Circulating Growth Factor Levels Are Associated with Tumorigenesis in Neurofibromatosis Type 1

Mashour, George A.; Driever, Pablo Hernáiz; Hartmann, Melanie; Drissel, Stephanie N; Zhang, Tingguo; Scharf, Bianca; Felderhoff-Müser, Ursula; Sakuma, Sadatoshi; Friedrich, Reinhard E; Martuza, Robert L.; Mautner, Victor; Kurtz, Armin

doi:10.1158/1078-0432.ccr-03-0769

Cited by 44 publications

(30 citation statements)

References 45 publications

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“…Schwann cells and Schwann cell lines from patients with NF1 secrete high concentrations of Kit-L. 8 Despite the diversity of proteins secreted by Nf1 Ϫ/Ϫ Schwann cells, we provide here genetic and pharmacological lines of evidence to demonstrate that Kit-L is the predominant growth factor in these conditioned media that promotes degranulation of Nf1 ϩ/Ϫ mast cells. These in vitro studies are intriguing, given previous studies demonstrating that Kit-L transcripts are increased in neurofibromas 34 and Kit-L is found in increased concentrations in serum from patients with NF1 9.…”

Section: Discussionmentioning

confidence: 94%

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

Chen

Burgin

McDaniel

et al. 2010

The American Journal of Pathology

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Neurofibromatosis type 1 (NF1) is a common genetic disorder and is characterized by both malignant and nonmalignant neurofibromas, which are composed of Schwann cells, degranulating mast cells, fibroblasts, and extracellular matrix. We and others have previously shown that hyperactivation of the c-Kit pathway in an Nf1 haploinsufficient microenvironment is required for both tumor formation and progression. Mast cells play a key role in both tumorigenesis and neoangiogenesis via the production of matrix metalloproteinases, heparin, and a range of different growth factors. In the present study, we show that tumorigenic Schwann cells derived from Nf1 ؊/؊ embryos promote increased degranulation of Nf1 ؉/؊ mast cells compared with wild-type mast cells via the secretion of the Kit ligand. Furthermore, we used genetic intercrosses as well as pharmacological agents to link the hyperactivation of the p21Ras -phosphatidylinositol 3-kinase (PI3K) pathway to the increased degranulation of Nf1 ؉/؊ mast cells both in vitro and in vivo. These studies identify the p21 Ras -PI3K pathway as a major regulator of the gain in Nf1 ؉/؊ mast cell degranulation in neurofibromas. Collectively, these studies identify both c-Kit and PI3K as molecular targets that modulate mast cell functions in cases

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Section: Discussionmentioning

confidence: 94%

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

Chen

Burgin

McDaniel

et al. 2010

The American Journal of Pathology

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“…The stimulating effect of hormones on neurofibroma growth has previously been studied by other groups. Most of these studies focused on the in vitro effects of hGH (18,19) whereas Fischbein et al (10) recently examined expression of various steroid hormone receptors and ligand-mediated cell growth in cultured normal and neurofibroma-derived Schwann cells. From a clinical point of view, there are well-documented observations showing that neurofibromas tend to grow during adolescence and pregnancy.…”

Section: Discussionmentioning

confidence: 99%

Schwann Cells From Human Neurofibromas Show Increased Proliferation Rates Under the Influence of Progesterone

et al. 2008

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Neurofibromatosis type 1 (NF1) is a hereditary disease caused by mutations of the NF1 gene at 17q11.2. Loss of the NF1 gene product in Schwann cells leads to the development of benign nerve sheath tumors. These neurofibromas may occur at any time but tend to arise during periods of hormonal imbalance, suggesting that hormones influence neurofibroma growth. As steroid hormone levels rise during these times, we hypothesized that progesterone has proliferative effects on neurofibroma-derived Schwann cells. We chose specific medium conditions for selective proliferation of NF (ϩ/Ϫ) and NF (Ϫ/Ϫ) cells from human neurofibromas. Genetic characterization was not performed, but former works have shown that under the conditions used (ϩ/Ϫ) and (Ϫ/Ϫ) cells can be selected. Different progesterone concentrations were added at different days with BrdU-staining was performed to investigate proliferation rates and DAB-staining to identify a progesterone receptor. We could demonstrate that Schwann cells from human neurofibromas express progesterone receptors. These cells show elevated proliferation rates (highest in NF(Ϫ/Ϫ) cells) under progesterone, whereas normal human Schwann cells were not affected. These data suggest that progesterone plays an important role in the development of neurofibromas in NF1. (1). Thus, NF1 represents one of the most frequent hereditary diseases. The disease is characterized by typical clinical symptoms that were summarized in a "diagnostic criteria list" at a National Institutes of Health consensus conference in 1988 (2). Despite a markedly variable clinical expression, the hallmark feature of the disease is benign peripheral nerve sheath tumors termed neurofibromas. These tumors consist of a mixed cellular population that mainly consists of Schwann cells and fibroblasts but also contains a significant proportion of mast cells, perineurial, and endothelial cells (3). All NF1 patients will inevitably develop neurofibromas during their lifetime (1) but the number, size, and age of onset of these tumors are entirely unpredictable.Homozygous inactivation of the NF1 gene and subsequent loss of its gene product neurofibromin in Schwann cells has been identified as the primary step in a pathogenetic process that ultimately results in the development of neurofibromas (4,5). Many investigators (6,7) have stressed the fact that apart from mutations at NF1, various additional factors are necessary to enable neurofibroma formation. However, still very little is known about these additional factors, which might affect tumor development and growth in NF1.From a clinical view, dermal neurofibromas tend to develop in adolescence as well as during pregnancy. These are times of increased hormonal influence and it has to be postulated that steroid hormones might affect neurofibroma development.In this context, it is intriguing that progesterone-as a steroid hormone with numerous functions in the human body-has been shown to play an important role in myelin synthesis of Schwann cells. Jung-Testas et al. (8)...

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“…[10][11][12][13][14] Overexpression of the full-length MK and MKC (C-terminal truncated isoform) promoted tumorigenesis in vitro and in vivo. 15,16 Since MK can promote various cellular processes (e.g., cell proliferation, survival, migration, angiogenesis, drug resistance and antiviral action) associated with cancer development, [17][18][19][20][21][22][23][24][25] identification of function-specific receptors should become an important task.…”

Section: Introductionmentioning

confidence: 99%

Midkine induces epithelial-mesenchymal transition through Notch2/Jak2-Stat3 signaling in human keratinocytes

Huang¹,

Hoque²,

Wu³

et al. 2008

Cell Cycle

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Epithelial-to-mesenchymal transition (EMT) underlies cell plasticity and embryonic development and is frequently observed in advanced tumorigenesis. We demonstrated that midkine (MK), a retinoic acid-inducible heparin-binding mitogen, promotes EMT in immortalized HaCaT keratinocytes. We showed that MK binds to the Notch2 receptor in HaCaT keratinocytes. We further found that MK activates Notch2 signaling leading to protein/protein interactions between Hes1 and Jak2/Stat3 intermediates. We thus suggest that MK-induced cross talk of Notch2/Jak2/Stat3 signaling pathways can regulate cell plasticity and motility contributing to the EMT and later stages of tumorigenesis.

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Circulating Growth Factor Levels Are Associated with Tumorigenesis in Neurofibromatosis Type 1

Cited by 44 publications

References 45 publications

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

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

Schwann Cells From Human Neurofibromas Show Increased Proliferation Rates Under the Influence of Progesterone

Midkine induces epithelial-mesenchymal transition through Notch2/Jak2-Stat3 signaling in human keratinocytes

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