of neurofibromi n-deficient SC cultures into the peripheral nerves of scid mice consistentl y produced persistent neurofibroma-like tumors with diffuse and often exten sive intraneural growth. These findings indicate that neurofibromin-deficie nt SCs are involved in neurofibroma formation and, by selective subculture, provide a resource for the development of an in vivo model to further exam ine the role of these mutant SCs in neurofibroma histogenesis.