Aberrant epidermal growth factor receptor (EGFR) expression promotes the 
pathogenesis of malignant peripheral nerve sheath tumors (MPNSTs), the most 
common malignancy associated with neurofibromatosis type 1, but the mechanisms 
by which EGFR expression promotes MPNST pathogenesis are poorly understood. We 
hypothesized that inappropriately expressed EGFRs promote MPNST invasion and 
found that these kinases are concentrated in MPNST invadopodia in vitro. 
Epidermal growth factor receptor knockdown inhibited the migration of 
unstimulated MPNST cells in vitro, and exogenous EGF further enhanced MPNST 
migration in a substrate-specific manner, promoting migration on laminin and, to 
a lesser extent, collagen. In this setting, EGF acts as a chemotactic factor. We 
also found that the 7 known EGFR ligands (EGF, betacellulin, epiregulin, 
heparin-binding EGF, transforming growth factor-α [TGF-α], amphiregulin, and 
epigen) variably enhanced MPNST migration in a concentration-dependent manner, 
with TGF-α being particularly potent. With the exception of epigen, these 
factors similarly promoted the migration of nonneoplastic Schwann cells. 
Although transcripts encoding all 7 EGFR ligands were detected in human MPNST 
cells and tumor tissues, only TGF-α was consistently overexpressed and was found 
to colocalize with EGFR in situ. These data indicate that constitutive EGFR 
activation, potentially driven by autocrine or paracrine TGF-α signaling, 
promotes the aggressive invasive behavior characteristic of MPNSTs.