Materiały źródłowe

• #1 Neurofibroma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK539707/

  Neurofibromas are the most prevalent benign peripheral nerve sheath tumor. […] A mutation in the NF1 gene causes neurofibromas. […] In both sporadic and syndromic cases, neurofibromas are a result of a deletion in the NF1 gene. […] In sporadic cases, only the lesional cells carry the NF1 mutation. […] In syndromic cases, neurofibromas are the result of a germline mutation in NF1, encoding the tumor suppressor protein neurofibromin, on chromosome 17q11.2. […] All types of neurofibromas are benign. Local recurrence is extremely rare complete excision of the lesion, and the risk of malignant transformation is exceedingly low; however, malignant transformation affects approximately 10% of patients with NF1. […] Plexiform types are also the most common precursor to malignant peripheral nerve sheath tumors.

• #2 Neurofibroma pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Neurofibroma_pathophysiology

  Neurofibromas arise from the nonmyelinating-type Schwann cells. […] Gene involved in the pathogenesis of plexiform neurofibroma is NF1 which codes for neurofibromin that leads to loss of RAS control causing increased activity of downstream RAS pathways involved in increased cell growth and survival. […] Plexiform neurofibroma may be caused by the bi-allelic inactivation of the neurofibromatosis type I tumor suppressor gene. […] Nearly one-half of the dry tumor weight is made up of collagen secreted by fibroblasts, which comprise the major cellular portion of neurofibroma. […] Fibroblasts migrate, proliferate, and synthesize collagen in response to transforming growth factor (TGF-). […] Nf1+/ mast cell is the critical effector in the paracrine induction of neurofibroma pathogenesis. […] TGF-dependent Nf1+/ fibroblast hyperactivity is a result of increased kinase activity of c-abl secondary to increased Ras-GTP.

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

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3694738/

  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. […] 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.

• #4 Neurofibromatosis Type 1 and tumorigenesis: molecular mechanisms and therapeutic implications in: Neurosurgical Focus Volume 28 Issue 1 (2010) Journals

  https://thejns.org/focus/view/journals/neurosurg-focus/28/1/article-pE8.xml

  Neurofibromatosis Type 1 (NF1) is a common autosomal dominant disease characterized by complex and multicellular neurofibroma tumors, and less frequently by malignant peripheral nerve sheath tumors (MPNSTs) and optic nerve gliomas. […] Neurofibromatosis Type 1 is caused by germline mutations of the NF1 tumor suppressor gene, which generally result in decreased intracellular neurofibromin protein levels, leading to increased cascade Ras signaling to its downstream effectors. […] Multiple key pathways are involved with the development of tumors in NF1, including Ras/mitogen-activated protein kinase (MAPK) and Akt/mammalian target of rapamycin (mTOR). […] In general, a somatic loss of the second NF1 allele, also referred to as loss of heterozygosity, in the progenitor cell, either the Schwann cell or its precursor, combined with haploinsufficiency in multiple supporting cells is required for tumor formation.

• #5 Neurofibromatosis – Wikipedia

  https://en.wikipedia.org/wiki/Neurofibromatosis

  Neurofibromatosis arise from the supporting cells of the nervous system rather than the neurons themselves. […] In NF1, the tumors are neurofibromas (tumors of the peripheral nerves), while in NF2 and schwannomatosis tumors of Schwann cells are more common. […] The pathophysiology is varied, and each NF type has a different one: Neurofibromatosis type I is the most common of the three types and is caused by genetic changes in the NF1 gene located on chromosome 17 (17q11.2). This gene encodes a cytoplasmic protein known the neurofibromin, which functions as a tumor suppressor and therefore serves as a signal regulator of cell proliferation and differentiation. A dysfunction or lack of neurofibromin can affect regulation, and cause uncontrolled cell proliferation, leading to the tumors (neurofibromas) that characterize NF1. The neurofibromas caused by NF consist of Schwann cells, fibroblasts, perineuronal cells, mast cells and axons embedded in an extracellular matrix.

• #6 Neurofibromatosis type 1 – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/neurofibromatosis-type-1/symptoms-causes/syc-20350490

  Neurofibromatosis type 1 is caused by an altered gene that either is passed down by a parent or occurs at conception. […] The NF1 gene is located on chromosome 17. This gene produces a protein called neurofibromin that helps regulate cell growth. When the gene is altered, it causes a loss of neurofibromin. This allows cells to grow without control.

• #7 Neurofibroma overview – wikidoc

  https://www.wikidoc.org/index.php/Neurofibroma_overview

  Neurofibromas are benign nerve sheath tumors of neural origin in peripheral nervous system, comprising all elements of the peripheral nerve (i.e. axons, Schwann cells and fibroblasts) and can occur anywhere in the body. […] Gene involved in the pathogenesis of plexiform neurofibroma is NF1 which codes for neurofibromin that leads to loss of RAS control causing increased activity of downstream RAS pathways involved in increased cell growth and survival. […] Neurofibromas arise from the nonmyelinating-type Schwann cells. […] Gene involved in the pathogenesis of plexiform neurofibroma is NF1 which codes for neurofibromin that leads to loss of RAS control causing increased activity of downstream RAS pathways involved in increased cell growth and survival. […] Plexiform neurofibroma may be caused by the bi-allelic inactivation of the neurofibromatosis type I tumor suppressor gene.

• #8 Neurofibromatosis type 1: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/neurofibromatosis-type-1/

  Neurofibromatosis type 1 is a condition characterized by changes in skin coloring (pigmentation) and the growth of tumors along nerves in the skin, brain, and other parts of the body. […] Most adults with neurofibromatosis type 1 develop neurofibromas, which are noncancerous (benign) tumors that are usually located on or just under the skin. […] Mutations in the NF1 gene cause neurofibromatosis type 1. The NF1 gene provides instructions for making a protein called neurofibromin. This protein is produced in many cells, including nerve cells and specialized cells surrounding nerves (oligodendrocytes and Schwann cells). Neurofibromin acts as a tumor suppressor, which means that it keeps cells from growing and dividing too rapidly or in an uncontrolled way. Mutations in the NF1 gene lead to the production of a nonfunctional version of neurofibromin that cannot regulate cell growth and division. As a result, tumors such as neurofibromas can form along nerves throughout the body.

• #9 Neurofibroma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK539707/

  Neurofibromas are the most prevalent benign peripheral nerve sheath tumor. […] A mutation in the NF1 gene causes neurofibromas. […] In both sporadic and syndromic cases, neurofibromas are a result of a deletion in the NF1 gene. […] In sporadic cases, only the lesional cells carry the NF1 mutation. […] In syndromic cases, neurofibromas are the result of a germline mutation in NF1, encoding the tumor suppressor protein neurofibromin, on chromosome 17q11.2. […] All types of neurofibromas are benign. Local recurrence is extremely rare complete excision of the lesion, and the risk of malignant transformation is exceedingly low; however, malignant transformation affects approximately 10% of patients with NF1. […] Plexiform types are also the most common precursor to malignant peripheral nerve sheath tumors.

• #10 Neurofibromatosis type 1-associated tumours: Their somatic mutational spectrum and pathogenesis | Human Genomics | Full Text

  https://humgenomics.biomedcentral.com/articles/10.1186/1479-7364-5-6-623

  The NF1 gene encodes neurofibromin, a negative regulator of the Ras/mitogen-activated protein kinase (MAPK) pathway. NF1 is a TSG and, consistent with Knudson’s two-hit hypothesis, most patients carry (in all their cells) both a normal and a dysfunctional NF1 gene copy — the latter harbouring the inherited (germline) mutation. It may be inferred that any tumours that arise will have acquired a second, somatic 'hit’ that inactivates the normal NF1 allele, resulting in a complete loss of functional neurofibromin; a double hit (NF1-/-) is critical for NF1 tumorigenesis to occur. […] The question as to why only a few of these benign tumours eventually go on to become malignant, however, is still puzzling. […] Neurofibromas exhibit extensive cellular heterogeneity, being composed of hyperproliferative Schwann cells (SCs), fibroblasts, mast cells and peri-neural cells. The SCs have been identified as the initiating cell type in neurofibromas and it is only in these cells that the NF1 gene becomes biallelically inactivated.

