transforming-growth-factor-alpha and Nerve-Sheath-Neoplasms

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.

Topics: Animals; Cells, Cultured; ErbB Receptors; Gene Knockdown Techniques; Humans; Immunoblotting; Immunohistochemistry; Ligands; Neoplasm Invasiveness; Nerve Sheath Neoplasms; Rats; Real-Time Polymerase Chain Reaction; Schwann Cells; Signal Transduction; Transforming Growth Factor alpha

Malignant peripheral nerve sheath tumors (MPNSTs) are sarcomas with poor prognosis and limited treatment options. Evidence for a role of epidermal growth factor receptor (EGFR) and receptor tyrosine kinase erbB2 in MPNSTs led us to systematically study these potential therapeutic targets in a larger tumor panel (n = 37). Multiplex ligation-dependent probe amplification and fluorescence in situ hybridization analysis revealed increased EGFR dosage in 28% of MPNSTs. ERBB2 and three tumor suppressor genes (PTEN [phosphatase and tensin homolog deleted on chromosome 10], CDKN2A [cyclin-dependent kinase inhibitor 2A], and TP53 [tumor protein p53]) were frequently lost or reduced. Reduction of CDKN2A was linked to appearance of metastasis. Comparison of corresponding neurofibromas and MPNSTs revealed an increase in genetic lesions in MPNSTs. No somatic mutations were found within tyrosine-kinase-encoding exons of EGFR and ERBB2. However, at the protein level, expression of EGFR and erbB2 was frequently detected in MPNSTs. EGFR expression was significantly associated with increased EGFR gene dosage. The EGFR ligands transforming growth factor alpha and EGF were more strongly expressed in MPNSTs than in neurofibromas. The effects of the drugs erlotinib and trastuzumab, which target EGFR and erbB2, were determined on MPNST cell lines. In contrast to trastuzumab, erlotinib mediated dose-dependent inhibition of cell proliferation. EGF-induced EGFR phosphorylation was attenuated by erlotinib. Summarized, our data indicate that EGFR and erbB2 are potential targets in treatment of MPNST patients.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Drug Delivery Systems; Drug Synergism; Epidermal Growth Factor; ErbB Receptors; Erlotinib Hydrochloride; Gene Dosage; Genes, p16; Genes, p53; Humans; Immunohistochemistry; Nerve Sheath Neoplasms; Polymorphism, Single-Stranded Conformational; PTEN Phosphohydrolase; Quinazolines; Receptor, ErbB-2; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor alpha; Trastuzumab