scholarly journals Neurofibromin Deficiency and Extracellular Matrix Cooperate to Increase Transforming Potential through FAK-Dependent Signaling

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2329
Author(s):  
Andrea Errico ◽  
Anna Stocco ◽  
Vincent M. Riccardi ◽  
Alberto Gambalunga ◽  
Franco Bassetto ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Peripheral Nerve ◽  
Neurofibromatosis Type ◽  
Mek Inhibitor ◽  
Colony Growth ◽  
Nerve Sheath Tumor ◽  
Genetic Syndrome ◽  
Peripheral Nerve Sheath Tumors ◽  
Nerve Sheath

Plexiform neurofibromas (Pnfs) are benign peripheral nerve sheath tumors that are major features of the human genetic syndrome, neurofibromatosis type 1 (NF1). Pnfs are derived from Schwann cells (SCs) undergoing loss of heterozygosity (LOH) at the NF1 locus in an NF1+/− milieu and thus are variably lacking in the key Ras-controlling protein, neurofibromin (Nfn). As these SCs are embedded in a dense desmoplastic milieu of stromal cells and abnormal extracellular matrix (ECM), cell–cell cooperativity (CCC) and the molecular microenvironment play essential roles in Pnf progression towards a malignant peripheral nerve sheath tumor (MPNST). The complexity of Pnf biology makes treatment challenging. The only approved drug, the MEK inhibitor Selumetinib, displays a variable and partial therapeutic response. Here, we explored ECM contributions to the growth of cells lacking Nfn. In a 3D in vitro culture, NF1 loss sensitizes cells to signals from a Pnf-mimicking ECM through focal adhesion kinase (FAK) hyperactivation. This hyperactivation correlated with phosphorylation of the downstream effectors, Src, ERK, and AKT, and with colony formation. Expression of the GAP-related domain of Nfn only partially decreased activation of this signaling pathway and only slowed down 3D colony growth of cells lacking Nfn. However, combinatorial treatment with both the FAK inhibitor Defactinib (VS-6063) and Selumetinib (AZD6244) fully suppressed colony growth. These observations pave the way for a new combined therapeutic strategy simultaneously interfering with both intracellular signals and the interplay between the various tumor cells and the ECM.

scholarly journals Malignant peripheral nerve sheath tumor with and without neurofibromatosis type 1

2017 ◽  
Vol 75 (6) ◽  
pp. 366-371 ◽  
Author(s):  
Roberto André Torres de Vasconcelos ◽  
Pedro Guimarães Coscarelli ◽  
Regina Papais Alvarenga ◽  
Marcus André Acioly
Keyword(s):  
Overall Survival ◽  
Peripheral Nerve ◽  
Neurofibromatosis Type 1 ◽  
Tumor Size ◽  
Retrospective Chart Review ◽  
Neurofibromatosis Type ◽  
Nerve Sheath Tumor ◽  
Peripheral Nerve Sheath Tumors ◽  
Nerve Sheath

ABSTRACT Objective In this study, we review the institution’s experience in treating malignant peripheral nerve sheath tumors (MPNSTs). A secondary aim was to compare outcomes between MPNSTs with and without neurofibromatosis type 1 (NF1). Methods Ninety-two patients with MPNSTs, over a period of 20 years, were reviewed. A retrospective chart review was performed. The median age was 43.5 years (range, 3–84 years) and 55.4% were female; 41 patients (44.6%) had NF1-associated tumors. Results Mean tumor sizes were 15.8 ± 8.2 cm and 10.8 ± 6.3 cm for patients with and without NF1, respectively. Combined two- and five-year overall survival was 48.5% and 29%. Multivariate analysis confirmed the association of tumor size greater than 10 cm (hazard ratio (HR) 2.99; 95% confidence interval (CI) 1.14–7.85; p = 0.0258) and presence of NF1 (HR 3.41; 95%CI 1.88–6.19; p < 0.001) with a decreased overall survival. Conclusion Tumor size and NF1 status were the most important predictors of overall survival in our population.

scholarly journals From Genes to -Omics: The Evolving Molecular Landscape of Malignant Peripheral Nerve Sheath Tumor

Genes ◽  
2020 ◽  
Vol 11 (6) ◽  
pp. 691
Author(s):  
Kathryn M. Lemberg ◽  
Jiawan Wang ◽  
Christine A. Pratilas
Keyword(s):  
Peripheral Nerve ◽  
Soft Tissue Sarcomas ◽  
Type I ◽  
Nerve Sheath Tumor ◽  
Genetic Changes ◽  
Genetic Syndrome ◽  
Genetic Sequencing ◽  
Peripheral Nerve Sheath Tumors ◽  
Nerve Sheath ◽  
Molecular Landscape