• #11 Cutaneous neurofibromas in the genomics era: current understanding and open questions | British Journal of Cancer

  https://www.nature.com/articles/s41416-018-0073-2

  More recent work demonstrated that implantation of NF1/ SKPs in sciatic nerve tissue, but not subcutaneous implantation in unprimed athymic mice, resulted in neurofibroma formation, further indicating that the microenvironment may be a key regulator of cNF development. […] It is not yet known whether human cNFs also originate from SKPs or other cell populations. […] The relationship between germline NF1 microdeletion and cNF is somewhat clearer, compared with our understanding of the role of germline and somatic intragenic NF1 mutations. […] Studies suggest that germline NF1 microdeletions guide cNF development; cNFs that form in NF1 microdeletion patients do not exhibit somatic loss of heterozygosity (LOH) of the second NF1 allele, but instead typically contain point mutations in NF1.

• #12 Understanding Possible Explanations for Isolated Features of NF – Neurofibromatosis Program

  https://www.uab.edu/medicine/nfprogram/blog/understanding-possible-explanations-for-isolated-features-of-nf

  For a neurofibroma to develop in someone with NF1, a random genetic mutation must occur to the other copy of the NF1 gene in the tissue that will become the neurofibroma, caf-au-lait spot, or other lesion; this is referred to as the second-hit mutation. […] Although an extremely rare occurrence, it is also possible for some individuals to acquire two random NF mutations, affecting each inherited copy of the NF1 gene, in a cell that could become a neurofibroma or other lesion.

• #13 Neurofibroma – Wikipedia

  https://en.wikipedia.org/wiki/Neurofibroma

  Neurofibromas arise from nonmyelinating-type Schwann cells that exhibit biallelic inactivation of the NF1 gene that codes for the protein neurofibromin. […] The formation of malignant cancers from neurofibromas is associated with the loss of expression of the CDKN2A or TP53 gene in nonmyelinating Schwann cells that also exhibit biallelic inactivation of the NF1 gene. […] 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. […] 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. […] In order for the neurofibroma to develop, cells that are heterozygous for the NF1 gene must be recruited to the site. […] 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. […] Dermal and plexiform neurofibromas differ in later development stages, but the details are unclear at this point.

• #14 Pathology Outlines – Neurofibroma-general

  https://www.pathologyoutlines.com/topic/softtissueneurofibroma.html

  Neurofibroma is a benign peripheral nerve sheath tumor comprised of neuronal and fibrous components. […] It is composed of Schwann cells, perineurial cells, fibroblasts, mast cells and interspersed myelinated and unmyelinated axons within a myxoid and collagenous extracellular matrix. […] In both sporadic and syndromic cases, neurofibromas are a result of biallelic genetic inactivation of the tumor suppressor gene NF1 with complete loss of function of the NF1 gene product, neurofibromin. […] Complete loss of function of the NF1 gene product, neurofibromin (NF1), is considered prerequisite for tumor development. […] Loss of NF1 results in increased RAS signaling → tumor development. […] Inflammatory signals mediated by various components of the microenvironment, such as mast cells, macrophages, lymphocytes and dendritic cells as well as Schwann cell interactions with axons are important for tumor development.

• #15 The role of nerve microenvironment for neurofibroma development | Oncotarget

  https://www.oncotarget.com/article/11133/text/

  Our results revealed that neither Nf1+/+ nor Nf1-/- SKPs can give rise to tumor subcutaneously. However, Nf1-/- SKPs but not Nf1+/+ controls robustly give rise to tumors in sciatic nerves. […] Taken together, all the histological and molecular characteristics of the tumors derived from Nf1-/- SKPs in sciatic nerve consistent with those of neurofibromas. […] Importantly, our discovery that Nf1-/- SKPs give rise to neurofibroma in sciatic nerves but not subcutaneous tissue indicates an essential role of nerve microenvironment for neurofibroma development. […] Our findings that Nf1-/-;P53-/- SKPs rapidly gave rise MPNST in nerve tissue demonstrates that nerve microenvironment is crucial for MPNST development. […] These skin rafts were initially maintained in in vitro culture for 5 days and then transplanted into the skin of nude mice in vivo.

• #16 Neurofibroma Development in Neurofibromatosis Type 1: Insights from Cellular Origin and Schwann Cell Lineage Development

  https://www.mdpi.com/2072-6694/14/18/4513

  While, for decades, neurofibromas have been believed to originate from cells within the SC lineage, the specific time of initiation and exact cellular origin of pNFs and cNFs remain controversial, despite intensive studies. […] This has aided the clarification of neurofibroma characteristics with regard to formation, progression, and transformation to malignancy. […] The significant differences between these two subtypes of neurofibromas and the phenomenon that mouse models develop pNF but fail to develop cNF at 100% frequency jointly indicate that the cellular origins of these lesions may differ. […] The study progress of the cellular origin of both pNF and cNF is summarized in Table 1. […] The capability of SKPs to express Dhh and generate both pNF and cNF was identified. […] The specific cell type within the SC lineage leading to neurofibroma formation is controversial.

• #17 Neurofibroma Development in Neurofibromatosis Type 1: Insights from Cellular Origin and Schwann Cell Lineage Development—-Shanghai Institute of Nutrition and Health,Chinese Academy of Sciences

  https://english.sinh.cas.cn/research/papers/202503/t20250319_907460.html

  Neurofibromas have been thought to originate from cells within the Schwann cell lineage, while no consensus has been reached so far about the specific time of initiation and the exact cellular origin. […] Moreover, the role of Schwann cell lineage transition in different developmental stages of neurofibromas, together with other determinant factors, remains controversial, despite intensive studies. […] In this review, we summarized the accumulating evidence about the full range of neurofibroma development based on cellular and molecular pathogenesis. […] We highlighted the Schwann cell (SC) lineage shift to better present the evolution of its corresponding cellular origin hypothesis and its important effects on the progression and malignant transformation of neurofibromas. […] By integrating findings relating to tumor formation, growth, and malignancy, we hope to reveal the role of SC lineage shift as well as the combined impact of additional determinants in the natural history of PNSTs.

• #18

  https://www.jci.org/articles/view/139807

  Previous studies using genetically engineered murine models have revealed that neurofibromas most likely derive from Schwannian lineage cells (SLCs) following somatic loss of the remaining Nf1 allele. […] To address this critical barrier, we used a unique series of human induced pluripotent stem cells (hiPSCs) harboring NF1 patient NF1 gene mutations to generate proliferating SCPs and examine the impact of NF1 mutations on Schwann cell lineage differentiation, as well as generate human neurofibromas in mice. […] Using this approach, we found that NF1 loss delayed SLC differentiation by expanding the pool of progenitors necessary to initiate tumor formation. […] The higher levels of GAP43 protein and mRNA in Cre virusinfected Nf1fl/fl DNSCs were consistent with levels detected in human NF1/ iPSCs-SCPs.

• #19 Neurofibroma Development in Neurofibromatosis Type 1: Insights from Cellular Origin and Schwann Cell Lineage Development

  https://www.mdpi.com/2072-6694/14/18/4513

  While, for decades, neurofibromas have been believed to originate from cells within the SC lineage, the specific time of initiation and exact cellular origin of pNFs and cNFs remain controversial, despite intensive studies. […] This has aided the clarification of neurofibroma characteristics with regard to formation, progression, and transformation to malignancy. […] The significant differences between these two subtypes of neurofibromas and the phenomenon that mouse models develop pNF but fail to develop cNF at 100% frequency jointly indicate that the cellular origins of these lesions may differ. […] The study progress of the cellular origin of both pNF and cNF is summarized in Table 1. […] The capability of SKPs to express Dhh and generate both pNF and cNF was identified. […] The specific cell type within the SC lineage leading to neurofibroma formation is controversial.

