Tumor suppressor mutations and growth factor signaling in the pathogenesis of NF1-associated peripheral nerve sheath tumors. I. The role of tumor suppressor mutations.

Patients with neurofibromatosis type 1 (NF1), a common autosomal dominant tumor predisposition syndrome, develop benign cutaneous, intraneural, and plexiform neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs), an aggressive form of Schwann cell neoplasm that frequently arises from plexiform neurofibromas. Impressive advances have been made in defining the molecular mechanisms responsible for neurofibroma and MPNST tumorigenesis, including the identification of key tumor suppressor gene mutations, an improved understanding of the functions of these tumor suppressors, and the production of transgenic mouse models in which tumor suppressor gene mutations predispose animals to the development of neurofibromas and MPNSTs. It has also become apparent that dysregulated growth factor signaling cooperates with tumor suppressor mutations to promote neurofibroma and MPNST tumorigenesis. In Part I of this two-part review, we consider findings demonstrating that Schwann cells are the primary neoplastic cell type in neurofibromas and MPNSTs and that specific tumor suppressor gene mutations promote the development of these tumors. In Part II, which will be published in a later issue, we will review evidence indicating that inappropriate growth factor signaling contributes to this process by stimulating the proliferation, survival, and migration of Schwann cells whose regulatory mechanisms have been crippled by a loss of tumor suppressor function.