Neurofibroma-associated growth factors activate a distinct signaling network to alter the function of neurofibromin-deficient endothelial cells

Munchhof, Amy M.; Li, Fang; White, Hilary; Mead, Laura E.; Krier, Theresa R.; Fenoglio, Amy; Li, Xiaohong; Yuan, Jin; Yang, Feng Chun; Ingram, David A.

doi:10.1093/hmg/ddl108

Cited by 52 publications

(52 citation statements)

References 50 publications

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“…Therefore, excessive infiltration of Nf1 +/-inflammatory cells into the neointima is an important observation, since chronic inflammation may promote EC senescence and increased VSMC proliferation (11,12) in NF1 patients, resulting in vascular lesion formation. Neurofibromin has clearly been established as a critical regulator of EC, VSMC, and BM cell function in vitro and in vivo in response to multiple growth factors implicated in vessel wall homeostasis and neointima formation (13)(14)(15)(16). However, despite these observations, it remains unclear which cell lineage(s) are the major contributor to neointima formation in Nf1 +/-mice, and this determination is essen-tial to understand the pathophysiology of NF1 vascular disease and potential therapeutic interventions.…”

Section: Introductionmentioning

confidence: 99%

Genetic and cellular evidence of vascular inflammation in neurofibromin-deficient mice and humans

Lasater¹,

Li²,

Bessler³

et al. 2010

J. Clin. Invest.

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Neurofibromatosis type 1 (NF1) results from mutations in the NF1 tumor suppressor gene, which encodes the protein neurofibromin. NF1 patients display diverse clinical manifestations, including vascular disease, which results from neointima formation and vessel occlusion. However, the pathogenesis of NF1 vascular disease remains unclear. Vessel wall homeostasis is maintained by complex interactions between vascular and bone marrow-derived cells (BMDCs), and neurofibromin regulates the function of each cell type. Therefore, utilizing cre/lox techniques and hematopoietic stem cell transplantation to delete 1 allele of Nf1 in endothelial cells, vascular smooth muscle cells, and BMDCs alone, we determined which cell lineage is critical for neointima formation in vivo in mice. Here we demonstrate that heterozygous inactivation of Nf1 in BMDCs alone was necessary and sufficient for neointima formation after vascular injury and provide evidence of vascular inflammation in Nf1 +/-mice. Further, analysis of peripheral blood from NF1 patients without overt vascular disease revealed increased concentrations of inflammatory cells and cytokines previously linked to vascular inflammation and vasoocclusive disease. These data provide genetic and cellular evidence of vascular inflammation in NF1 patients and Nf1 +/-mice and provide a framework for understanding the pathogenesis of NF1 vasculopathy and potential therapeutic and diagnostic interventions. IntroductionNeurofibromatosis type 1 (NF1) is an autosomal dominant disorder that results from mutations in the tumor suppressor gene NF1 (1). Neurofibromin, the protein product of NF1, functions as a p21 Ras (Ras) GTPase-activating protein (GAP) to negatively regulate Ras activity (2). More than 240 different mutations have been described within the NF1 gene, all of which result in little or no protein product (3). While loss of heterozygosity has been described in primary tumor samples (4), the germline mutations that cause NF1 affect only 1 copy of the NF1 gene. Haploinsufficiency of NF1 results in disease with complete penetrance and a range of clinical complications.The most common clinical manifestations of NF1 include dermal and plexiform neurofibromas, learning deficits, and skeletal abnormalities. Vascular disease associated with NF1 is an underrecognized complication that results in increased morbidity and mortality, particularly among younger patients (5, 6). In 2001, an analysis of 3,253 death certificates of persons with NF1 indicated that the median age of death for NF1 patients was 15 years lower that of the general population (6). In this report, a diagnosis suggestive of NF1 vasculopathy was listed 7.2 times more often than expected among NF1 patients less than 30 years old at time of death and 2.2 times more often than expected among patients 30-40 years old at the time of death (6). Another study demonstrated that 2.5% of children with NF1 who had undergone brain MRI were found to have cerebrovascular system abnormalities including narrowed vessels, moyamoya, va...