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

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3694738/

  Plexiform neurofibromas are typically a lifelong source of disfigurement, disability, and mortality. In many cases, plexiform neurofibromas compress cranial nerves and/or peripheral nerve roots at the vertebral column and create an array of morbidity, including paresthesia, paralysis, drooling, sleeplessness, respiratory and gastrointestinal distress, blindness, and loss of bowel and bladder control. […] Currently, the tumors have no medical therapy or cure, although several molecularly-targeted compounds are in preclinical or clinical testing. […] The pro-inflammatory activities of recruited mast cells and other immune effector cells have been shown to sustain tumor microenvironments in various disease models. […] These recruited cells, in turn, coordinate vascular in-growth, collagen deposition, and the pathological inflammation promoting extracellular matrix remodeling, tumor expansion, invasion, and metastasis.

• #21 Cutaneous neurofibromas in the genomics era: current understanding and open questions | British Journal of Cancer

  https://www.nature.com/articles/s41416-018-0073-2

  In this review, we summarise the present understanding of cNF pathogenesis including recent studies that propose a putative tumour cell of origin, the identification of mutations in NF1 and other genes in cNF, the role of the tumour microenvironment and endocrine signalling in cNF, and past, recent and ongoing clinical trials for cNF. […] The cNF-tumour-initiating event in humans is currently unknown and the cell of origin has yet to be identified; however, studies in mice have led to the identification of Schwann-cell-like skin-derived precursor (SKP) cells as the likely murine cNF tumour cell of origin. […] These observations revealed that loss of NF1 gene expression in SKPs is required, but not sufficient, for neurofibroma development, and revealed critical roles for the tumour microenvironment.

• #22

  https://www.jci.org/articles/view/99424

  Our study details the role of inflammation in neurofibromagenesis. Our data indicate that prevention of inflammation and possibly also nerve injury at the observed tumor locations are therapeutic approaches for neurofibroma prophylaxis and that such treatment should be explored. […] Neurofibromas are heterogeneous tumors comprised of neoplastic Schwann cells and nonneoplastic fibroblasts, vascular endothelial cells, and mast cells, as well as dense collagen. […] The presence of mast cell infiltration can be frequently observed in neurofibromas; however, it is not common in other types of neoplasms. […] Efforts have been made to understand the role of mast cells in the neurofibroma tumor microenvironment, and most importantly, to determine whether mast cell metabolism could be a viable therapeutic target against neurofibromas.

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

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3694738/

  Mast cells have been associated with NF1 since 1911, when H. Greggio first noted les cellules granuleuses in neurofibroma tissue. […] Recent biochemical, transplantation, and pharmacological studies have implicated a preponderant role for SCF-mediated mast cell gain-in-functions in orchestrating the neurofibroma microenvironment. […] Thus, heterotypic interactions between the tumor, the hematopoietic system, and other stromal components critically promote and sustain the neurofibroma microenvironment. […] Overall, genetic dosage of NF1 is central to neurofibroma pathogenesis, with a requirement for NF1 nullizygosity in the tumorigenic cell and, in several disease models, Nf1 heterozygosity in the hematopoietic system.

• #24 Pathology Outlines – Neurofibroma-general

  https://www.pathologyoutlines.com/topic/softtissueneurofibroma.html

  Neurofibromin deficient Schwann cells secrete 5 times the normal kit ligand, which serves as a chemoattractant for mast cells expressing c-kit receptor. […] Mast cells secret a variety of factors, including immunomodulatory factors (such as histamine) as well as profibrotic factor TGFβ, to induce fibroblasts to proliferate and deposit collagen.

• #25 Immune system changes in the pathogenesis of neurofibromatosis type 1

  https://ouci.dntb.gov.ua/en/works/7pbq8PBl/

  Neurofibromatosis type 1 (NF1) is caused by germline heterozygous mutations in the NF1 gene, which encodes the oncosuppressor neurofibromin. […] The disease has a specific progressive course with multiple neurofibromas, in the initiation and growth of which NF1+/ – mast cells, macrophages and lymphocytes play an important role. […] Accordingly, the deficiency of neurofibromin impairs the differentiation and correct functioning of immune system cells. […] The development of neurofibromas is associated with the fact that NF1–/– Schwann cells stimulate the migration of mast cells into the tumor microenvironment, which actively degranulate. […] The released cytokines promote neoangiogenesis, inflammation, fibroblast proliferation and the production of excess collagen. […] Macrophages and T-lymphocytes in neurofibromas do not provide an antitumor response, but promote inflammation and tumor growth.

• #26 Immune system changes in the pathogenesis of neurofibromatosis type 1

  https://ouci.dntb.gov.ua/en/works/7pbq8PBl/

  Neurofibromatosis type 1 (NF1) is caused by germline heterozygous mutations in the NF1 gene, which encodes the oncosuppressor neurofibromin. […] The disease has a specific progressive course with multiple neurofibromas, in the initiation and growth of which NF1+/ – mast cells, macrophages and lymphocytes play an important role. […] Accordingly, the deficiency of neurofibromin impairs the differentiation and correct functioning of immune system cells. […] The development of neurofibromas is associated with the fact that NF1–/– Schwann cells stimulate the migration of mast cells into the tumor microenvironment, which actively degranulate. […] The released cytokines promote neoangiogenesis, inflammation, fibroblast proliferation and the production of excess collagen. […] Macrophages and T-lymphocytes in neurofibromas do not provide an antitumor response, but promote inflammation and tumor growth.

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

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3694738/

  Plexiform neurofibromas are typically a lifelong source of disfigurement, disability, and mortality. In many cases, plexiform neurofibromas compress cranial nerves and/or peripheral nerve roots at the vertebral column and create an array of morbidity, including paresthesia, paralysis, drooling, sleeplessness, respiratory and gastrointestinal distress, blindness, and loss of bowel and bladder control. […] Currently, the tumors have no medical therapy or cure, although several molecularly-targeted compounds are in preclinical or clinical testing. […] The pro-inflammatory activities of recruited mast cells and other immune effector cells have been shown to sustain tumor microenvironments in various disease models. […] These recruited cells, in turn, coordinate vascular in-growth, collagen deposition, and the pathological inflammation promoting extracellular matrix remodeling, tumor expansion, invasion, and metastasis.

• #28 Neurofibroma pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Neurofibroma_pathophysiology

  Neurofibromas arise from the nonmyelinating-type Schwann cells. […] Gene involved in the pathogenesis of plexiform neurofibroma is NF1 which codes for neurofibromin that leads to loss of RAS control causing increased activity of downstream RAS pathways involved in increased cell growth and survival. […] Plexiform neurofibroma may be caused by the bi-allelic inactivation of the neurofibromatosis type I tumor suppressor gene. […] Nearly one-half of the dry tumor weight is made up of collagen secreted by fibroblasts, which comprise the major cellular portion of neurofibroma. […] Fibroblasts migrate, proliferate, and synthesize collagen in response to transforming growth factor (TGF-). […] Nf1+/ mast cell is the critical effector in the paracrine induction of neurofibroma pathogenesis. […] TGF-dependent Nf1+/ fibroblast hyperactivity is a result of increased kinase activity of c-abl secondary to increased Ras-GTP.

• #29 Neurofibroma pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Neurofibroma_pathophysiology

  Neurofibromas arise from the nonmyelinating-type Schwann cells. […] Gene involved in the pathogenesis of plexiform neurofibroma is NF1 which codes for neurofibromin that leads to loss of RAS control causing increased activity of downstream RAS pathways involved in increased cell growth and survival. […] Plexiform neurofibroma may be caused by the bi-allelic inactivation of the neurofibromatosis type I tumor suppressor gene. […] Nearly one-half of the dry tumor weight is made up of collagen secreted by fibroblasts, which comprise the major cellular portion of neurofibroma. […] Fibroblasts migrate, proliferate, and synthesize collagen in response to transforming growth factor (TGF-). […] Nf1+/ mast cell is the critical effector in the paracrine induction of neurofibroma pathogenesis. […] TGF-dependent Nf1+/ fibroblast hyperactivity is a result of increased kinase activity of c-abl secondary to increased Ras-GTP.

