Nf1−/− Schwann Cell-Conditioned Medium Modulates Mast Cell Degranulation by c-Kit-Mediated Hyperactivation of Phosphatidylinositol 3-Kinase

Chen, Shi; Burgin, Sarah J.; McDaniel, Andrew S.; Li, Xiaohong; Yuan, Jin; Chen, Mia; Khalaf, Waleed; Clapp, D. Wade; Yang, Feng Chun

doi:10.2353/ajpath.2010.100369

Cited by 35 publications

(34 citation statements)

References 34 publications

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“…Specifically, a Rac2-Pak1-p38 signaling pathway induces F-actin rearrangement and cell motility, although the precise downstream effectors remain unknown (136). These cytoskeletal observations directly correlate with a genetic study showing that Nf1 +/- mast cells require PI-3K activity for Nf1 -/- Schwann cell conditioned media-dependent degranulation (140). Moreover, SCF-induced PI-3K-Rac2 activity promotes Akt's modulation of Bcl-2 family proteins (e.g.…”

Section: Schwann Cells Nf1 Haploinsufficient Mast Cells and The Tumsupporting

confidence: 78%

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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 Tumsupporting

confidence: 78%

“…(130, 135, 136, 138-140). However, biochemical investigations have additionally shown that the PI-3K-dependent pathway reinforces the classical Raf-Mek-Erk cascade through the activity of the p21 activated kinases (Paks) (130, 136).…”

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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“…This cell-to-cell interaction is mediated through the cell surface cytokine receptor known as c-kit. [9][10][11] Schwann cells in patients with NF1 express higher levels of c-kit compared with normal Schwann cells. 12 It is known that more mast cells are recruited and activated in plexiform than in encapsulated neurofibromas, but that increased mast cell signaling is seen in both NF1 tumor types.…”

Section: Figurementioning

confidence: 94%

Concurrent Ulcerative Colitis and Neurofibromatosis Type 1: The Question of a Common Pathway

et al. 2016

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Patients with neurofibromatosis type 1 (NF1) are prone to the development of gastrointestinal stromal tumors, which may present clinically with hematochezia, obstruction, or abdominal pain. These symptoms are also commonly associated with the presentation of ulcerative colitis (UC). Within the past 5 years, there have been 2 reports of concurrent NF1 and UC and a common pathophysiologic pathway involving mast cells has been postulated. We present the case of a 15-year-old boy with a known history of NF1 who presented with 3 months of hematochezia and loose stools. A colonoscopy revealed pancolitis and histology demonstrating acute cryptitis, focal crypt abscesses, and architectural distortion consistent with UC. Due to the paucity of reported cases, the findings of both diseases in the same individual could reasonably be discounted as coincidence. However, in light of increasing reports of concurrent NF1 and UC, advances in characterizing the microenvironment within neurofibromas, and recent findings regarding potential shared genetic susceptibility, it is increasingly possible that the proposed common pathway is accurate. Our case adds to the literature and underscores the need for further investigation.

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“…Using a combination of bone marrow transplantation and pharmacological inhibitor approaches, mast cells are required for murine plexiform neurofibroma formation and continued growth [47]. In these experiments, mast cells recruited by Nf1- deficient Schwann cell-produced stem cell factor (SCF or KIT-ligand) secrete cytokines that increase neurofibroma growth [48]. Moreover, SCF can also stimulate Nf1 +/− mast cells to increase fibroblast proliferation and collagen deposition, thereby forming a permissive tumor microenvironment [49].…”

Section: Tissue Levelmentioning

confidence: 99%

Contextual signaling in cancer

Smithson

Anastasaki

Chen

et al. 2016

Seminars in Cell & Developmental Biology

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The formation and maintenance of an organism is highly dependent on the orderly control of cell growth, differentiation, death, and migration. These processes are tightly regulated by signaling cascades in which a limited number of molecules dictate these cellular events. While these signaling pathways are highly conserved across species and cell types, the functional outcomes that result from their engagement are specified by the context in which they are activated. Using the Neurofibromatosis type-1 (NF1) cancer predisposition syndrome as an illustrative platform, we discuss how NF1/RAS signaling can create functional diversity at multiple levels (molecular, cellular, tissue, and genetic/genomic). As such, the ability of related molecules (e.g., K-RAS, H-RAS) to activate distinct effectors, as well as cell type- and tissue-specific differences in molecular composition and effector engagement, generate numerous unique functional effects. These variations, coupled with a multitude of extracellular cues and genomic/genetic changes that each modify the innate signaling properties of the cell, enable precise control of cellular physiology in both health and disease. Understanding these contextual influences is important when trying to dissect the underlying pathogenic mechanisms of cancer relevant to molecularly-targeted therapeutics.

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Nf1−/− Schwann Cell-Conditioned Medium Modulates Mast Cell Degranulation by c-Kit-Mediated Hyperactivation of Phosphatidylinositol 3-Kinase

Cited by 35 publications

References 34 publications

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

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

Concurrent Ulcerative Colitis and Neurofibromatosis Type 1: The Question of a Common Pathway

Contextual signaling in cancer

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