Activation of the neuregulin-1/ErbB signaling pathway promotes the proliferation of neoplastic Schwann cells in human malignant peripheral nerve sheath tumors

Abstract

Patients with neurofibromatosis type 1 develop aggressive Schwann cell neoplasms known as malignant peripheral nerve sheath tumors (MPNSTs). Although tumor suppressor gene mutations play an important role in MPNST pathogenesis, it is likely that dysregulated signaling by as yet unidentified growth factors also contributes to the formation of these sarcomas. To test the hypothesis that neuregulin-1 (NRG-1) growth factors promote mitogenesis in MPNSTs, we examined the expression and action of NRG-1 in human MPNSTs and neurofibromas, the benign precursor lesions from which MPNSTs arise. Multiple a and b transmembrane precursors from the class II and III NRG-1 subfamilies are present in both tumor types. Neoplastic Schwann cells within these neoplasms variably express the erbB kinases mediating NRG-1 responses (erbB2, erbB3 and/or erbB4). Human MPNST cell lines (Mash-1, YST-1, NMS-2 and NMS-2PC cells) similarly coexpress multiple NRG-1 isoforms and erbB receptors. These MPNST lines are NRG-1 responsive and demonstrate constitutive erbB phosphorylation. Treatment with PD168393 and PD158780, two structurally and mechanistically distinct erbB inhibitors, abolishes erbB phosphorylation and reduces DNA synthesis in these lines. These findings suggest that autocrine and/or paracrine NRG-1/erbB signaling promotes neoplastic Schwann cell proliferation and may be an important therapeutic target in neurofibromas and MPNSTs.

EGFR and erbB2 in malignant peripheral nerve sheath tumors and implications for targeted therapy

“…In contrast to other erbB family members (EGFR, erbB3, erbB4), erbB2 lacks a ligand-binding domain. ErbB2 must therefore form heterodimers with other family members, all of which were detected in MPNSTs, 15 to respond to growth factors. Application of pan-erbB inhibitors appears tempting to inhibit this cross talk (heterodimerization).…”

“…Although there is cumulating evidence of a role for EGFR and erbB2 in nerve sheath tumors, 14,15 previous studies did not systematically analyze these potential therapeutic targets in larger panels of human MPNSTs. We therefore studied genetic alterations and expression of erbB2 and EGFR in a set of 37 human MPNSTs and four MPNST cell lines.…”

The Challenge of Cancer Genomics in Rare Nervous System Neoplasms

“…One of these is NRG1, a growth factor that regulates Schwann cell proliferation, survival, migration, and maturation during development. We have shown that NRG1 and all three of its receptors (the erbB2, erbB3, and erbB4 receptor tyrosine kinases) are co-expressed in human neurofibromas and MPNSTs; the resulting constitutive activation of these receptors drives the proliferation, 92 survival, 93 and migration 94 of human MPNST cells. To determine whether inappropriate activation of the NRG1/erbB signaling is sufficient to induce tumorigenesis, we created transgenic mice in which a secreted NRG1 isoform is overexpressed in Schwann cells (P 0 -GGFb3 mice).…”

Experimental therapeutic approaches to peripheral nerve tumors

“…Preclinical studies have demonstrated that blockade of the EGF receptor-related erbB receptors with PD168393 and PD158780 have blocked proliferation of MPNST cells in an in vitro setting. 144 The utility of direct EGF receptor blockade with gefitinib (Iressa) as a potential therapeutic end point for MPNST treatment has also been demonstrated in an in vitro setting. 30 In addition to having been demonstrated in preclinical and clinical studies for the treatment of a wide variety of cancers, 34 EGF receptor blockade has been extended into the clinical context for treatment of MPNSTs.…”