• #30 Neurofibromatosis Type 1 and tumorigenesis: molecular mechanisms and therapeutic implications in: Neurosurgical Focus Volume 28 Issue 1 (2010) Journals

  https://thejns.org/focus/view/journals/neurosurg-focus/28/1/article-pE8.xml

  Neurofibromatosis Type 1 (NF1) is a common autosomal dominant disease characterized by complex and multicellular neurofibroma tumors, and less frequently by malignant peripheral nerve sheath tumors (MPNSTs) and optic nerve gliomas. […] Neurofibromatosis Type 1 is caused by germline mutations of the NF1 tumor suppressor gene, which generally result in decreased intracellular neurofibromin protein levels, leading to increased cascade Ras signaling to its downstream effectors. […] Multiple key pathways are involved with the development of tumors in NF1, including Ras/mitogen-activated protein kinase (MAPK) and Akt/mammalian target of rapamycin (mTOR). […] In general, a somatic loss of the second NF1 allele, also referred to as loss of heterozygosity, in the progenitor cell, either the Schwann cell or its precursor, combined with haploinsufficiency in multiple supporting cells is required for tumor formation.

• #31 Recent advances in Neurofibromatosis type 1 research: Towards tailored therapeutics and treatment strategies

  https://www.e-kjgm.org/journal/view.html?uid=375&&vmd=Full

  Neurofibromatosis type 1 (NF1) is an autosomal dominant multisystem disorder caused by germline mutations in the NF1 gene, classified as a RASopathy. The NF1 gene encodes neurofibromin, a RAS GTPase-activating protein that modulates the Ras-MAPK signaling cascade. […] Loss of NF1 function results in constitutive Ras/Raf/MEK/ERK signaling activation, a primary driver of tumorigenesis in NF1 patients. […] The involvement of the tumor microenvironment (TME) in NF1 pathogenesis is increasingly recognized. Recent advances in single-cell RNA sequencing have delineated the intricate cellular composition and signaling dynamics within mature neurofibromas, elucidating the complexity of the TME. […] Research has demonstrated that schwann cells-immunes (mast cells, T cells) in PNs, microglia and T cells in LGGs, and hematopoietic cells in MPNSTs play a significant role in promoting the development of NF1-associated tumors.

• #32 Neurofibromatosis Type 1 and tumorigenesis: molecular mechanisms and therapeutic implications in: Neurosurgical Focus Volume 28 Issue 1 (2010) Journals

  https://thejns.org/focus/view/journals/neurosurg-focus/28/1/article-pE8.xml

  Neurofibromatosis Type 1 (NF1) is a common autosomal dominant disease characterized by complex and multicellular neurofibroma tumors, and less frequently by malignant peripheral nerve sheath tumors (MPNSTs) and optic nerve gliomas. […] Neurofibromatosis Type 1 is caused by germline mutations of the NF1 tumor suppressor gene, which generally result in decreased intracellular neurofibromin protein levels, leading to increased cascade Ras signaling to its downstream effectors. […] Multiple key pathways are involved with the development of tumors in NF1, including Ras/mitogen-activated protein kinase (MAPK) and Akt/mammalian target of rapamycin (mTOR). […] In general, a somatic loss of the second NF1 allele, also referred to as loss of heterozygosity, in the progenitor cell, either the Schwann cell or its precursor, combined with haploinsufficiency in multiple supporting cells is required for tumor formation.

• #33 2019 Neurofibromatosis Highlight – Investigating the Role of Fibroblasts in the Tumor Microenvironment and Hippo Signaling Pathway in Neurofibromas, Neurofibromatosis Research Program, Congressionally Directed Medical Research Programs

  https://cdmrp.health.mil/nfrp/research_highlights/19lu_le_highlight

  Neurofibromatosis consists of a family of syndromes, including neurofibromatosis type I (NF1), neurofibromatosis type II (NF2), and schwannomatosis. […] With support from a Fiscal Year (FY) 2015 Exploration-Hypothesis Development Award through the Neurofibromatosis Research Program (NFRP), Dr. Lu Le and his team are investigating the contributions of fibroblasts in the pathogenesis of neurofibromas by defining the cellular interactions in the tumor microenvironment, specifically between neoplastic Schwann cells and fibroblasts. […] Dr. Le was also awarded an FY16 Investigator-Initiated Research Award through the NFRP to define molecular and developmental pathogenesis of Schwann cell tumors and elucidate the mechanisms by which specific cancer pathways may affect tumor formation. […] Furthermore, this work demonstrated that neurofibroma tumorigenesis is susceptible to modification through modulation of the Hippo pathway, a signaling pathway that controls cell growth and has been implicated in numerous cancer types. […] Furthermore, potential modifications to the Hippo pathway, in addition to NF1 deletion, may be an attractive therapeutic target for NF1 patients and could provide neurofibroma treatment options where none currently exist.

• #34 Researchers Identify Mechanism and Possible Drug Treatment for Growth of Nerve Tumors in Neurofibromatosis | Technology Networks

  https://www.technologynetworks.com/genomics/news/researchers-identify-mechanism-and-possible-drug-treatment-for-growth-of-nerve-tumors-in-neurofibromatosis-207496

  Researchers studying neurofibromatosis type 1; a rare disease in which tumors grow within nerves; have found that the tumors are triggered by crosstalk between cells in the nerves and cells in the blood. […] Combined with previous findings, the new study suggests that the formation of plexiform neurofibromas requires two steps: complete loss of NF1 in Schwann cells (rendering them NF1 -/-) and an interaction between NF1 -/- Schwann cells and NF1+/- mast cells. While Schwann cells appear to be the primary tumor causing cell, mast cells appear to stimulate tumor growth by recruiting other cell types and blood vessels to the tumor. […] „The mast cell inflammatory response appears to be co-opted by the tumor to enhance tumor growth,” says Dr. Parada. […] The researchers also examined the role of c-kit, a molecule that is expressed by mast cells and other cell types, and is known to become overactive in some kinds of cancer. When c-kit was genetically deleted in NF1+/- bone marrow cells prior to transplantation, the transplanted cells failed to induce neurofibromas. Meanwhile, in mice that were prone to develop neurofibromas, the cancer drug Gleevec – an inhibitor of c-kit – reduced the metabolic activity and size of the tumors. […] The researchers say that the complex origin of tumors in neurofibromatosis – which has thwarted therapeutic development until now – could be the chink in the disease’s armor.

• #35 Neurofibromatosis type 1-associated optic pathway gliomas: pathogenesis and emerging treatments

  https://www.europeanreview.org/article/32804

  Over the past decade, basic research and the development of genetically engineered mice models of NF1-associated OPG have shed light on the cellular and molecular mechanisms underlying the disease and inspired animal and human testing of several compounds. […] A promising line of research is focusing on the inhibition of mTOR, a protein kinase controlling proliferation, protein synthesis rate and cell motility that is highly expressed in neoplastic cells. […] A different strategy aims at restoring cAMP levels in neoplastic astrocytes and non-neoplastic neurons, since reduced intracellular cAMP levels contribute to OPG growth and, more importantly, are the major determinant of NF1-OPG-associated visual decline. […] Stroma-directed molecular therapies seeking to target Nf1 heterozygous brain microglia and retinal ganglion cells (RGCs) are another fascinating field.

