Toward Understanding the Mechanisms of Malignant Peripheral Nerve Sheath Tumor Development

Mohamad, Teddy; Plante, Camille; Brosseau, Jean-Philippe

doi:10.3390/ijms22168620

Cited by 15 publications

(15 citation statements)

References 110 publications

(160 reference statements)

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“…As malignant sarcomas of the soft tissue, NF1-associated MPNSTs tend to arise from the progression of patients with pNF rather than cNF; however, the underlying mechanisms are poorly understood. Although researchers have proposed the hypothesis that the unique susceptibility of pNFs to malignant transformation indicates that this subtype includes specific susceptible cell populations [ 11 ], no relevant models have been established, and there is little supporting evidence. In addition, the lack of comprehensive genetic data for numerous MPNST cell lines has largely hindered pathogenesis study and novel therapy development [ 101 ].…”

Section: Discussion and Future Directionsmentioning

confidence: 99%

“…[ 75 , 76 , 77 , 78 , 79 , 80 , 81 ]. Despite extensive studies on the genetics of MPNSTs, a full understanding of their molecular diversity is lacking [ 11 ].…”

Section: Malignant Transformation Of Neurofibromamentioning

confidence: 99%

“…Growing pNFs can put pressure on the surrounding tissues, resulting in severe pain, neurological damage, and skeletal destruction. In addition, there is an approximately 10% lifetime risk of pNFs transforming into NF1-related malignant PNSTs (MPNSTs) [ 8 , 9 , 10 ]; these often arise within pre-existing pNFs, rather than cNFs, as a result of additional genetic mutations occurring in a subset of key genes in a specific order [ 11 ]. Given the occurrence of tumors at two distinct developmental stages (adolescent versus embryonic), in different locations (body surface versus nerve plexus), with differing malignant transformation potential (none versus 10%), the spatiotemporal heterogeneity of cNF versus pNF reasonably supports distinct cellular origins for these neurofibromas.…”

Section: Introductionmentioning

confidence: 99%

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

Xing

Zhang

et al. 2022

Cancers

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Background: Neurofibromatosis type 1 (NF1), a genetic tumor predisposition syndrome that affects about 1 in 3000 newborns, is caused by mutations in the NF1 gene and subsequent inactivation of its encoded neurofibromin. Neurofibromin is a tumor suppressor protein involved in the downregulation of Ras signaling. Despite a diverse clinical spectrum, one of several hallmarks of NF1 is a peripheral nerve sheath tumor (PNST), which comprises mixed nervous and fibrous components. 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. Methods: We retrieved published literature from PubMed, EMBASE, and Web of Science up to 21 June 2022 and searched references cited in the selected studies to identify other relevant papers. Original articles reporting the pathogenesis of PNSTs during development were included in this review. 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. Conclusions: In this review, we summarized the vast array of evidence obtained on the full range of neurofibroma development based on cellular and molecular pathogenesis. 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.

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Section: Discussion and Future Directionsmentioning

confidence: 99%

“…[ 75 , 76 , 77 , 78 , 79 , 80 , 81 ]. Despite extensive studies on the genetics of MPNSTs, a full understanding of their molecular diversity is lacking [ 11 ].…”

Section: Malignant Transformation Of Neurofibromamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Xing

Zhang

et al. 2022

Cancers

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“…Some humans with nerve sheath tumors do now no longer enjoy symptoms; however, others might also additionally notice: pain, numbness, tingling, itching or a burning sensation, weakness, and a mass that the character can see or feel. 29,30…”

Section: Introductionmentioning

confidence: 99%

Comprehensions keen on the biology of Brain tumors: Possibilities and Challenges

Habib

2022

IJPI

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The word "tumor" is a Greek term that refers to a swelling or a lump. In modern medical terms, a tumor is usually an abnormal mass of cells and tissues which grows due to the abnormal division of cells. The unnatural division of cells occurs due to the cancerous nature of these cells, which no longer obey standard checkpoints that prevent healthy or non-cancerous cells from uncontrolled cell divisions. Tumors may be circumscribed or diffuse depending on whether they remain localized to a part of the brain or spread to other parts aggressively by metastasis; in 2016, WHO has classified tumors of the brain or central nervous system by taking into account the latest molecular genetic data along with classic histopathological features characteristic of each kind of tumor. The new classification system makes diagnosis more precise, but a better prognosis analysis is now possible since genotype is far more determinative and accurate than histological phenotype. Modern technologies like high throughput gene sequencing, CRISPR-Cas9 gene editing, and personalized medicine approaches have improved the prognosis of brain tumor patients.They have also revolutionized our understanding of the biology of brain tumors and how they are now being treated. In this review, we will discuss the latest knowledge about the biology of brain tumors and how modern technologies are helping to understand the molecular basis of these pathologies and develop better treatment options to improve patient survival.

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“…Notably, MEK inhibitors (MEKi) represent the most effective targeted therapy against PNs, recognized precursors of MPNSTs, and they are being tested in clinical trials for MPNSTs (6). In addition to tumor-cell intrinsic mechanisms, alterations in the tumor microenvironment (TME) are now recognized as critical elements influencing MPNST development (7). Particularly, tumor angiogenesis plays a crucial role in the transformation and progression of MPNSTs (8).…”

Section: Introductionmentioning

confidence: 99%

Endoglin, a novel biomarker and therapeutical target to prevent malignant peripheral nerve sheath tumor growth and metastasis

González-Muñoz

Giannatale

García‐Silva

et al. 2022

Preprint

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Purpose: Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft-tissue sarcomas that lack effective treatments, underscoring the urgent need to uncover novel mediators of MPNST pathogenesis that may serve as potential therapeutic targets. Tumor angiogenesis is considered a critical event in MPNST transformation and progression. Here, we have investigated whether endoglin (ENG), a TGF-β coreceptor with a crucial role in angiogenesis, could be a novel therapeutic target in MPNSTs. Experimental Design: ENG expression was evaluated in human peripheral nerve sheath tumor tissues and plasma samples. Effects of tumor cell-specific ENG expression on gene expression, signaling pathways and in vivo MPNST growth and metastasis were investigated. The efficacy of ENG targeting in monotherapy or in combination with MEK inhibition was analyzed in xenograft models. Results: ENG expression was found to be upregulated in both human MPNST tumor tissues and plasma circulating small extracellular vesicles. We demonstrated that ENG modulates Smad1/5 and MAPK/ERK pathway activation and pro-angiogenic and pro-metastatic gene expression in MPNST cells and plays an active role in tumor growth and metastasis in vivo. Targeting with ENG-neutralizing antibodies (TRC105/M1043) decreased MPNST tumor growth and metastasis in xenograft models by reducing tumor cell proliferation and angiogenesis. Importantly, combination of anti-ENG therapy with MEK inhibition reduced more effectively tumor cell growth and angiogenesis. Conclusions: Our data unveil a tumor-promoting function of ENG in MPNSTs and support the combined use of anti-ENG antibodies and MEK inhibitors as a novel potential combination to control MPNSTs growth and metastasis.

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Toward Understanding the Mechanisms of Malignant Peripheral Nerve Sheath Tumor Development

Cited by 15 publications

References 110 publications

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

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

Comprehensions keen on the biology of Brain tumors: Possibilities and Challenges

Endoglin, a novel biomarker and therapeutical target to prevent malignant peripheral nerve sheath tumor growth and metastasis

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