Role for the stem cell factor/KIT complex in schwann cell neoplasia and mast cell proliferation associated with neurofibromatosis

Ryan, John; Klein, Karen A.; Neuberger, T. J.; Leftwich, Julie A.; Westin, Eric H.; Kauma, Scott W.; Fletcher, Jonathan A.; DeVries, George H.; Huff, Thomas

doi:10.1002/jnr.490370314

Cited by 85 publications

(75 citation statements)

References 66 publications

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“…51 Previous studies have suggested that mast cells may induce or contribute to tumor formation in Nf1 mutant mouse models. 11,52 We found that mast cells infiltrate sNF96.2 xenografted tumors in scid mice, and do so in a manner similar to mast cell infiltrates seen in human NF1 MPNSTs. 53 Mast cells may be important contributors to NF1 tumor angiogenesis and progression in the tumor environment.…”

Section: Discussionsupporting

confidence: 55%

An orthotopic xenograft model of intraneural NF1 MPNST suggests a potential association between steroid hormones and tumor cell proliferation

Perrin

Fishbein

et al. 2007

Laboratory Investigation

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Malignant peripheral nerve sheath tumors (MPNST) are the most aggressive cancers associated with neurofibromatosis type 1 (NF1). Here we report a practical and reproducible model of intraneural NF1 MPNST, by orthotopic xenograft of an immortal human NF1 tumor-derived Schwann cell line into the sciatic nerves of female scid mice. Intraneural injection of the cell line sNF96.2 consistently produced MPNST-like tumors that were highly cellular and showed extensive intraneural growth. These xenografts had a high proliferative index, were angiogenic, had significant mast cell infiltration and rapidly dominated the host nerve. The histopathology of engrafted intraneural tumors was consistent with that of human NF1 MPNST. Xenograft tumors were readily examined by magnetic resonance imaging, which also was used to assess tumor vascularity. In addition, the intraneural proliferation of sNF96.2 cell tumors was decreased in ovariectomized mice, while replacement of estrogen or progesterone restored tumor cell proliferation. This suggests a potential role for steroid hormones in supporting tumor cell growth of this MPNST cell line in vivo. The controlled orthotopic implantation of sNF96.2 cells provides for the precise initiation of intraneural MPNST-like tumors in a model system suitable for therapeutic interventions, including inhibitors of angiogenesis and further study of steroid hormone effects on tumor cell growth. KEYWORDS: neurofibromatosis; malignant peripheral nerve sheath tumor; angiogenesis; xenografts; orthotopic; steroid hormone Malignant peripheral nerve sheath tumors (MPNST) are often associated with neurofibromatosis type 1 (NF1), and are thought to arise from plexiform neurofibromas. 1,2 In fact, neurofibromas coexisting with MPNSTs were found in 81% of patients with NF1 but only in 41% of non-NF1 patients. 3 Progression to malignancy from plexiform neurofibroma occurs in about 6% of NF1 patients, although the lifetime risk of MPNST in NF1 has been estimated as high as 8-13%, 4 and is associated with high mortality. 5 NF1 MPNSTs have distinctive characteristics. 6 They are densely hypercellular and composed of spindle-shaped cells. The clonal elements with Schwann cell (SC) characteristics have a high proliferative index (5-38% Ki67-positive cells) and exhibit nuclear hyperchromasia and nuclear enlargement. Their growth is characterized by abrupt variation in cellularity and tissue pattern. They are firm, gray-tan and opaque, may grow very large and can be surrounded by a pseudocapsule. They may have areas of localized necrosis and tend to extend intraneurally.A great deal of progress has been made developing cell lines and mouse models of NF1 tumors for experimental study and clinical testing. These cell lines and models have proven invaluable in furthering our understanding of the biology of NF1. Mice generated with a null mutation in the

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Section: Discussionsupporting

confidence: 55%

An orthotopic xenograft model of intraneural NF1 MPNST suggests a potential association between steroid hormones and tumor cell proliferation

Perrin

Fishbein

et al. 2007

Laboratory Investigation

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“…Although the nature of these paracrine signaling factors is incompletely understood, there is good evidence that at least one of them is stem cell factor (SCF, also known as Kit ligand), a protein that promotes the migration, survival, maturation, and activation of mast cells. 35,36 NF1 loss enhances SCF expression, with NF1 À/À Schwann cells secreting sixfold higher levels of SCF than NF1 þ/À or wild-type Schwann cells. 37 Intriguingly, changes in NF1 copy number also affects mast cell physiology; NF1 þ/À mast cells show enhanced proliferation, survival, and migration when challenged with SCF.…”

Section: Oncogenomics In Mpnst Modelsmentioning

confidence: 96%

The Challenge of Cancer Genomics in Rare Nervous System Neoplasms

Carroll

2016

The American Journal of Pathology

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Comprehensive genomic analyses of common nervous system cancers provide new insights into their pathogenesis, diagnosis, and treatment. Although analogous studies of rare nervous system tumors are needed, there are major barriers to performing such studies. Cross-species comparative oncogenomics, identifying driver mutations in mouse cancer models and validating them in human tumors, is a promising alternative. Although still in its infancy, this approach is being applied to malignant peripheral nerve sheath tumors (MPNSTs), rare Schwann cellederived malignancies that occur sporadically, after radiotherapy, and in neurofibromatosis type 1. Studies of human neurofibromatosis type 1eassociated tumors suggest that NF1 tumor suppressor loss in Schwann cells triggers cell-autonomous and intercellular changes, resulting in development of benign neurofibromas; subsequent neurofibroma-MPNST progression is caused by aberrant growth factor signaling and mutations affecting the p16 INK4A -cyclin D1-CDK4-Rb and p19 ARF -Mdm2-p53 cell cycle pathways. Mice with Nf1, Trp53, and/or Cdkn2a mutations that overexpress the Schwann cell mitogen neuregulin-1 or overexpress the epidermal growth factor receptor validate observations in human tumors and, to various degrees, model human tumorigenesis. Genomic analyses of MPNSTs arising in neuregulin-1 and epidermal growth factor receptor-overexpressing mice and forward genetic screens with Sleeping Beauty transposons implicate additional signaling cascades in MPNST pathogenesis. These studies confirm the utility of mouse models for MPNST driver gene discovery and provide new insights into the complexity of MPNST pathogenesis. (Am J Pathol 2016, 186: 464e477; http://dx

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“…SC/nervous system interdependence leads to mutual disturbances. For example, experimental and genetically determined SC diseases often result in axonal pathology (Ryan et al 1994). Mycobacterium leprae, the causative agent of leprosy, presents a unique characteristic among human pathogens in its ability to invade and survive inside SC (Rambukkana et al 1997).…”

mentioning

confidence: 99%

Morphological and functional characterizations of Schwann cells stimulated with Mycobacterium leprae

Silva¹,

Silva²,

Baruque³

et al. 2008

Mem. Inst. Oswaldo Cruz

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Role for the stem cell factor/KIT complex in schwann cell neoplasia and mast cell proliferation associated with neurofibromatosis

Cited by 85 publications

References 66 publications

An orthotopic xenograft model of intraneural NF1 MPNST suggests a potential association between steroid hormones and tumor cell proliferation

An orthotopic xenograft model of intraneural NF1 MPNST suggests a potential association between steroid hormones and tumor cell proliferation

The Challenge of Cancer Genomics in Rare Nervous System Neoplasms

Morphological and functional characterizations of Schwann cells stimulated with Mycobacterium leprae

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