Neuregulin growth factors and their ErbB receptors form a potential signaling network for schwannoma tumorigenesis.

Sporadic and neurofibromatosis type 2-associated schwannomas contain a glial growth factor (GGF)-like activity that has been hypothesized to promote neoplastic Schwann cell mitogenesis. It is not known whether this GGF-like activity is neuregulin-1 (NRG-1), an epidermal growth factor (EGF)-related molecule that regulates the proliferation, survival, and differentiation of developing Schwann cells, the related factor NRG-2, or another NRG/EGF ligand. We report that neoplastic Schwann cells within schwannomas overexpress multiple alpha and beta transmembrane precursors from the class II and class III NRG-1 subfamilies.

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

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.

Tumor suppressor mutations and growth factor signaling in the pathogenesis of NF1-associated peripheral nerve sheath tumors: II. The role of dysregulated growth factor signaling.

Patients with neurofibromatosis type 1 (NF1), one of the most common genetic disease affecting the nervous system, develop multiple neurofibromas that can transform into aggressive sarcomas known as malignant peripheral nerve sheath tumors (MPNSTs). Studies of human tumors and newly developed transgenic mouse models indicate that Schwann cells are the primary neoplastic cell type in neurofibromas and MPNSTs and that development of these peripheral nerve sheath tumors involves mutations of multiple tumor suppressor genes. However, it is widely held that tumor suppressor mutations alone are not sufficient to induce peripheral nerve sheath tumor formation and that dysregulated growth factor signaling cooperates with these mutations to promote neurofibroma and MPNST tumorigenesis.

Tumor suppressor mutations and growth factor signaling in the pathogenesis of NF1-associated peripheral nerve sheath tumors. I. The role of tumor suppressor mutations.

Patients with neurofibromatosis type 1 (NF1), a common autosomal dominant tumor predisposition syndrome, develop benign cutaneous, intraneural, and plexiform neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs), an aggressive form of Schwann cell neoplasm that frequently arises from plexiform neurofibromas. Impressive advances have been made in defining the molecular mechanisms responsible for neurofibroma and MPNST tumorigenesis, including the identification of key tumor suppressor gene mutations, an improved understanding of the functions of these tumor suppressors, and the production of transgenic mouse models in which tumor suppressor gene mutations predispose animals to the development of neurofibromas and MPNSTs. It has also become apparent that dysregulated growth factor signaling cooperates with tumor suppressor mutations to promote neurofibroma and MPNST tumorigenesis.

Constitutive activation of the neuregulin-1/ErbB receptor signaling pathway is essential for the proliferation of a neoplastic Schwann cell line.

Neuregulin-1 (NRG-1) proteins promote Schwann cell survival, differentiation and proliferation during development. High levels of an NRG-like activity are also present in some human peripheral nerve sheath tumors, suggesting that NRG-1 isoforms may be involved in the development of these neoplasms. We examined the expression of NRG-1 and its receptors, the erbB membrane tyrosine kinases, in JS1 cells, a rapidly proliferating line derived from a chemically induced rat malignant peripheral nerve sheath tumor (MPNST).

Lysophosphatidic acid promotes the proliferation of adult Schwann cells isolated from axotomized sciatic nerve.

We have previously found that adult Schwann cells express receptors for lysophosphatidic acid (EDG2, EDG7) and sphingosine-1-phosphate (EDG5) and that expression of these receptors is significantly upregulated in injured sciatic nerve coincident with postaxotomy Schwann cell proliferation. Based on these observations, we hypothesized that lysophosphatidic acid and/or sphingosine-1-phosphate promote Schwann cell mitogenesis in injured adult nerve. We found that both saturated and unsaturated forms of lysophosphatidic acid, but not sphingosine-1-phosphate, induce DNA synthesis in adult Schwann cells isolated from surgically transected sciatic nerve.