Neurofibromas in NF1: Schwann Cell Origin and Role of Tumor Environment

TLDR

Neurofibromatosis type 1 is a common dominantly inherited disease whose loss of the NF1 tumor suppressor leads to complex neurofibromas composed of axonal processes, Schwann cells, fibroblasts, perineurial cells, and mast cells. The study demonstrates that loss of NF1 in Schwann cells is sufficient to generate neurofibromas. This was achieved using a conditional Cre/lox allele to delete NF1 specifically in the Schwann cell lineage. Tumorigenesis requires NF1 loss in Schwann cells and heterozygosity in surrounding non‑neoplastic cells, suggesting that a permissive haploinsufficient microenvironment may be a therapeutic target.

Abstract

Neurofibromatosis type 1 (NF1) is one of the most prevalent dominantly inherited genetic diseases of the nervous system. NF1 encodes a tumor suppressor whose functional loss results in the development of benign neurofibromas that can progress to malignancy. Neurofibromas are complex tumors composed of axonal processes, Schwann cells, fibroblasts, perineurial cells, and mast cells. Through use of a conditional ( cre / lox ) allele, we show that loss of NF1 in the Schwann cell lineage is sufficient to generate tumors. In addition, complete NF1-mediated tumorigenicity requires both a loss of NF1 in cells destined to become neoplastic as well as heterozygosity in non-neoplastic cells. The requirement for a permissive haploinsufficient environment to allow tumorigenesis may have therapeutic implications for NF1 and other familial cancers.