ReviewGenetically engineered mouse models shed new light on the pathogenesis of neurofibromatosis type I-related neoplasms of the peripheral nervous system
Highlights
► Evidence that NF1 loss in the Schwann cell lineage is essential for tumorigenesis. ► What cell type in the Schwann cell lineage gives rise to neurofibromas and MPNSTs. ► How the tumor microenvironment contributes to neoplasia. ► What additional mutations contribute to neurofibroma-MPNST progression. ► How dysregulated growth factor signaling facilitates PNS tumorigenesis.
Introduction
Tumors of the peripheral nervous system (PNS) – neurofibromas, schwannomas and malignant peripheral nerve sheath tumors (MPNSTs) – cause considerable morbidity and mortality in afflicted individuals. This class of tumors is also common, representing 8.9% of the nervous system neoplasms resected in the United States between 2004 and 2006 [13]. While these tumors do occur sporadically, they are also often seen in association with the genetic disorders neurofibromatosis type I (NF1), neurofibromatosis type 2 (NF2), schwannomatosis, and Carney complex. Early transgenic modeling of these tumors thus focused on replicating the genetic defects seen in human patients with these disorders. This work provided insights into the role these mutated genes play in key signaling cascades, how they interact with other intratumoral abnormalities (e.g., aberrant growth factor signaling) and how their mutation enhances tumorigenesis via effects on the tumor microenvironment. These findings enabled the production of a second generation of genetically engineered murine (GEM) models that have further refined our understanding of tumorigenesis in the peripheral nervous system.
As the pathogenesis of NF1-related neoplasms (neurofibromas and MPNSTs) has been most extensively studied, we will focus on NF1-related GEM models in this review. We will first discuss the pathology of human NF1-related peripheral nerve sheath tumors, the genetic syndrome with which they are associated and our current understanding of the function(s) of the NF1 gene. We will then consider the mouse models that have been developed to investigate the mechanisms underlying NF1-related PNS tumorigenesis and the fundamental new insights that resulted from these models.
Section snippets
The anatomy of peripheral nerve and its implications for the pathogenesis of peripheral nerve sheath tumors
As peripheral nerve sheath tumors are derived from cells normally found in peripheral nerve, it is useful to first consider the composition and architecture of this complex tissue. The outermost layer of the nerve, the epineurium (Fig. 1), is composed of dense connective tissue and contains the highly anastamotic vascular supply of the nerve (the vasa nervorum). Within the epineurium, fascicles of nerve fibers are ensheathed by the perineurium, a dense concentric layer of specialized cells.
Initial Nf1 knockout models
In 1994, the Copeland and Weinberg labs independently described knockout mice with null mutations of Nf1 exon 31, a region that is often mutated in human NF1 patients. Both groups found that homozygous Nf1Δ31/Δ31 mice died by embryonic day 13.5 (E13.5) due to cardiac failure [8], [33]. Defects in renal, hepatic, and skeletal muscle development were also observed [8]. However, nervous system pathology was limited to enlargement of sympathetic ganglia secondary to neuronal hyperplasia [8] and,
Summary
The findings from the mouse models described above (summarized in Table 1) together with observations from human tumors suggest that neurofibroma pathogenesis and subsequent progression to become MPNSTs results from the accumulation of a series of molecular abnormalities (Fig. 7). In this scenario, the initial step in neurofibroma pathogenesis is loss of the remaining functional NF1 allele in a Schwann cell. It is likely that Ras surveillance mechanisms as well as additional tumor suppressors
Acknowledgements
This work was supported by the National Institute of Neurological Diseases and Stroke (R01 NS048353 to S.L.C.; F30 NS063626 to N.M.B.), the National Cancer Institute (R01 CA122804 to S.L.C.; R01 CA134773 to Kevin A. Roth and S.L.C.) and the Department of Defense (X81XWH-09-1-0086 to S.L.C.). We thank the Alabama Neuroscience Blueprint Core Center (P30 NS57098) and the UAB Neuroscience Core Center (P30 NS47466) for technical assistance with studies from our laboratory that are described in this
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2022, Advances in Cancer ResearchCitation Excerpt :It is also notable that dermal neurofibromas have no malignant potential. In contrast, plexiform neurofibromas are typically congenital and are prone to transform into aggressive spindle cell neoplasms derived from the Schwann cell lineage that are known as malignant peripheral nerve sheath tumors (MPNSTs) (Brossier & Carroll, 2012; Carroll, 2012). MPNSTs are the most common malignancy and the leading cause of death in NF1 patients.
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2021, JID InnovationsMalignant peripheral nerve sheath tumor arising from solitary neurofibroma
2014, Dermatologica SinicaCitation Excerpt :A superficial form of MPNSTs with a cutaneous or subcutaneous origin has been identified, and association with solitary neurofibromas was observed.4–6,8,12 It has been demonstrated that loss of functional NF1 allele in a Schwann cell may be the initial step in neurofibroma pathogenesis, and subsequent progression from neurofibroma to MPNST is associated with additional molecular alterations.13 However, several key steps in this process remain poorly understood.