Molecular mechanisms promoting the pathogenesis of Schwann cell neoplasms

Abstract

Neurofibromas, schwannomas and malignant peripheral nerve sheath tumors (MPNSTs) all arise from the Schwann cell lineage. Despite their common origin, these tumor types have distinct pathologies and clinical behaviors; a growing body of evidence indicates that they also arise via distinct pathogenic mechanisms. Identification of the genes that are mutated in genetic diseases characterized by the development of either neurofibromas and MPNSTs [neurofibromatosis type 1 (NF1)] or schwannomas [neurofibromatosis type 2 (NF2), schwannomatosis and Carney complex type 1] has greatly advanced our understanding of these mechanisms. The development of genetically engineered mice with ablation of NF1, NF2, SMARCB1/INI1 or PRKAR1A has confirmed the key role these genes play in peripheral nerve sheath tumorigenesis. Establishing the functions of the NF1, NF2, SMARCB1/INI1 and PRKAR1A gene products has led to the identification of key cytoplasmic signaling pathways promoting Schwann cell neoplasia and identified new therapeutic targets. Analyses of human neoplasms and genetically engineered mouse models have established that interactions with other tumor suppressors such as TP53 and CDKN2A promote neurofibroma-MPNST progression and indicate that intratumoral interactions between neoplastic and non-neoplastic cell types play an essential role in peripheral nerve sheath tumorigenesis. Recent advances have also provided new insights into the identity of the neural crest-derived populations that give rise to different types of peripheral nerve sheath tumors. Based on these findings, we now have an initial outline of the molecular mechanisms driving the pathogenesis of neurofibromas, MPNSTs and schwannomas. However, this improved understanding in turn raises a host of intriguing new questions.

Expression profiling of 519 kinase genes in matched malignant peripheral nerve sheath tumor/plexiform neurofibroma samples is discriminatory and identifies mitotic regulators BUB1B, PBK and NEK2 as overexpressed with transformation

“…29,33 Neurofibromatosis type 1-associated neurofibromas and malignant peripheral nerve sheath tumors arise in a background of a 'rasopathy' with altered Ras/MAP kinase signaling. 3,14,34,35 We therefore looked for changes occurring with the transformation from plexiform neurofibroma to malignant peripheral nerve sheath tumor in the expression level of kinases in this signaling cascade. Most kinases of this set are again downregulated in malignant peripheral nerve sheath tumors.…”

“…Changes in MAP kinase signaling and receptor tyrosine kinases like EGFR have been suggested as possible additional biological changes driving malignant transformation of plexiform neurofibromas towards malignant peripheral nerve sheath tumor beyond the shared neurofibromin mutation. 14 Receptor tyrosine kinases have also been proposed as possible therapeutic targets. 53 The presented data suggests that this malignant transformation is associated with rather complex diverse changes and that it does not rely on a single biological switch.…”

“…[3][4][5][6] A number of miRNAs, cell cycle regulators, signaling molecules and transcription factors have been shown to be differentially expressed between neurofibromas and malignant peripheral nerve sheath tumors including CDKN2A, TP53, RB1, EGFR, CD44, PDGFRB, PDGFRA, HGF, MET, IGFR1, SOX9, SOX10, miR-34a and miR-21. 3,[7][8][9][10][11][12][13][14] Neurofibromatosis type 1 patients often have multiple plexiform neurofibromas. Their risk of developing a malignant peripheral nerve sheath tumor is estimated to be in the range from 3-13%.…”

The Challenge of Cancer Genomics in Rare Nervous System Neoplasms

“…24 Although completely penetrant, the manifestations of NF1 are highly variable, even in the same family. NF1 patients commonly have learning disabilities, pigmentary lesions of the iris (Lisch nodules) and skin (axillary freckling, café-au-lait macules), bone dysplasias, and glial neoplasms in brain (optic gliomas, glioblastomas), large peripheral nerves (plexiform neurofibromas, MPNSTs), and skin (dermal neurofibromas).…”

“…We do know that neurofibromin inactivates members of the Ras family of small GTP-binding proteins. 24 This function is mediated by a centrally located domain (amino acids 1203 to 1549) within neurofibromin that is homologous to the Saccharomyces cerevisiae GTPase-activating proteins (GAPs) IRA1 and IRA2. Ras proteins are activated on binding GTP; the neurofibromin Ras GAP domain stimulates an intrinsic GTPase activity in Ras proteins, causing them to cleave a phosphate from the bound GTP and inactivate themselves.…”