• #36 Neurofibromatosis type 1-associated optic pathway gliomas: pathogenesis and emerging treatments

  https://www.europeanreview.org/article/32804

  Over the past decade, basic research and the development of genetically engineered mice models of NF1-associated OPG have shed light on the cellular and molecular mechanisms underlying the disease and inspired animal and human testing of several compounds. […] A promising line of research is focusing on the inhibition of mTOR, a protein kinase controlling proliferation, protein synthesis rate and cell motility that is highly expressed in neoplastic cells. […] A different strategy aims at restoring cAMP levels in neoplastic astrocytes and non-neoplastic neurons, since reduced intracellular cAMP levels contribute to OPG growth and, more importantly, are the major determinant of NF1-OPG-associated visual decline. […] Stroma-directed molecular therapies seeking to target Nf1 heterozygous brain microglia and retinal ganglion cells (RGCs) are another fascinating field.

• #37 The role of nerve microenvironment for neurofibroma development | Oncotarget

  https://www.oncotarget.com/article/11133/text/

  Our results revealed that neither Nf1+/+ nor Nf1-/- SKPs can give rise to tumor subcutaneously. However, Nf1-/- SKPs but not Nf1+/+ controls robustly give rise to tumors in sciatic nerves. […] Taken together, all the histological and molecular characteristics of the tumors derived from Nf1-/- SKPs in sciatic nerve consistent with those of neurofibromas. […] Importantly, our discovery that Nf1-/- SKPs give rise to neurofibroma in sciatic nerves but not subcutaneous tissue indicates an essential role of nerve microenvironment for neurofibroma development. […] Our findings that Nf1-/-;P53-/- SKPs rapidly gave rise MPNST in nerve tissue demonstrates that nerve microenvironment is crucial for MPNST development. […] These skin rafts were initially maintained in in vitro culture for 5 days and then transplanted into the skin of nude mice in vivo.

• #38 The role of nerve microenvironment for neurofibroma development | Oncotarget

  https://www.oncotarget.com/article/11133/text/

  These findings indicate that Nf1-deficient SKPs can give rise to bona fide neurofibromas in a skin raft culture system in vitro, contingent on their local microenvironment. […] Our data indicate that genetically ablating Nf1 in the cell of origin of neurofibroma is required but not sufficient for tumorigenesis, pointing to the essential role of the additional signals from the tumor microenvironment, including peripheral nerves. […] These are exciting results that offer an additional area of investigation for mechanisms vital to neurofibromagenesis.

• #39

  https://www.jci.org/articles/view/99424

  These results are in agreement with our previous mouse model experiments presented earlier. […] Taken together, these results indicate that the cervical nerves and the thoracic nerves at T5T8 are the hot zones for paraspinal plexiform neurofibroma formation. […] Our observation that cervical nerves serve as a hot zone for plexiform neurofibroma in this mouse model appears to mimic similar observations in human NF1 studies. […] In summary, our study highlighted the contribution of inflammation (possibly due to nerve injury) in neurofibroma initiation.

• #40

  https://www.jci.org/articles/view/99424

  These results are in agreement with our previous mouse model experiments presented earlier. […] Taken together, these results indicate that the cervical nerves and the thoracic nerves at T5T8 are the hot zones for paraspinal plexiform neurofibroma formation. […] Our observation that cervical nerves serve as a hot zone for plexiform neurofibroma in this mouse model appears to mimic similar observations in human NF1 studies. […] In summary, our study highlighted the contribution of inflammation (possibly due to nerve injury) in neurofibroma initiation.

• #41 Neurofibroma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK539707/

  Neurofibromas are the most prevalent benign peripheral nerve sheath tumor. […] A mutation in the NF1 gene causes neurofibromas. […] In both sporadic and syndromic cases, neurofibromas are a result of a deletion in the NF1 gene. […] In sporadic cases, only the lesional cells carry the NF1 mutation. […] In syndromic cases, neurofibromas are the result of a germline mutation in NF1, encoding the tumor suppressor protein neurofibromin, on chromosome 17q11.2. […] All types of neurofibromas are benign. Local recurrence is extremely rare complete excision of the lesion, and the risk of malignant transformation is exceedingly low; however, malignant transformation affects approximately 10% of patients with NF1. […] Plexiform types are also the most common precursor to malignant peripheral nerve sheath tumors.

• #42 Neurofibromatosis type 1-associated tumours: Their somatic mutational spectrum and pathogenesis | Human Genomics | Full Text

  https://humgenomics.biomedcentral.com/articles/10.1186/1479-7364-5-6-623

  The homozygous loss of the cyclin-dependent kinase inhibitor 2A gene (CDKN2A), which encodes p16INK4A and p14ARF, has also been associated with NF1 malignancy. […] Recent studies of the micro-RNA expression profile of MPNSTs have expanded the pathogenic spectrum associated with this tumour. […] In summary, the more severe MPNSTs show a greater degree of genetic abnormality than other tumour types, with LOH constituting a much more frequent event in these tumours. Further comparison within and between the rarer tumour types would not be valid, however, owing to the relative paucity of mutation data currently available for analysis.

• #43 Neurofibromatosis type 1-associated tumours: Their somatic mutational spectrum and pathogenesis | Human Genomics | Full Text

  https://humgenomics.biomedcentral.com/articles/10.1186/1479-7364-5-6-623

  An NF1-/+ haploinsufficient cellular environment is also considered necessary, probably because of the growth advantage conferred by the signalling deficiency due to reduced neurofibromin levels. […] The molecular mechanisms underlying both PNF and cutaneous neurofibroma formation are becoming clearer, although the major details are still lacking. […] Although it is clear that biallelic NF1 gene inactivation is required for transformation to occur, mutations at the NF1 locus are insufficient to explain the process of tumorigenesis, as most benign neurofibromas also exhibit such biallelic NF1 inactivation. […] The best evidence for the involvement of other loci relates to the tumour protein 53 gene (TP53), for which several different mutations have been found in MPNSTs that have not been reported in benign neurofibromas.

• #44 Neurofibromatosis type 1-associated tumours: Their somatic mutational spectrum and pathogenesis | Human Genomics | Full Text

  https://humgenomics.biomedcentral.com/articles/10.1186/1479-7364-5-6-623

  The homozygous loss of the cyclin-dependent kinase inhibitor 2A gene (CDKN2A), which encodes p16INK4A and p14ARF, has also been associated with NF1 malignancy. […] Recent studies of the micro-RNA expression profile of MPNSTs have expanded the pathogenic spectrum associated with this tumour. […] In summary, the more severe MPNSTs show a greater degree of genetic abnormality than other tumour types, with LOH constituting a much more frequent event in these tumours. Further comparison within and between the rarer tumour types would not be valid, however, owing to the relative paucity of mutation data currently available for analysis.

• #45 Neurofibroma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK539707/

  Neurofibromas are the most prevalent benign peripheral nerve sheath tumor. […] A mutation in the NF1 gene causes neurofibromas. […] In both sporadic and syndromic cases, neurofibromas are a result of a deletion in the NF1 gene. […] In sporadic cases, only the lesional cells carry the NF1 mutation. […] In syndromic cases, neurofibromas are the result of a germline mutation in NF1, encoding the tumor suppressor protein neurofibromin, on chromosome 17q11.2. […] All types of neurofibromas are benign. Local recurrence is extremely rare complete excision of the lesion, and the risk of malignant transformation is exceedingly low; however, malignant transformation affects approximately 10% of patients with NF1. […] Plexiform types are also the most common precursor to malignant peripheral nerve sheath tumors.

• #46 Neurofibroma Development in Neurofibromatosis Type 1: Insights from Cellular Origin and Schwann Cell Lineage Development

  https://www.mdpi.com/2072-6694/14/18/4513

  Neurofibromas have been thought to originate from cells within the Schwann cell lineage, while no consensus has been reached so far about the specific time of initiation and the exact cellular origin. […] In this review, we summarized the accumulating evidence about the full range of neurofibroma development based on cellular and molecular pathogenesis. […] The distinct spatiotemporal characteristics of plexiform and cutaneous neurofibromas have prompted hypotheses about the origin and developmental features of these tumors, involving various cellular transition processes. […] We highlighted the Schwann cell (SC) lineage shift to better present the evolution of its corresponding cellular origin hypothesis and its important effects on the progression and malignant transformation of neurofibromas.

