Fig. 3.

Schematic illustrating some of the multiple factors contributing to the development of neurofibromas in NF1 patients and their subsequent progression to become MPNSTs. The development of neurofibromas is initiated when an NF1 haploinsufficient cell in the Schwann cell lineage loses its remaining functional copy of NF1. This results in increases in the activity of Ras and other signaling molecules; tumorigenesis is enhanced by interactions with other cell types, inappropriate expression of EGFR and possibly the action of other growth factors. Subsequent progression to become an MPNST is associated with loss of additional tumor suppressor genes in the p19^ARF-MDM2-TP53 and p16^INK4A-Rb signaling cascades. Amplification or mutation of several growth factors receptors also contributes to MPNST pathogenesis.