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| __NOTOC__ | | __NOTOC__ |
| {{Neurofibroma}} | | {{Neurofibroma}} |
| {{CMG}}; {{AE}} {{SC}} | | {{CMG}}; {{AE}}{{S.M.}} {{SC}} |
| ==Overview== | | ==Overview== |
| | [[Plexiform neurofibroma]] may be [[Causes|caused]] by the bi-[[Allele|allelic]] inactivation of the [[neurofibromatosis type I]] [[tumor suppressor gene]]. |
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| ==Causes== | | ==Causes== |
| | | [[Plexiform neurofibroma]] may be [[Causes|caused]] by the bi-[[Allelle|allelic]] inactivation of the [[neurofibromatosis type I]] [[Tumor suppressor genes|tumor suppressor gene]].<ref name="pmid7550323">{{cite journal |vauthors=Colman SD, Williams CA, Wallace MR |title=Benign neurofibromas in type 1 neurofibromatosis (NF1) show somatic deletions of the NF1 gene |journal=[[Nature Genetics]] |volume=11 |issue=1 |pages=90–2 |year=1995 |pmid=7550323 |doi=10.1038/ng0995-90 |url=http://dx.doi.org/10.1038/ng0995-90 |issn= |accessdate=2015-11-16}}</ref> |
| This section discusses the [[tumorigenesis]] of neurofibroma in terms of [[genetics]], [[cell signaling]], [[histology]] and the [[cell cycle]].
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| ===Neurofibromin 1 gene===
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| The NF1 gene is composed of 60 [[exons]] spanning 350kb of genomic data, and maps to chromosomal region [[CCL7|17q11.2]].<ref name="pmid8825042">{{cite journal |author=MH Shen, PS Harper, M Upadhyaya. |title=Molecular genetics of neurofibromatosis type 1 (NF1) |journal=Journal of Medical Genetics |volume=33 |issue=1 |pages=2–17 |year=1996 |pmid= 8825042|doi=10.1136/jmg.33.1.2 |pmc=1051805}}</ref> This gene codes for neurofibromin which is a large 220-250 KDa [[cytoplasm]]ic [[protein]] that is composed of 2,818 amino acids with three alternatively spliced exons (9a, 23a and 48a) in the encoding gene. The functional part of neurofibromin is a [[GTPase activating protein|GAP]], or GTPase-activating protein. GAP accelerates the conversion of the active GTP-bound RAS to its inactive GDP-bound form, inactivating RAS and reducing RAS-mediated growth signaling. Loss of RAS control leads to increased activity of other signaling pathways including [[c-Raf|RAF]], [[Extracellular signal-regulated kinases|ERK1/2]], [[Phosphoinositide 3-kinase|PI3K]], [[PAK1|PAK]] and [[Mammalian target of rapamycin|mTOR-S6 kinase]]. It is suspected that this increased activity of downstream RAS pathways might work together to increase cell growth and survival.<ref name="pmid16069817">{{cite journal |author=Rubin JB, Gutmann DH. |title= Neurofibromatosis type 1 - a model for nervous system tumour formation? |journal=Nature Reviews Cancer |volume=5 |issue=7 |pages=557–64 |year=2005 |pmid=16069817|doi=10.1038/nrc1653}}</ref> Genes that code for proteins that regulate cell growth, such as [[Neurofibromin 1|NF1]] and [[p53|TP53]], are referred to as [[tumor suppressor genes]]. Neurofibromin has other growth-regulatory properties besides its ability to regulate RAS activity, but these other functions are poorly understood at this time.<ref name="pmid8516298">{{cite journal |author=Johnson MR, Look AT, DeClue JE, Valentine MB, Lowy DR. |title= Inactivation of the NF1 gene in human melanoma and neuroblastoma cell lines without impaired regulation of GTP.Ras. |journal=Proceedings of the National Academy of Sciences of the USA |volume=90 |issue=12 |pages=5539–43 |year=1993 |pmid=8516298|doi=10.1073/pnas.90.12.5539 |pmc=46756}}</ref>
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| ===Schwann cells===
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| There are two kinds of [[Schwann cells]], myelinating and nonmyelinating. While myelinating Schwann cells cover large diameter (>1 micrometer) [[peripheral nervous system]] (PNS) axons with [[myelin]], nonmyelinating Schwann cells encapsulate small diameter PNS axons with their cytoplasmic processes.
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| Nonmyelinating Schwann cells are the [[neoplasm|neoplastic]] element in neurofibromas. This conglomeration of nonmyelinating Schwann cells and axons is called a [[Group C nerve fiber|Remak bundle]].
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| While nonmyelinating Schwann cells are the origin of neurofibromas, the mutations that make them susceptible to this transformation occur in Schwann cell precursors during early nerve development. Mutated nonmyelinating Schwann cells do not form normal Remak bundles. Instead, they fail to properly surround and segregate target axons. It is unknown at this time why, if both types of Schwann cells exhibit bilallelic inactivation of the NF1 gene, only the nonmyelinating variety give rise to neurofibromas.<ref name="pmid18242512">{{cite journal |author= Zheng H, Chang L, Patel N, Yang J, Lowe L, Burns DK, Zhu Y. |journal=Cancer Cell |volume=13 |issue=2 |pages=117–28 |year=2008 |pmid=18242512|doi=10.1016/j.ccr.2008.01.002 |title= Induction of Abnormal Proliferation by Nonmyelinating Schwann Cells Triggers Neurofibroma Formation}}</ref>
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| ===Loss of tumor suppressor function===
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| Neurofibromas arise from nonmyelinating [[Schwann cells]] that only express the inactive version of the NF1 gene, which leads to a complete loss of expression of functional [[neurofibromin 1|neurofibromin]]. While one defective allele may be inherited, [[loss of heterozygosity]] (LOH) must occur before a neurofibroma can form; this is called the ‘two-hit hypothesis’. This LOH happens by the same mechanisms, such as oxidative [[DNA damage]], that causes [[mutations]] in other cells.
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| Once a nonmyelinating Schwann cell has suffered inactivation of its NF1 genes, it begins to proliferate rapidly. This condition is called [[hyperplasia]], which is cell growth beyond what is normally seen. However, despite increased numbers of nonmyelinating Schwann cells, there is no neurofibroma yet. In order for the neurofibroma to develop, cells that are [[heterozygous]] for the NF1 gene must be recruited to the site. It has been hypothesized that the proliferating nonmyelinating Schwann cells secrete [[chemoattractant]]s such as the [[Stem cell factor|KIT ligand]], and [[angiogenic]] factors such as the heparin-binding growth factor [[midkine]]. These chemicals promote the migration of different kinds of cells that are heterozygous for the NF1 gene into the hyperplastic [[lesions]] created by the nonmyelinating Schwann cells. These cell types include [[fibroblasts]], [[perineurial cells]], [[endothelial cells]], and [[mast cells]]. The mast cells then secrete [[mitogens]] or [[Nerve growth factor|survival factors]] that alter the developing tumor microenvironment and result in neurofibroma formation.
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| Dermal and plexiform neurofibromas differ in later development stages, but the details are unclear at this point.
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| ==References== | | ==References== |
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