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

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3694738/

  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. […] 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.

• #48 Neurofibroma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK539707/

  Neurofibromas are the most prevalent benign peripheral nerve sheath tumor. […] A mutation in the NF1 gene causes neurofibromas. […] In both sporadic and syndromic cases, neurofibromas are a result of a deletion in the NF1 gene. […] In sporadic cases, only the lesional cells carry the NF1 mutation. […] In syndromic cases, neurofibromas are the result of a germline mutation in NF1, encoding the tumor suppressor protein neurofibromin, on chromosome 17q11.2. […] All types of neurofibromas are benign. Local recurrence is extremely rare complete excision of the lesion, and the risk of malignant transformation is exceedingly low; however, malignant transformation affects approximately 10% of patients with NF1. […] Plexiform types are also the most common precursor to malignant peripheral nerve sheath tumors.

• #49 KIR2DL5 mutation and loss underlies sporadic dermal neurofibroma pathogenesis and growth | Oncotarget

  https://www.oncotarget.com/article/17736/text/

  Dermal neurofibromas (DNFs) are benign peripheral nerve sheath tumors thought to originate from Schwann cell progenitors. […] Herein, we employed whole-exome sequencing of sp-DNFs to identify a recurrent mutation in the KIR2DL5 gene, which codes for a protein suppressor of natural killer (NK) cell activity. […] Moreover, loss of KIR2DL5 expression was demonstrated in 15 of 45 independently-identified sp-DNFs. […] Collectively, these findings establish KIR2DL5 as a new Schwann cell growth regulator relevant to sp-DNF pathogenesis, which links sporadic and NF1-associated DNFs through RAS pathway hyperactivation. […] While KIR2DL5 is an orphan receptor with no known ligands, its phosphorylation in NK cells recruits the Src homology region 2-containing protein tyrosine phosphatase-2 (SHP-2) molecule, resulting in activation of downstream signaling pathways.

• #50 RAS Signaling Gone Awry in the Skin: The Complex Role of RAS in Cutaneous Neurofibroma Pathogenesis, Emerging Biological Insights.

  https://escholarship.org/uc/item/5964f9bf

  Cutaneous neurofibromas (cNFs) are the most common tumor in people with the rasopathy neurofibromatosis type 1. […] To facilitate the identification of novel and effective therapies, essential studies including a more refined understanding of cNF biology and the role of RAS signaling and downstream effector pathways responsible for cNF initiation, growth, and maintenance are needed. […] This review highlights the current state of knowledge of RAS signaling in cNF pathogenesis and therapeutic development for cNF treatment. […] Nf1/RAS-DEPENDENT SIGNALING AS A MASTER REGULATOR OF cNF PATHOGENESIS.

• #51 Neurofibroma Development in Neurofibromatosis Type 1: Insights from Cellular Origin and Schwann Cell Lineage Development

  https://www.mdpi.com/2072-6694/14/18/4513

  While, for decades, neurofibromas have been believed to originate from cells within the SC lineage, the specific time of initiation and exact cellular origin of pNFs and cNFs remain controversial, despite intensive studies. […] This has aided the clarification of neurofibroma characteristics with regard to formation, progression, and transformation to malignancy. […] The significant differences between these two subtypes of neurofibromas and the phenomenon that mouse models develop pNF but fail to develop cNF at 100% frequency jointly indicate that the cellular origins of these lesions may differ. […] The study progress of the cellular origin of both pNF and cNF is summarized in Table 1. […] The capability of SKPs to express Dhh and generate both pNF and cNF was identified. […] The specific cell type within the SC lineage leading to neurofibroma formation is controversial.

• #52 Neurofibroma Market Expected to Exhibit a CAGR of 11.5% During 2025-2035, Impelled by Advances in Genetic Research and Precision Medicine – BioSpace

  https://www.biospace.com/press-releases/neurofibroma-market-expected-to-exhibit-a-cagr-of-11-5-during-2025-2035-impelled-by-advances-in-genetic-research-and-precision-medicine

  The neurofibroma market is demonstrating a promising trajectory, with a projected CAGR of 11.5% across the 7 major markets between 2025 and 2035. […] This can be attributed to the growing appreciation of the genetic, molecular, and environmental contributions to the disease process, which leads to the development of neurofibromas, especially Neurofibromatosis Type 1 (NF1). […] The mutations discovered responsible for the development of these tumors include some found in the NF1 gene that encodes for neurofibromin protein. […] This deeper understanding is leading to the design of more accurate and targeted therapies that oppose the development of neurofibromas on a genetic basis. […] These neurological therapies, besides preventing the growth of neurofibromas, are intended for reduction of the tumor size and enhancement of the health of the patient.

• #53 Neurofibromatosis: Molecular Pathogenesis and Natural Compounds as Potential Treatments

  https://patrinum.ch/record/571355?ln=en

  The neurofibromatosis syndromes, including NF1, NF2, and schwannomatosis, are tumor suppressor syndromes characterized by multiple nervous system tumors, particularly Schwann cell neoplasms. […] Recent advances in molecular genetics and genomics alongside the development of multiple animal models have provided a better understanding of NF tumor biology and facilitated target identification and therapeutic evaluation. […] One major advance is the FDA approval of the MEK inhibitor selumetinib for the treatment of NF1-associated plexiform neurofibroma. […] Here we review the natural compounds that have been evaluated in NF models. Some have demonstrated potent anti-tumor effects and may become viable treatments in the future.

• #54 Neurofibromatosis Type 1 and tumorigenesis: molecular mechanisms and therapeutic implications in: Neurosurgical Focus Volume 28 Issue 1 (2010) Journals

  https://thejns.org/focus/view/journals/neurosurg-focus/28/1/article-pE8.xml

  Importantly, a complex series of interactions with these other cell types in neurofibroma tumorigenesis is mediated by abnormal expression of growth factors and their receptors and modification of gene expression, a key example of which is the process of recruitment and involvement of the NF1+/ heterozygous mast cell. […] In general, for malignant transformation to occur, there must be accumulation of additional mutations of multiple genes including INK4A/ARF and P53, with resulting abnormalities of their respective signal cascades. […] Further, abnormalities of the NF1 gene and molecular cascade described above have been implicated in the tumorigenesis of NF1 and some sporadically occurring gliomas, and thus, these treatment options may have wider applicability. […] Finally, increased knowledge of molecular and cellular mechanisms involved with NF1 tumorigenesis has led to multiple preclinical and clinical studies of targeted therapy, including the mTOR inhibitor rapamycin, which is demonstrating promising preclinical results for treatment of MPNSTs and gliomas.

• #55 Researchers Identify Mechanism and Possible Drug Treatment for Growth of Nerve Tumors in Neurofibromatosis | Technology Networks

  https://www.technologynetworks.com/genomics/news/researchers-identify-mechanism-and-possible-drug-treatment-for-growth-of-nerve-tumors-in-neurofibromatosis-207496

  Researchers studying neurofibromatosis type 1; a rare disease in which tumors grow within nerves; have found that the tumors are triggered by crosstalk between cells in the nerves and cells in the blood. […] Combined with previous findings, the new study suggests that the formation of plexiform neurofibromas requires two steps: complete loss of NF1 in Schwann cells (rendering them NF1 -/-) and an interaction between NF1 -/- Schwann cells and NF1+/- mast cells. While Schwann cells appear to be the primary tumor causing cell, mast cells appear to stimulate tumor growth by recruiting other cell types and blood vessels to the tumor. […] „The mast cell inflammatory response appears to be co-opted by the tumor to enhance tumor growth,” says Dr. Parada. […] The researchers also examined the role of c-kit, a molecule that is expressed by mast cells and other cell types, and is known to become overactive in some kinds of cancer. When c-kit was genetically deleted in NF1+/- bone marrow cells prior to transplantation, the transplanted cells failed to induce neurofibromas. Meanwhile, in mice that were prone to develop neurofibromas, the cancer drug Gleevec – an inhibitor of c-kit – reduced the metabolic activity and size of the tumors. […] The researchers say that the complex origin of tumors in neurofibromatosis – which has thwarted therapeutic development until now – could be the chink in the disease’s armor.