Malignant peripheral nerve sheath tumors (MPNST) are rare, aggressive soft tissue sarcomas that occur with significantly increased incidence in people with the neuro-genetic syndrome neurofibromatosis type I (NF1). These complex karyotype sarcomas are often difficult to resect completely due to the involvement of neurovascular bundles, and are relatively chemotherapy- and radiation-insensitive. The lifetime risk of developing MPNST in the NF1 population has led to great efforts to characterize the genetic changes that drive the development of these tumors and identify mutations that may be used for diagnostic or therapeutic purposes. Advancements in genetic sequencing and genomic technologies have greatly enhanced researchers’ abilities to broadly and deeply investigate aberrations in human MPNST genomes. Here, we review genetic sequencing efforts in human MPNST samples over the past three decades. Particularly for NF1-associated MPNST, these overall sequencing efforts have converged on a set of four common genetic changes that occur in most MPNST, including mutations in neurofibromin 1 (NF1), CDKN2A, TP53, and members of the polycomb repressor complex 2 (PRC2). However, broader genomic studies have also identified recurrent but less prevalent genetic variants in human MPNST that also contribute to the molecular landscape of MPNST and may inform further research. Future studies to further define the molecular landscape of human MPNST should focus on collaborative efforts across multiple institutions in order to maximize information gathered from large numbers of well-annotated MPNST patient samples, both in the NF1 and the sporadic MPNST populations.

scholarly journals Diagnosis and management of malignant peripheral nerve sheath tumors: Current practice and future perspectives

2019 ◽  
Vol 2 (Supplement_1) ◽  
pp. i40-i49 ◽  
Author(s):  
Bethany C Prudner ◽  
Tyler Ball ◽  
Richa Rathore ◽  
Angela C Hirbe
Keyword(s):  
Peripheral Nerve ◽  
Treatment Options ◽  
Neurofibromatosis Type ◽  
Current Treatment ◽  
Nerve Sheath Tumor ◽  
Preclinical Research ◽  
Cancer Predisposition Syndrome ◽  
Peripheral Nerve Sheath Tumors ◽  
Nerve Sheath ◽  
Investigational Treatment

Abstract One of the most common malignancies affecting adults with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome is the malignant peripheral nerve sheath tumor (MPNST), a highly aggressive sarcoma that typically develops from benign plexiform neurofibromas. Approximately 8–13% of individuals with NF1 will develop MPNST during young adulthood. There are few therapeutic options, and the vast majority of people with these cancers will die within 5 years of diagnosis. Despite efforts to understand the pathogenesis of these aggressive tumors, the overall prognosis remains dismal. This manuscript will review the current understanding of the cellular and molecular progression of MPNST, diagnostic workup of patients with these tumors, current treatment paradigms, and investigational treatment options. Additionally, we highlight novel areas of preclinical research, which may lead to future clinical trials. In summary, MPNST remains a diagnostic and therapeutic challenge, and future work is needed to develop novel and rational combinational therapy for these tumors.

scholarly journals Ral Overactivation in Malignant Peripheral Nerve Sheath Tumors

2009 ◽  
Vol 29 (14) ◽  
pp. 3964-3974 ◽  
Author(s):  
Vidya Bodempudi ◽  
Farnaz Yamoutpoor ◽  
Weihong Pan ◽  
Arkadiusz Z. Dudek ◽  
Tuba Esfandyari ◽  
...  
Keyword(s):  
Peripheral Nerve ◽  
Cell Cycle Progression ◽  
Epithelial Mesenchymal Transition ◽  
Neurofibromatosis Type ◽  
Dominant Negative ◽  
Nerve Sheath Tumor ◽  
Mesenchymal Transition ◽  
Peripheral Nerve Sheath Tumors ◽  
Nerve Sheath

