The ecology of brain tumors: lessons learned from neurofibromatosis-1

Pong, Winnie W.; Gutmann, David H.

doi:10.1038/onc.2010.519

Cited by 16 publications

(12 citation statements)

References 125 publications

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“…Mouse models of NF1-associated optic glioma formation have demonstrated the importance of heterotypic interactions between the tumorigenic astrocyte and gliomagen-elaborating microglia, hematopoietic effectors derived from monocyte precursor cells (reviewed in (146)). Neoplastic and pre-neoplastic astrocytes secrete multiple factors attracting and expanding microglia populations (146).…”

Section: Schwann Cells Nf1 Haploinsufficient Mast Cells and The Tummentioning

confidence: 99%

“…Neoplastic and pre-neoplastic astrocytes secrete multiple factors attracting and expanding microglia populations (146). Similar to the Nf1 +/- mast cell, Nf1 +/- microglia demonstrate multiple gain-in-functions, including enhanced macrophage-colony stimulated factor- (M-CSF)-mediated proliferation and production of hyaluronidase (105).…”

Section: Schwann Cells Nf1 Haploinsufficient Mast Cells and The Tummentioning

confidence: 99%

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Pathogenesis of Plexiform Neurofibroma: Tumor-Stromal/Hematopoietic Interactions in Tumor Progression

Staser¹,

Yang

Clapp

2012

Annu. Rev. Pathol. Mech. Dis.

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Neurofibromatosis type 1 (NF1) is a genetic disease that results from either heritable or spontaneous autosomal dominant mutations in the NF1 gene. A second-hit mutation precedes the predominant NF1 neoplasms, including myeloid leukemia, optic glioma, and plexiform neurofibroma formation. Despite this requisite NF1 loss of heterozygosity in the tumor cell of origin, non-tumorigenic cells contribute to both generalized and specific disease manifestations. In mouse models of plexiform neurofibroma formation, Nf1 haploinsufficient mast cells promote inflammation accelerating tumor formation and growth. These recruited mast cells, hematopoietic effector cells long known to permeate neurofibroma tissue, mediate key mitogenic signals promoting vascular in-growth, collagen deposition, and tumor growth. Thus, the plexiform neurofibroma microenvironment involves a tumor/stromal interaction with the hematopoietic system which depends, at the molecular level, on a stem cell factor/c-kit-mediated signaling axis. These observations parallel findings in other NF1 disease manifestations and have clear relevance toward medical neurofibroma management.

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Section: Schwann Cells Nf1 Haploinsufficient Mast Cells and The Tummentioning

confidence: 99%

Section: Schwann Cells Nf1 Haploinsufficient Mast Cells and The Tummentioning

confidence: 99%

Pathogenesis of Plexiform Neurofibroma: Tumor-Stromal/Hematopoietic Interactions in Tumor Progression

Staser¹,

Yang

Clapp

2012

Annu. Rev. Pathol. Mech. Dis.

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“…The egh nerve phenotype somewhat resembles the human inherited disease neurofibromatosis 1 (NF1), where deregulated reciprocal signaling between glial cells and immune cells is thought to be an important factor (Pong and Gutmann, ; Yang et al, ). The overgrown egh nerves often exhibit a striking accumulation of plasmatocytes, a macrophage‐like cell type (Dahlgaard et al, ).…”

Section: Resultsmentioning

confidence: 99%

Mactosylceramide prevents glial cell overgrowth by inhibiting insulin and fibroblast growth factor receptor signaling

Gerdøe-Kristensen

Lund

Wandall

et al. 2017

Journal Cellular Physiology

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Receptor tyrosine kinase (RTK) signaling controls key aspects of cellular differentiation, proliferation, survival, metabolism, and migration. Deregulated RTK signaling also underlies many cancers. Glycosphingolipids (GSL) are essential elements of the plasma membrane. By affecting clustering and activity of membrane receptors, GSL modulate signal transduction, including that mediated by the RTK. GSL are abundant in the nervous system, and glial development in Drosophila is emerging as a useful model for studying how GSL modulate RTK signaling. Drosophila has a simple GSL biosynthetic pathway, in which the mannosyltransferase Egghead controls conversion of glucosylceramide (GlcCer) to mactosylceramide (MacCer). Lack of elongated GSL in egghead (egh) mutants causes overgrowth of subperineurial glia (SPG), largely due to aberrant activation of phosphatidylinositol 3-kinase (PI3K). However, to what extent this effect involves changes in upstream signaling events is unresolved. We show here that glial overgrowth in egh is strongly linked to increased activation of Insulin and fibroblast growth factor receptors (FGFR). Glial hypertrophy is phenocopied when overexpressing gain-of-function mutants of the Drosophila insulin receptor (InR) and the FGFR homolog Heartless (Htl) in wild type SPG, and is suppressed by inhibiting Htl and InR activity in egh. Knockdown of GlcCer synthase in the SPG fails to suppress glial overgrowth in egh nerves, and slightly promotes overgrowth in wild type, suggesting that RTK hyperactivation is caused by absence of MacCer and not by GlcCer accumulation. We conclude that an early product in GSL biosynthesis, MacCer, prevents inappropriate activation of insulin and fibroblast growth factor receptors in Drosophila glia.

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“…The dependence on these stromal cells and growth factors is nicely illustrated by Nf1 mouse models of plexiform neurofibroma and optic glioma [93]. In these genetically engineered mouse strains, loss of Nf1 gene expression in neoplastic Schwann cell or neuroglial progenitors alone is not sufficient for plexiform neurofibroma [94] or optic glioma [95, 96] formation, respectively.…”

Section: Nf1 Gene Structure and Functionmentioning

confidence: 99%

Using the Neurofibromatosis Tumor Predisposition Syndromes to Understand Normal Nervous System Development

Garcia

Gutmann

2014

Scientifica

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Development is a tightly regulated process that involves stem cell self-renewal, differentiation, cell-to-cell communication, apoptosis, and blood vessel formation. These coordinated processes ensure that tissues maintain a size and architecture that is appropriate for normal tissue function. As such, tumors arise when cells acquire genetic mutations that allow them to escape the normal growth constraints. In this regard, the study of tumor predisposition syndromes affords a unique platform to better understand normal development and the process by which normal cells transform into cancers. Herein, we review the processes governing normal brain development, discuss how brain cancer represents a disruption of these normal processes, and highlight insights into both normal development and cancer made possible by the study of tumor predisposition syndromes.

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The ecology of brain tumors: lessons learned from neurofibromatosis-1

Cited by 16 publications

References 125 publications

Pathogenesis of Plexiform Neurofibroma: Tumor-Stromal/Hematopoietic Interactions in Tumor Progression

Pathogenesis of Plexiform Neurofibroma: Tumor-Stromal/Hematopoietic Interactions in Tumor Progression

Mactosylceramide prevents glial cell overgrowth by inhibiting insulin and fibroblast growth factor receptor signaling

Using the Neurofibromatosis Tumor Predisposition Syndromes to Understand Normal Nervous System Development

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