Neurofibroma Development in Neurofibromatosis Type 1: Insights from Cellular Origin and Schwann Cell Lineage Development

Abstract

Background: Neurofibromatosis type 1 (NF1), a genetic tumor predisposition syndrome that affects about 1 in 3000 newborns, is caused by mutations in the NF1 gene and subsequent inactivation of its encoded neurofibromin. Neurofibromin is a tumor suppressor protein involved in the downregulation of Ras signaling. Despite a diverse clinical spectrum, one of several hallmarks of NF1 is a peripheral nerve sheath tumor (PNST), which comprises mixed nervous and fibrous components. The distinct spatiotemporal characteristics of plexiform and cutaneous neurofibromas have prompted hypotheses about the origin and developmental features of these tumors, involving various cellular transition processes. Methods: We retrieved published literature from PubMed, EMBASE, and Web of Science up to 21 June 2022 and searched references cited in the selected studies to identify other relevant papers. Original articles reporting the pathogenesis of PNSTs during development were included in this review. We highlighted the Schwann cell (SC) lineage shift to better present the evolution of its corresponding cellular origin hypothesis and its important effects on the progression and malignant transformation of neurofibromas. Conclusions: In this review, we summarized the vast array of evidence obtained on the full range of neurofibroma development based on cellular and molecular pathogenesis. By integrating findings relating to tumor formation, growth, and malignancy, we hope to reveal the role of SC lineage shift as well as the combined impact of additional determinants in the natural history of PNSTs.

Mediastinal Teratoma Mimicking Neurofibroma in CT-Guided Biopsy in a Patient With Neurofibromatosis Type 1

“…However, the exact point in their development from neural crest stem cells to mature myelinating or non-myelinating Schwann cells is a topic of ongoing research. Similarly, details in the pathogenesis and cell origin of the cutaneous neurofibromas also remain unanswered [10].…”

“…This is a protein that acts as a GTPase that down-regulates the RAS pathway [ 9 ]. The pathogenesis, intracellular pathways, and even cell of origin that result in the formation of neurofibromas have been widely debated [ 10 ]. The most prominent cellular lineage for the development of plexiform neurofibromas has been the Schwann cells.…”

“…However, the exact point in their development from neural crest stem cells to mature myelinating or non-myelinating Schwann cells is a topic of ongoing research. Similarly, details in the pathogenesis and cell origin of the cutaneous neurofibromas also remain unanswered [ 10 ]. Evidence suggests that cutaneous neurofibromas arise from a stem cell population, which is found in the skin dermis, and known as skin-derived precursors.…”

The NF1+/- Immune Microenvironment: Dueling Roles in Neurofibroma Development and Malignant Transformation

“…Postnatally, immature SCs bifurcate along either myelinating or non-myelinating trajectories, depending on the diameter of contacting axons [68]. Immature SCs with a small SC-to-axon ratio differentiate into mature non-myelinating SCs (nmSCs), while immature SCs with a large SC-to-axon ratio become mature myelinating SCs (mSCs) [69]. Nf1 loss in mature nmSCs, also known as Remak bundles, triggers abnormal proliferation that results in PNF formation [33].…”

Icariin Promotes Osteogenic Differentiation in a Cell Model with NF1 Gene Knockout by Activating the cAMP/PKA/CREB Pathway

“…Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease, is an autosomal dominant disease with an incidence of 1:3000 [ 1 ]. The National Organization for Rare Disorders (NORD) defines this condition as a typical rare disorder.…”