ABSTRACT Ras leads an important signaling pathway that is deregulated in neurofibromatosis type 1 and malignant peripheral nerve sheath tumor (MPNST). In this study, we show that overactivation of Ras and many of its downstream effectors occurred in only a fraction of MPNST cell lines. RalA, however, was overactivated in all MPNST cells and tumor samples compared to nontransformed Schwann cells. Silencing Ral or inhibiting it with a dominant-negative Ral (Ral S28N) caused a significant reduction in proliferation, invasiveness, and in vivo tumorigenicity of MPNST cells. Silencing Ral also reduced the expression of epithelial mesenchymal transition markers. Expression of the NF1-GTPase-related domain (NF1-GRD) diminished the levels of Ral activation, implicating a role for neurofibromin in regulating RalA activation. NF1-GRD treatment caused a significant decrease in proliferation, invasiveness, and cell cycle progression, but cell death increased. We propose Ral overactivation as a novel cell signaling abnormality in MPNST that leads to important biological outcomes with translational ramifications.

scholarly journals A Case Report of a Malignant Peripheral Nerve Sheath Tumor of the Oral Cavity in Neurofibromatosis Type 1

2012 ◽  
Vol 2012 ◽  
pp. 1-3 ◽  
Author(s):  
Özmen Öztürk ◽  
Alper Tutkun
Keyword(s):  
Peripheral Nerve ◽  
Neurofibromatosis Type 1 ◽  
Malignant Tumors ◽  
Rapid Change ◽  
Neurofibromatosis Type ◽  
Nerve Sheath Tumor ◽  
Peripheral Nerve Sheath Tumors ◽  
Nerve Sheath ◽  
Adjacent Structures

Patients with neurofibromatosis type 1 develop both benign and malignant tumors at an increased frequency. Most of the malignant peripheral nerve sheath tumors (MPNSTs) are considered as high-grade sarcomas originating from tissues of mesenchymal origin. It is generally accepted that MPNSTs occur in about 2% to 5% of neurofibromatosis patients. In this paper, we present a 16-year-old male patient with neurofibromatosis who developed MPNST of the retromolar area. The mass enlarged rapidly in a period of 6 weeks. The patient was treated surgically, and a tumor mass with a diameter of  cm was excised, but after 8 months a recurrence was observed at the same site. The sarcomatous change in a neurofibroma has an extremely poor prognosis, so patients with neurofibromatosis should be closely monitored for a possible malignancy. A rapid change in size of a preexisting neurofibroma, infiltration of the adjacent structures, intralesional hemorrhage, and pain indicate a possible malignant transformation to MPNST.

scholarly journals KIF11 and KIF15 mitotic kinesins are potential therapeutic vulnerabilities for malignant peripheral nerve sheath tumors

2020 ◽  
Vol 2 (Supplement_1) ◽  
pp. i62-i74 ◽  
Author(s):  
Ernest Terribas ◽  
Marco Fernández ◽  
Helena Mazuelas ◽  
Juana Fernández-Rodríguez ◽  
Josep Biayna ◽  
...  
Keyword(s):  
Peripheral Nerve ◽  
Cell Survival ◽  
Cell Lines ◽  
Nerve Sheath Tumor ◽  
Division Rate ◽  
Peripheral Nerve Sheath Tumors ◽  
Nerve Sheath ◽  
Genetic Suppression ◽  
The Impact

Abstract Background Malignant peripheral nerve sheath tumor (MPNST) constitutes the leading cause of neurofibromatosis type 1–related mortality. MPNSTs contain highly rearranged hyperploid genomes and exhibit a high division rate and aggressiveness. We have studied in vitro whether the mitotic kinesins KIF11, KIF15, and KIF23 have a functional role in maintaining MPNST cell survival and can represent potential therapeutic vulnerabilities. Methods We studied the expression of kinesin mRNAs and proteins in tumors and cell lines and used several in vitro functional assays to analyze the impact of kinesin genetic suppression (KIF15, KIF23) and drug inhibition (KIF11) in MPNST cells. We also performed in vitro combined treatments targeting KIF11 together with other described MPNST targets. Results The studied kinesins were overexpressed in MPNST samples. KIF15 and KIF23 were required for the survival of MPNST cell lines, which were also more sensitive than benign control fibroblasts to the KIF11 inhibitors ispinesib and ARRY-520. Co-targeting KIF11 and BRD4 with ARRY-520 and JQ1 reduced MPNST cell viability, synergistically killing a much higher proportion of MPNST cells than control fibroblasts. In addition, genetic suppression of KIF15 conferred an increased sensitivity to KIF11 inhibitors alone or in combination with JQ1. Conclusions The mitotic spindle kinesins KIF11 and KIF15 and the cytokinetic kinesin KIF23 play a clear role in maintaining MPNST cell survival and may represent potential therapeutic vulnerabilities. Although further in vivo evidences are still mandatory, we propose a simultaneous suppression of KIF11, KIF15, and BRD4 as a potential therapy for MPNSTs.