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Section: Introductionmentioning

confidence: 99%

Genetic and cellular evidence of vascular inflammation in neurofibromin-deficient mice and humans

Lasater¹,

Li²,

Bessler³

et al. 2010

J. Clin. Invest.

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“…Surprisingly, Krox20cre mice crossed into mice with mice carrying two distinct W mutations, a mutation which compromises c-kit receptor tyrosine kinase activity and inhibits mast cell production and bioactivity [36]. [20,[38][39][40]. Moreover, SCF-stimulated Nf1 +/− mast cells, as compared to WT mast cells, proliferate more quickly, demonstrate enhanced survival, and secrete greater concentrations of inflammatory cytokines [38,[41][42][43].…”

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confidence: 99%

The Plexiform Neurofibroma Microenvironment

Yang

Staser

2012

Cancer Microenvironment

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Dynamic interactions between tumorigenic cells and surrounding cells, including immunomodulatory hematopoietic cells, can dictate tumor initiation, progression, and transformation. Hematopoietic-stromal interactions underpin the plexiform neurofibroma, a debilitating tumor arising in individuals afflicted with Neurofibromatosis type 1 (NF1), a common genetic disorder resulting from mutations in the NF1 tumor suppressor gene. At the tissue level, plexiform neurofibromas demonstrate a complex microenvironment composed of Schwann cells, fibroblasts, perineural cells, mast cells, secreted collagen, and blood vessels. At the cellular level, specific interactions between these cells engender tumor initiation and progression. In this microenvironment hypothesis, tumorigenic Schwann cells secrete pathological concentrations of stem cell factor, which recruit c-kit expressing mast cells. In turn, activated mast cells release inflammatory effectors stimulating the tumorigenic Schwann cells and their supporting fibroblasts and blood vessels, thus promoting tumor expansion in a feed-forward loop. Bone marrow transplantation experiments in plexiform neurofibroma mouse models have shown that tumorigenesis requires Nf1 haploinsufficiency in the hematopoietic compartment, suggesting that tumor microenvironments can depend on intricate interactions at both cellular and genetic levels. Overall, our continued understanding of critical tumor-stromal interactions will illuminate novel therapeutic targets, as shown by the first-ever successful medical treatment of a plexiform neurofibroma by targeted inhibition of the stem cell factor/c-kit axis.

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“…Wu et al 163 have recently demonstrated that NF1 +/-endothelial cells undergo increased neovascularization when exposed to hypoxia and the angiogenic factor bFGF, as compared to wildtype littermates in a mouse model. Separately, Munchoff et al 107 have provided mouse in vitro and in vivo data corroborating these findings and implicating a Ras-dependent pathway, verified in tissue from a patient with NF1, in the process of neoangiogenesis. A wide variety of additional stimulatory autocrine and paracrine growth factors have been implicated as contributors to the tumor-promoting environment.…”

Section: Contributions Of the Local Microenvironment A Large Quantitmentioning

confidence: 79%

Experimental therapeutic approaches to peripheral nerve tumors

Riley¹,

Spiotta

Boulis³

2007

FOC

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✓Discovery that the Schwann cell is the primary cell type responsible for both the neurofibroma as well as the schwannoma has proven to represent a crucial milestone in understanding the pathogenesis of peripheral nerve tumor development. This information and related findings have served as a nidus for research aimed at more fully characterizing this family of conditions. Recent discoveries in the laboratory have clarified an understanding of the molecular mechanisms underlying the pathogenesis of benign peripheral nerve tumors. Similarly, the mechanisms whereby idiopathic and syndromic (NF1- and NF2-associated) nerve sheath tumors progress to malignancy are being elucidated. This detailed understanding of the molecular pathogenesis of peripheral nerve tumors provides the information necessary to create a new generation of therapies tailored specifically to the prevention, cessation, or reversal of pathological conditions at the fundamental level of dysfunction. The authors review the data that have helped to elucidate the molecular pathogenesis of this category of conditions, explore the current progress toward exploitation of these findings, and discuss potential therapeutic avenues for future research.

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Neurofibroma-associated growth factors activate a distinct signaling network to alter the function of neurofibromin-deficient endothelial cells

Cited by 52 publications

References 50 publications

Genetic and cellular evidence of vascular inflammation in neurofibromin-deficient mice and humans

Genetic and cellular evidence of vascular inflammation in neurofibromin-deficient mice and humans

The Plexiform Neurofibroma Microenvironment

Experimental therapeutic approaches to peripheral nerve tumors

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