Genetic Events and Signaling Mechanisms Underlying Schwann Cell Fate in Development and Cancer

Abstract

In this review, we describe Schwann cell development from embryonic neural crest cells to terminally differentiated myelinated and nonmyelinated mature Schwann cells. We focus on the genetic drivers and signaling mechanisms mediating decisions to proliferate versus differentiate during Schwann cell development, highlighting pathways that overlap with Schwann cell development and are dysregulated in tumorigenesis. We conclude by considering how our knowledge of the events underlying Schwann cell development and mouse models of schwannoma, neurofibroma, and malignant peripheral nerve sheath tumor can inform novel therapeutic strategies for patients with cancers derived from Schwann cell lineages.

Keywords: Malignant peripheral nerve sheath tumor; NF1; NF2; Neural crest; Neurofibroma; Schwann cell; Schwannoma.

FIGURE 1.

Overview of normal Schwann cell development and transformation to peripheral nerve tumors.

FIGURE 2.

MRI appearance of Schwann cell-derived peripheral nerve tumors. A, Enhancing left cerebellopontine angle mass extending into the internal auditory canal along the course of the vestibulocochlear nerve (cranial nerve VIII) with resultant mass effect upon the adjacent pons and cerebellum consistent with a vestibular schwannoma. A′, Bilateral vestibular schwannomas are pathognomonic of NF2. B, T2 hyperintense ovoid lesion extending along the course of the right C7 nerve root consistent with a deep intraneural neurofibroma. B′, Left cervical mass with intense enhancement and multicompartmental extension from the posterior neck and into the prevertebral soft tissues consistent with a plexiform neurofibroma in the setting of NF1. C, Rapid interval growth (upper image at baseline, lower image 12 mo later) of an intensely enhancing nodule within a left cervical plexiform neurofibroma in a patient with NF1. Plexiform neurofibromas are at risk of malignant transformation to MPNSTs, particularly in the setting of rapid growth. C′, Large heterogeneous, enhancing, T2 hyperintense right thigh mass with internal degeneration intimately associated with the sciatic nerve. Size and irregular margins along the posterior thigh muscles are consistent with an MPNST.

FIGURE 3.

Histopathologic appearance of Schwann cell-derived peripheral nerve tumors. Representative hematoxylin and eosin (H/E) staining A-C as well as S100 A′, B′, C′ and SOX10 A′, B′, C′ immunohistochemistry for A, schwannoma, B, neurofibroma, and C, MPNST.