Induction of Abnormal Proliferation by Nonmyelinating Schwann Cells Triggers Neurofibroma Formation

Abstract

Recent evidence suggests that alterations in the self-renewal program of stem/progenitor cells can cause tumorigenesis. By utilizing genetically engineered mouse models of neurofibromatosis type 1 (NF1), we demonstrated that plexiform neurofibroma, the only benign peripheral nerve sheath tumor with potential for malignant transformation, results from Nf1 deficiency in fetal stem/progenitor cells of peripheral nerves. Surprisingly, this did not cause hyperproliferation or tumorigenesis in early postnatal period. Instead, peripheral nerve development appeared largely normal in the absence of Nf1 except for abnormal Remak bundles, the nonmyelinated axon-Schwann cell unit, identified in postnatal mutant nerves. Subsequent degeneration of abnormal Remak bundles was accompanied by initial expansion of nonmyelinating Schwann cells. We suggest abnormally differentiated Remak bundles as a cell of origin for plexiform neurofibroma.

Sustained Axon–Glial Signaling Induces Schwann Cell Hyperproliferation, Remak Bundle Myelination, and Tumorigenesis

“…Interestingly, it has been suggested that the induction of abnormal proliferation of nmSC triggers neurofibroma formation. In Nf1 flox/Ϫ ;P0A-cre ϩ mice, Zheng et al (2008) have shown that Nf1 deficiency does not cause hyperproliferation or tumorigenesis during the early postnatal period. The only differential trait found at this time is the existence of abnormal Remak bundles.…”

“…We also show that overexpression of SMDF provokes a dramatic proliferation of nmSC, suggesting that neuregulin is an in vivo mitogenic signal for these cells. Akin to type I neurofibromatosis (Ling et al, 2005;Zheng et al, 2008), mutant nerves show increased deposits of collagen fibrils in the extracellular space and, in some cases, develop big tumors, suggesting that neuregulin overexpression in the small-sized axons of Remak bundles could be involved in the development of neurofibroma and other peripheral nerve tumors.…”

The Activation of the WNT Signaling Pathway Is a Hallmark in Neurofibromatosis Type 1 Tumorigenesis

“…During development, neural-crest cells migrate along the peripheral nerves, and a subset of cells commit to the Schwann cell lineage. Zheng and colleagues demonstrated that plexiform neurofibromas could originate from Nf1 deficiency in fetal nonmyelinating Schwann cells (4). Le and colleagues identified a population of progenitor cells residing in the dermis, termed "skin-derived precursors" that form dermal neurofibromas through loss of Nf1 (5).…”

“…In NF1 tumorigenesis, the question whether these tumors arise from neural crest stem cells or differentiates glia remains very controversial (4,5,16,17). In this regard, we have previously shown a dedifferentiation of Schwann cells, as well as an activation of the Hedgehog signaling pathway, during malignant transformation of plexiform neurofibromas (18).…”

The Dark Side of Cellular Plasticity: Stem Cells in Development and Cancer

“…In other tissular context, targeting astrocytoma-associated oncogenic lesions to the nervous system progenitors results in tumour development, whereas targeting them to the zone containing just differentiated cells only gives rise to local astrogliosis (Alcantara Llaguno et al, 2009). In all these and other similar cases (Dirks, 2008;Joseph et al, 2008;Zheng et al, 2008) it is therefore clear that the initiating event must take place in a stem cell, even if, afterwards, the macroscopic tumour is composed by differentiated cells. This indicates a pathological direct reprogramming mediated by the oncogenic lesions.…”