Plexiform and Dermal Neurofibromas and Pigmentation Are Caused by Nf1 Loss in Desert Hedgehog-Expressing Cells

Wu, Jianqiang; Williams, Jonathan; Rizvi, Tilat A.; Kordich, Jennifer J.; Witte, David P.; Meijer, Dies; Stemmer‐Rachamimov, Anat; Cancelas, José A.; Ratner, Nancy

doi:10.1016/j.ccr.2007.12.027

Cited by 198 publications

(252 citation statements)

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“…A follow-up study using reciprocal bone-marrow transplantation between Nf1 +/-and Nf1 +/+ mice provide evidence that an Nf1 +/-c-Kit expressing hematopoietic cell contributes strongly to the plexiform neurofibroma phenotype, independent of Cre-mediated recombination ). In contrast, recent studies have reported the generation of plexiform neurofibromas in a wildtype Nf1 environment (Wu et al 2008) and that wildtype mast cells can contribute to tumor formation (Monk et al 2007). With the data presented in this paper, we can now reconcile these seemingly disparate results, clarifying the role of the Nf1 +/-microenvironment in peripheral nerve sheath tumorigenesis.…”

Section: The Contribution Of the Nf1 Heterozygous Environmentsupporting

confidence: 50%

Characterization of Neurofibromas of the Skin and Spinal Roots in a Mouse Model

Zhu¹

2011

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE (DD-MM-YYYY)2. REPORT TYPE 3. DATES COVERED (From -To) 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER 5e. TASK NUMBER E-Mail:5f. WORK UNIT NUMBER Benign neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs) contribute to the majority of morbidity and mortality associated with NF1. The proposed studies are attempting to provide insights into one of the fundamental questions in neurofibroma biology: whether bi-allelic NF1 inactivation is necessary for neurofibroma formation. The objectives of this proposal are to use a series of newly established mouse models to (1) identify and characterize neurofibromas that are exclusively or predominantly comprised of NF1+/-cells (designated NF1+/-neurofibromas hereafter) in the skin and spinal roots; and (2) determine whether in this model, neurofibromas in the skin are similar to human dermal neurofibromas and thus are fundamentally different from the plexiform neurofibromas found in spinal roots. Previous studies of human tumors suggest that dermal and plexiform neurofibromas have fundamental differences in their dependence on the NF1 heterozygous environment and have different malignant transformation potentials. We have made substantial progress in the past four years of the award. For Task 1, we demonstrated that bi-allelic inactivation of Nf1 in neural crest stem cells is required for neurofibroma formation. These results resulted in publication of 3 manuscripts in 2008 (see appendices). For Task 2, we have determined that the Nf1 heterozygous environment promotes neurofibroma progression, but is not required for tumor initiation. For Task 3, we demonstrate that the Nf1 heterozygous environment is not required for malignant transformation of neurofibroma. We have established novel mouse models for MPNST, in which neurofibroma arises first followed by MPNST formation -a stepwise process that closely resembles the progressive nature of human MPNST. We are currently working on a manuscript to publish these results. We have written a manuscript based upon the results from Task 2...

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Section: The Contribution Of the Nf1 Heterozygous Environmentsupporting

confidence: 50%

Characterization of Neurofibromas of the Skin and Spinal Roots in a Mouse Model

Zhu¹

2011

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“…The bi-allelic inactivation leading to the development of plexiform neurofibromas apparently takes place in embryonic cells that have the potential to generate large populations of cells carrying a single NF1 second-hit mutation. 77,81 The growth of plexiform neurofibromas during early childhood distinguishes these tumors from cutaneous neurofibromas, which are undetectable before puberty. 5 Mouse studies have demonstrated that Nf1 Ϫ/Ϫ Schwann cells are necessary, but not sufficient, for tumor formation to occur.…”

Section: Pathogenesis Of Plexiform Neurofibromasmentioning

confidence: 99%

The Pathoetiology of Neurofibromatosis 1

Jouhilahti

Peltonen

Heape

et al. 2011

The American Journal of Pathology

158

150

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Although a mutation in the NF1 gene is the only factor required to initiate the neurocutaneous-skeletal neurofibromatosis 1 (NF1) syndrome, the pathoetiology of the multiple manifestations of this disease in different organ systems seems increasingly complex. The wide spectrum of different clinical phenotypes and their development, severity, and prognosis seem to result from the cross talk between numerous cell types, cell signaling networks, and cell-extracellular matrix interactions. The bi-allelic inactivation of the NF1 gene through a "second hit" seems to be of crucial importance to the development of certain manifestations, such as neurofibromas, café-au-lait macules, and glomus tumors. In each case, the second hit involves only one cell type, which is subsequently clonally expanded in a discrete lesion. Neurofibromas, which are emphasized in this review, and cutaneous neurofibromas in particular, are known to contain a subpopulation of NF1-diploinsufficient Schwann cells and a variety of NF1-haploinsufficient cell types. A recent study identified a multipotent precursor cell population with an NF1 ؉/؊ genotype that resides in human cutaneous neurofibromas and that has been suggested to play a role in their pathogenesis. café-au-lait macules and multiple benign cutaneous neurofibromas, which, typically, are detectable in adulthood by simple visual inspection.NF1 can affect nearly every organ system, and the complications vary between individuals, even within a single family. The clinical diagnosis is based on the presence of two or more of the following findings: six or more café-au-lait macules with diameters Ͼ5 mm in prepubertal patients and Ͼ15 mm in postpubertal patients; two or more neurofibromas of any type or one plexiform neurofibroma; axillary or inguinal freckling; optic glioma; two or more Lisch nodules of the iris; a distinctive osseous lesion, such as sphenoid wing dysplasia or pseudarthrosis; or a first-degree relative diagnosed as having NF1 according to the preceding criteria. 3 It has been suggested that a pathogenic mutation in the NF1 gene be added to the list of diagnostic criteria. 4 The most common complications of NF1 are included in the previously listed diagnostic criteria. Additional features include short stature, scoliosis, headache, speech disorders, attention deficit disorder and attention-deficit/ hyperactivity disorder, and learning disabilities. Rare complications, affecting Ͻ5% of patients, include epilepsy, hydrocephalus, cardiovascular problems, and dystrophic scoliosis. 5 The lifetime risk of malignant tumors arising from peripheral nerves is estimated to be 10% to 13%. 6 The pathoetiology of the complications in NF1 is, however, largely unknown. Genetic BackgroundNF1 is caused by mutations in the NF1 gene that encodes the tumor suppressor protein neurofibromin. 7,8 The NF1 gene is located on chromosome band 17q11.2, spanning approximately 280 kb of genomic DNA, and is composed of 57 constitutive exons and 4 alternatively spliced exons (9a, 10a2, 23a, and 48a). 9 Howeve...

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“…While data from certain mouse models suggest that tumor formation requires Nf1 +/− mast cells, other models using developmentally earlier and more widespread glial cell deletions have not shown this requirement for Nf1 +/− mast cells [46]. Regardless, all mouse models to date have shown the pervasive presence of degranulating mast cells within the tumor tissue.…”

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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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Plexiform and Dermal Neurofibromas and Pigmentation Are Caused by Nf1 Loss in Desert Hedgehog-Expressing Cells

Cited by 198 publications

References 50 publications

Characterization of Neurofibromas of the Skin and Spinal Roots in a Mouse Model

Characterization of Neurofibromas of the Skin and Spinal Roots in a Mouse Model

The Pathoetiology of Neurofibromatosis 1

The Plexiform Neurofibroma Microenvironment

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