• #56 Immune system changes in the pathogenesis of neurofibromatosis type 1

  https://ouci.dntb.gov.ua/en/works/7pbq8PBl/

  Therefore, a promising direction is NF1 therapy with STAT3 inhibitors and immune checkpoint inhibitors that block programmed cell death ligand 1 (PD-L1). […] Activation of MEK signaling pathways in NF1 leads to PD-L1 stimulation; therefore, MEK inhibitors, which also suppress the RAS/RAF/MEK/ERK system, turned out to be effective in the treatment of NF1. […] For the treatment of sporadic malignant neoplasms, in the development of which NF1 mutations play a role, the developed methods of NF1 therapy can be used.

• #57

  https://www.nfnetwork.org/pages-news/investigating-the-role-of-fibroblasts-in-the-pathogenesis-in-neurofibromas/?lang=en

  If successful, Dr. Les work will pave the way toward understanding the developmental origin and biology of cNF. Furthermore, potential modifications to the Hippo pathway, in addition to NF1 deletion, may be an attractive therapeutic target for NF1 patients and could provide neurofibroma treatment options where none currently exist.

• #58 Neurofibroma Market Expected to Exhibit a CAGR of 11.5% During 2025-2035, Impelled by Advances in Genetic Research and Precision Medicine – BioSpace

  https://www.biospace.com/press-releases/neurofibroma-market-expected-to-exhibit-a-cagr-of-11-5-during-2025-2035-impelled-by-advances-in-genetic-research-and-precision-medicine

  A significant driver behind this market expansion is the emerging shift away from traditional treatments like surgery and radiation and towards precision medicine, incorporating targeted and effective treatments. […] Central strategies in these directions include gene therapies, MEK inhibitors, and regenerative therapies such as stem cell interventions that aim at the genetic and molecular underpinning of the growth of neurofibroma with a potential of durable solutions. […] Advanced approaches like gene editing and novel drug combinations are also under investigation with the aim of stopping tumor progression and minimizing side effects.

• #59

  https://www.jci.org/articles/view/99424

  Neurofibromatosis type 1 associates with multiple neoplasms, and the Schwann cell tumor neurofibroma is the most prevalent. A hallmark feature of neurofibroma is mast cell infiltration, which is recruited by chemoattractant stem cell factor (SCF) and has been suggested to sustain neurofibroma tumorigenesis. […] We demonstrate that mast cell infiltration is dependent on SCF from tumor Schwann cells. However, removal of mast cells by depleting the main SCF source only slightly affects neurofibroma progression. Other inflammation signatures show that all neurofibromas are associated with high levels of macrophages regardless of SCF status. These findings suggest an active inflammation in neurofibromas and partly explain why mast cell removal alone is not sufficient to relieve tumor burden in this experimental neurofibroma model.

• #60

  https://link.springer.com/article/10.1007/s11910-001-0012-z

  Neurofibromatosis type 1 peripheral nerve tumors: aberrant activation of the Ras pathway. […] Mouse models of tumor development in neurofibromatosis type 1. […] This paper provides evidence for a heterozygous effect of NF1 mutation. […] Genetic and cellular defects contributing to benign tumor formation in neurofibromatosis type 1.

• #61

  https://www.jci.org/articles/view/139807

  Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome caused by NF1 gene mutation, in which affected patients develop Schwann cell lineage peripheral nerve sheath tumors (neurofibromas). […] To investigate human neurofibroma pathogenesis, we differentiated a series of isogenic, patient-specific NF1-mutant human induced pluripotent stem cells (hiPSCs) into Schwannian lineage cells (SLCs). […] Moreover, we discovered that NF1 loss impaired Schwann cell differentiation by inducing a persistent stem-like state to expand the pool of progenitors required to initiate tumor formation, indicating that, in addition to regulating MAPK-mediated cell growth, NF1 loss also altered Schwann cell differentiation to promote neurofibroma development. […] Taken together, we established a complementary humanized neurofibroma explant and, to our knowledge, first-in-kind genetically engineered nodular cutaneous neurofibroma mouse models that delineate neurofibroma pathogenesis amenable to future therapeutic target discovery and evaluation.

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

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3694738/

  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. […] 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.

• #63 The role of nerve microenvironment for neurofibroma development | Oncotarget

  https://www.oncotarget.com/article/11133/text/

  Our results revealed that neither Nf1+/+ nor Nf1-/- SKPs can give rise to tumor subcutaneously. However, Nf1-/- SKPs but not Nf1+/+ controls robustly give rise to tumors in sciatic nerves. […] Taken together, all the histological and molecular characteristics of the tumors derived from Nf1-/- SKPs in sciatic nerve consistent with those of neurofibromas. […] Importantly, our discovery that Nf1-/- SKPs give rise to neurofibroma in sciatic nerves but not subcutaneous tissue indicates an essential role of nerve microenvironment for neurofibroma development. […] Our findings that Nf1-/-;P53-/- SKPs rapidly gave rise MPNST in nerve tissue demonstrates that nerve microenvironment is crucial for MPNST development. […] These skin rafts were initially maintained in in vitro culture for 5 days and then transplanted into the skin of nude mice in vivo.

• #64 Cutaneous neurofibromas in the genomics era: current understanding and open questions | British Journal of Cancer

  https://www.nature.com/articles/s41416-018-0073-2

  In this review, we summarise the present understanding of cNF pathogenesis including recent studies that propose a putative tumour cell of origin, the identification of mutations in NF1 and other genes in cNF, the role of the tumour microenvironment and endocrine signalling in cNF, and past, recent and ongoing clinical trials for cNF. […] The cNF-tumour-initiating event in humans is currently unknown and the cell of origin has yet to be identified; however, studies in mice have led to the identification of Schwann-cell-like skin-derived precursor (SKP) cells as the likely murine cNF tumour cell of origin. […] These observations revealed that loss of NF1 gene expression in SKPs is required, but not sufficient, for neurofibroma development, and revealed critical roles for the tumour microenvironment.

• #65 The role of nerve microenvironment for neurofibroma development | Oncotarget

  https://www.oncotarget.com/article/11133/text/

  Our results revealed that neither Nf1+/+ nor Nf1-/- SKPs can give rise to tumor subcutaneously. However, Nf1-/- SKPs but not Nf1+/+ controls robustly give rise to tumors in sciatic nerves. […] Taken together, all the histological and molecular characteristics of the tumors derived from Nf1-/- SKPs in sciatic nerve consistent with those of neurofibromas. […] Importantly, our discovery that Nf1-/- SKPs give rise to neurofibroma in sciatic nerves but not subcutaneous tissue indicates an essential role of nerve microenvironment for neurofibroma development. […] Our findings that Nf1-/-;P53-/- SKPs rapidly gave rise MPNST in nerve tissue demonstrates that nerve microenvironment is crucial for MPNST development. […] These skin rafts were initially maintained in in vitro culture for 5 days and then transplanted into the skin of nude mice in vivo.

• #66

  https://www.jci.org/articles/view/139807

  These results reveal a precise coordination between proliferation and differentiation in SLCs relevant to neurofibroma development. […] The local nerve microenvironment is important for neurofibroma formation. […] These findings confirm that, while hiPSC-NCSCs can give rise to different neural crest derivatives, including chondrocytes and SLCs in vivo, the local nerve microenvironment is essential for the differentiation of NF1/ NCSCs into SLCs and the formation of neurofibromas. […] Taken together, the generation and authentication of these neurofibroma models establishes tractable platforms for future preclinical therapeutic discovery and testing.

