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 in approximately half of the total
neurofibromas examined. Highly enriched SC cultures were established from 10 dermal and eight
plexiform neurofibromas by selective subculture using glial growth factor-2 and
laminin. These cultures had low tumorigenic potential in classical in vitro assays yet several unique preneoplastic properties were frequently observed, including delayed senescence, a lack of density-limited growth, and a strong propensity to spontaneously form proliferative cell aggregates rich in extracellular matrix. Western blot analysis failed to detect full-length
neurofibromin in any of the
neurofibroma SC cultures, indicating that
neurofibromin-deficient SCs had a substantial growth advantage. Immunohistochemical staining of the originating
tumors showed the majority were comprised principally of
neurofibromin-negative SCs, whereas the remainder contained both
neurofibromin-negative and
neurofibromin-positive SCs. Lastly, engraftment of
neurofibromin-deficient SC cultures into the peripheral nerves of scid mice consistently produced persistent
neurofibroma-like
tumors with diffuse and often extensive intraneural growth. These findings indicate that
neurofibromin-deficient SCs are involved in
neurofibroma formation and, by selective subculture, provide a resource for the development of an in vivo model to further examine the role of these mutant SCs in
neurofibroma histogenesis.