Malignant peripheral nerve sheath tumor invasion requires aberrantly expressed EGF receptors and is variably enhanced by multiple EGF family ligands.

Abstract

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.

• Authors: Stephanie J Byer, Nicole M Brossier, Lafe T Peavler, Jenell M Eckert, Stacey Watkins, Kevin A Roth, Steven L Carroll
• Journal: Journal of neuropathology and experimental neurology (J Neuropathol Exp Neurol) Vol. 72 Issue 3 Pg. 219-33 (Mar 2013) ISSN: 1554-6578 [Electronic] England
• PMID: 23399900 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Ligands
• Transforming Growth Factor alpha
• ErbB Receptors

Topics

• Animals
• Cells, Cultured
• ErbB Receptors (metabolism)
• Gene Knockdown Techniques
• Humans
• Immunoblotting
• Immunohistochemistry
• Ligands
• Neoplasm Invasiveness (pathology)
• Nerve Sheath Neoplasms (metabolism, pathology)
• Rats
• Real-Time Polymerase Chain Reaction
• Schwann Cells
• Signal Transduction (physiology)
• Transforming Growth Factor alpha (metabolism)