Radiation-Induced Glandular Malignant Peripheral Nerve Sheath Tumor

2017 ◽  
Vol 25 (7) ◽  
pp. 635-639 ◽  
Author(s):  
Ivy John ◽  
David L. Bartlett ◽  
Uma N. M. Rao
Keyword(s):  
Peripheral Nerve ◽  
Femoral Nerve ◽  
Neurofibromatosis Type ◽  
Soft Tissue Tumors ◽  
Nerve Sheath Tumor ◽  
Nerve Sheath Tumors ◽  
Peripheral Nerve Sheath Tumors ◽  
Nerve Sheath ◽  
Divergent Differentiation ◽  
Radiation Induced

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft-tissue tumors. They can occur in patients with neurofibromatosis type-1 (NF-1) or as sporadic tumors. Only 10% of MPNSTs are radiation induced. Divergent differentiation in MPNSTs can occur in 15% of cases and may include cartilage, bone, skeletal muscle, blood vessels, and very rarely well-formed glands, the latter typically described in NF-1–associated MPNSTs. We report an exceedingly rare case of radiation induced glandular MPNST arising in a neurofibroma of the femoral nerve in a patient previously irradiated for endometrial carcinoma.

Radiation-induced intradural malignant peripheral nerve sheath tumor of the cauda equina with diffuse leptomeningeal metastasis

2014 ◽  
Vol 21 (5) ◽  
pp. 719-726 ◽  
Author(s):  
Darryl Lau ◽  
Dominic H. Moon ◽  
Paul Park ◽  
Shawn Hervey-Jumper ◽  
Paul E. McKeever ◽  
...  
Keyword(s):  
Peripheral Nerve ◽  
Management Strategies ◽  
Cauda Equina ◽  
Leptomeningeal Metastasis ◽  
Neurofibromatosis Type ◽  
Nerve Sheath Tumor ◽  
Testicular Seminoma ◽  
Peripheral Nerve Sheath Tumors ◽  
Metastatic Lesions ◽  
Nerve Sheath

Malignant peripheral nerve sheath tumors (MPNSTs) are rare, affecting only a small portion of the general population. In many cases, MPNSTs occur in association with neurofibromatosis Type 1 and at times arise secondary to previous radiation therapy (RT). These tumors can be found essentially anywhere a peripheral nerve is present, but they rarely originate primarily from the spinal nerve or cauda equina and cause leptomeningeal spread. This report describes the treatment course of a 43-year-old man with a history of testicular seminoma treated with RT a decade before, who was found to have a large sacral MPNST. The patient underwent complete sacrectomy for gross-total resection. Despite this effort, he was eventually found to have metastatic lesions throughout the spine and brain, ultimately resulting in acute hydrocephalus and death. Biopsy results of these metastatic lesions proved to be characteristic of his original MPNST. The literature is also reviewed and the diagnostic modalities, management strategies, and prognosis of MPNST are discussed.

Malignant Peripheral Nerve Sheath Tumor With Divergent Glandular Differentiation

2017 ◽  
Vol 25 (4) ◽  
pp. 310-313 ◽  
Author(s):  
Yurina Miki ◽  
Khin Thway
Keyword(s):  
Differential Diagnosis ◽  
Peripheral Nerve ◽  
Neurofibromatosis Type ◽  
Nerve Sheath Tumor ◽  
Histologic Diagnosis ◽  
Nerve Sheath Tumors ◽  
Peripheral Nerve Sheath Tumors ◽  
Immunohistochemical Markers ◽  
Nerve Sheath ◽  
Divergent Differentiation

Malignant peripheral nerve sheath tumors (MPNST) are soft tissue neoplasms with evidence of nerve sheath differentiation. They usually arise from peripheral nerves or from preexisting benign nerve sheath neoplasms, often in patients with neurofibromatosis type 1 (NF1). The histologic diagnosis of MPNST is challenging as their morphology is highly variable, and there has been a lack of routine diagnostic immunohistochemical markers and specific genetic aberrations. Although divergent differentiation is well documented in MPNST, it is most frequently toward mesenchymal elements. Differentiation toward epithelial elements is very rare, and we illustrate a case of MPNST with glandular differentiation, comprising prominent well-formed glands, with a brief discussion of biphasic (spindle and glandular) neoplasms in the differential diagnosis. An index of suspicion for MPNST is necessary, due to the differing management from tumors in its differential diagnosis, and because of the potential for therapies toward molecular targets in future.

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