• #67 Neurofibroma Development in Neurofibromatosis Type 1: Insights from Cellular Origin and Schwann Cell Lineage Development

  https://www.mdpi.com/2072-6694/14/18/4513

  The complex effects of the tumor microenvironment on neurofibroma formation and progression, especially the intricate interactions of both cellular and non-cellular components, have been summarized in detail in a review published in 2021; however, specific mechanisms remain unclear. […] The occurrence of neurofibroma in normal individuals, as well as the recognition of patient subgroups with mosaic NF1 caused by postzygotic NF1 mutation, suggest that an NF1+/− environment may not necessarily be required for neurofibroma formation. […] The wide range of tumor subtypes and their diverse locations support the concept of NF1 loss in undifferentiated precursor cells during early developmental stages. […] However, there remains a view that the development of the SC lineage from NCSCs to immature stages and onward to maturity is not firmly governed by defined and periodic transitions. […] The facility for further investigation of specific cellular origin provides fertile ground for additional insights into the entire process of neurofibroma development from benign lesions to MPNSTs.

• #68 Neurofibroma Development in Neurofibromatosis Type 1: Insights from Cellular Origin and Schwann Cell Lineage Development—-Shanghai Institute of Nutrition and Health,Chinese Academy of Sciences

  https://english.sinh.cas.cn/research/papers/202503/t20250319_907460.html

  Neurofibromas have been thought to originate from cells within the Schwann cell lineage, while no consensus has been reached so far about the specific time of initiation and the exact cellular origin. […] Moreover, the role of Schwann cell lineage transition in different developmental stages of neurofibromas, together with other determinant factors, remains controversial, despite intensive studies. […] In this review, we summarized the accumulating evidence about the full range of neurofibroma development based on cellular and molecular pathogenesis. […] We highlighted the Schwann cell (SC) lineage shift to better present the evolution of its corresponding cellular origin hypothesis and its important effects on the progression and malignant transformation of neurofibromas. […] By integrating findings relating to tumor formation, growth, and malignancy, we hope to reveal the role of SC lineage shift as well as the combined impact of additional determinants in the natural history of PNSTs.

• #69 Neurofibroma Development in Neurofibromatosis Type 1: Insights from Cellular Origin and Schwann Cell Lineage Development

  https://www.mdpi.com/2072-6694/14/18/4513

  The complex effects of the tumor microenvironment on neurofibroma formation and progression, especially the intricate interactions of both cellular and non-cellular components, have been summarized in detail in a review published in 2021; however, specific mechanisms remain unclear. […] The occurrence of neurofibroma in normal individuals, as well as the recognition of patient subgroups with mosaic NF1 caused by postzygotic NF1 mutation, suggest that an NF1+/− environment may not necessarily be required for neurofibroma formation. […] The wide range of tumor subtypes and their diverse locations support the concept of NF1 loss in undifferentiated precursor cells during early developmental stages. […] However, there remains a view that the development of the SC lineage from NCSCs to immature stages and onward to maturity is not firmly governed by defined and periodic transitions. […] The facility for further investigation of specific cellular origin provides fertile ground for additional insights into the entire process of neurofibroma development from benign lesions to MPNSTs.

• #70 Neurofibromatosis type 1-associated tumours: Their somatic mutational spectrum and pathogenesis | Human Genomics | Full Text

  https://humgenomics.biomedcentral.com/articles/10.1186/1479-7364-5-6-623

  An NF1-/+ haploinsufficient cellular environment is also considered necessary, probably because of the growth advantage conferred by the signalling deficiency due to reduced neurofibromin levels. […] The molecular mechanisms underlying both PNF and cutaneous neurofibroma formation are becoming clearer, although the major details are still lacking. […] Although it is clear that biallelic NF1 gene inactivation is required for transformation to occur, mutations at the NF1 locus are insufficient to explain the process of tumorigenesis, as most benign neurofibromas also exhibit such biallelic NF1 inactivation. […] The best evidence for the involvement of other loci relates to the tumour protein 53 gene (TP53), for which several different mutations have been found in MPNSTs that have not been reported in benign neurofibromas.

• #71 Neurofibroma Market Expected to Exhibit a CAGR of 11.5% During 2025-2035, Impelled by Advances in Genetic Research and Precision Medicine – BioSpace

  https://www.biospace.com/press-releases/neurofibroma-market-expected-to-exhibit-a-cagr-of-11-5-during-2025-2035-impelled-by-advances-in-genetic-research-and-precision-medicine

  There is another area of rapid advancement within molecular biology that is shedding light on the pathways of the molecular level driving neurofibroma growth, hence allowing the development of drugs that will stop those pathways and thereby prevent tumor formation. […] The treatment landscape for neurofibromas is undergoing a dynamic shift, driven by intense competition and continuous innovation in the healthcare and biotechnology sectors. […] A growing focus on precision medicine and the integration of combination therapies underscores the industry’s commitment to providing more effective, individualized care. […] Ultimately, these concerted efforts aim not only to improve tumor management and overall patient well-being but also to offer hope for a future where genetic causes of neurofibromas can be effectively treated, and perhaps even eradicated.

• #72 Recent Advances in the Diagnosis and Pathogenesis of Neurofibromatosis Type 1 (NF1)-associated Peripheral Nervous Syste…

  https://ouci.dntb.gov.ua/en/works/4k2m3k67/

  The diagnosis of a neurofibroma or a malignant peripheral nerve sheath tumor (MPNST) often raises the question of whether the patient has the genetic disorder neurofibromatosis type 1 (NF1) as well as how this will impact the patient’s outcome, what their risk is for developing additional neoplasms and whether treatment options differ for NF1-associated and sporadic peripheral nerve sheath tumors. […] We then focus on NF1-associated neurofibromas, considering first the complicated clinical behavior and pathology of these neoplasms and then discussing our current understanding of the genomic abnormalities that drive their pathogenesis, including the mutations encountered in atypical neurofibromas. […] The mutations involved in neurofibroma-MPNST progression, including the recent identification of mutations affecting epigenetic regulators, are then considered. […] Finally, we explore how our current understanding of neurofibroma and MPNST pathogenesis is informing the design of new therapies for these neoplasms.

• #73 Recent advances in Neurofibromatosis type 1 research: Towards tailored therapeutics and treatment strategies

  https://www.e-kjgm.org/journal/view.html?uid=375&&vmd=Full

  Neurofibromatosis type 1 (NF1) is an autosomal dominant multisystem disorder caused by germline mutations in the NF1 gene, classified as a RASopathy. The NF1 gene encodes neurofibromin, a RAS GTPase-activating protein that modulates the Ras-MAPK signaling cascade. […] Loss of NF1 function results in constitutive Ras/Raf/MEK/ERK signaling activation, a primary driver of tumorigenesis in NF1 patients. […] The involvement of the tumor microenvironment (TME) in NF1 pathogenesis is increasingly recognized. Recent advances in single-cell RNA sequencing have delineated the intricate cellular composition and signaling dynamics within mature neurofibromas, elucidating the complexity of the TME. […] Research has demonstrated that schwann cells-immunes (mast cells, T cells) in PNs, microglia and T cells in LGGs, and hematopoietic cells in MPNSTs play a significant role in promoting the development of NF1-associated tumors.

• #74 Recent advances in Neurofibromatosis type 1 research: Towards tailored therapeutics and treatment strategies

  https://www.e-kjgm.org/journal/view.html?uid=375&&vmd=Full

  Recent studies suggest that NF1 LOH occurs in multipotent precursors, explaining the diverse phenotypes observed in NF1 patients. […] Enhanced understanding of the TME has been instrumental in the development of targeted therapies, including combination approaches, and has propelled the application of personalized medicine for NF1-associated malignancies.

Zobacz więcej