Stem cells undergo self-renewal divisions, as well as produce daughter cells that differentiate into specific tissue lineages, thus playing an essential role in tissue homeostasis. Whether self-renewal or differentiation occurs is under strict regulation by both intrinsic and extrinsic factors. There is increasing evidence that in many tissues, tumor initiation can result from acquisition of genetic mutations in stem cells or their progenitors followed by alterations of the surrounding microenvironment (1
). Neurofibromatosis Type 1 (NF1) is a heritable genetic disease in which afflicted individuals suffer a germ line loss of function mutation in one allele. Upon stochastic somatic loss of heterozygosity (LOH), deregulation of the Ras signal transduction pathway leads to the development of multiple neurofibromas, which are benign tumors of the peripheral nerves. A large body of direct and indirect studies has provided evidence that NF1
gene deletion in the Schwann cell lineage is the requisite initial step that precedes the cascade of interactions with other cell types in the microenvironment as well as additional cell autonomous modifications (3
). Many studies further suggest that somatic stem cells or their progenitors may be the cells of origin of neurofibromas (3
). This stem cell model of tumorigenesis has important implications for understanding early cellular events that dictate neurofibromagenesis, as well as other tumor types. In addition, the concept of neurofibroma as a disease of stem and progenitor cells has implications for the development of novel therapies targeting these tumors.
NF1 is one of the most common genetic disorders of the nervous system, affecting 1 in 3,500 individuals worldwide (13
). NF1 patients have a wide spectrum of clinical presentations, including developmental, pigment or neoplastic aberrations of the skin, nervous system, bones, endocrine organs, blood vessels and eyes. The cardinal features of NF1 are café au lait macules, axillary and groin freckling, combined with multiple peripheral and central nerve tumors (16
The development of neurofibromas, the most frequent tumor in NF1, and malignant peripheral nerve sheath tumors (MPNSTs) represents a serious complication. These are unique and complex tumors that contain proliferating Schwann-like cells and other local supporting elements of the nerve fibers, including perineurial cells, neurons, fibroblasts, and blood vessels, as well as infiltration of mast cells. Neurofibromas are classified as dermal or plexiform. Dermal neurofibromas are exclusively in the skin and occur in virtually all individuals with NF1 primarily emerging around puberty. Plexiform neurofibromas, although similar to dermal neurofibromas at the cellular and ultrastructural levels, develop along a nerve plexus. They occur in about 30% of NF1 individuals and are virtually pathognomonic of the disease (21
). Plexiform neurofibromas are thought to be congenital and owing to their unusual capacity for growth, can be life threatening through physical impairment of organ or neural function. In addition, patients with plexiform neurofibromas have a 10% lifetime risk of developing MPNSTs, which can widely metastasize and often signal a fatal outcome (21
). Current treatment options for NF1-related tumors are primarily limited to surgery and longitudinal surveillance.
The temporally and spatially distinct clinical presentation of dermal versus plexiform neurofibromas supports the hypothesis that these neurofibromas may originate from distinct progenitor cells. The use of mouse models of temporal and spatial somatic NF1
gene deletion has shed light on this hypothesis. We recently reported that Skin-derived Precursors (SKPs), a neural-crest like neural stem cell residing in the dermis, are the cell of origin for dermal neurofibromas (3
). Additional and varied mouse models of NF1 plexiform neurofibromas are consistent with the idea that some form of Schwann cell lineage cells are the likeliest candidates to give rise to plexiform tumors (9
). During the development of peripheral nerves, neural crest cells generate myelinating and non-myelinating Schwann cells in a process that parallels embryonic development. Migrating neural crest cells move through immature connective tissue before the time of nerve formation at mouse embryonic days E9-E11, and then differentiate into Schwann cell precursors (SCPs) between E12-E13. These Schwann cell precursors then become immature Schwann cells, which are generated from E14 until early neonatal stages. The immature Schwann cells eventually differentiate into mature Schwann cells after birth (25
). Given that the majority of plexiform neurofibromas are generally detected at birth or in infancy, we hypothesize that there must exist a temporal “window of opportunity” for NF1
loss in cells of the Schwann cell lineage to elicit tumor development. To gain insight into this question we employed spatially and temporally-controlled Cre driver transgenes to ablate NF1
function in the Schwann cell lineage at various developmental time points. In this model, we find that tumor incidence is highest when NF1
function is deleted during the embryonic period when Schwann cell precursor and immature Schwann cells predominate, suggesting that these cells are the likely sources for plexiform neurofibroma tumorigenesis.