scholarly journals Cdkn2a (Arf) loss drives NF1-associated atypical neurofibroma and malignant transformation

2019 ◽  
Vol 28 (16) ◽  
pp. 2752-2762 ◽  
Author(s):  
Steven D Rhodes ◽  
Yongzheng He ◽  
Abbi Smith ◽  
Li Jiang ◽  
Qingbo Lu ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Plexiform Neurofibroma ◽  
Neurofibromatosis Type ◽  
Ras Proteins ◽  
Reading Frame ◽  
Cancer Predisposition Syndrome ◽  
Nerve Sheath Tumors ◽  
Peripheral Nerve Sheath Tumors ◽  
Clinical Series ◽  
Clonal Development

Abstract Plexiform neurofibroma (PN) tumors are a hallmark manifestation of neurofibromatosis type 1 (NF1) that arise in the Schwann cell (SC) lineage. NF1 is a common heritable cancer predisposition syndrome caused by germline mutations in the NF1 tumor suppressor, which encodes a GTPase-activating protein called neurofibromin that negatively regulates Ras proteins. Whereas most PN are clinically indolent, a subset progress to atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP) and/or to malignant peripheral nerve sheath tumors (MPNSTs). In small clinical series, loss of 9p21.3, which includes the CDKN2A locus, has been associated with the genesis of ANNUBP. Here we show that the Cdkn2a alternate reading frame (Arf) serves as a gatekeeper tumor suppressor in mice that prevents PN progression by inducing senescence-mediated growth arrest in aberrantly proliferating Nf1−/− SC. Conditional ablation of Nf1 and Arf in the neural crest-derived SC lineage allows escape from senescence, resulting in tumors that accurately phenocopy human ANNUBP and progress to MPNST with high penetrance. This animal model will serve as a platform to study the clonal development of ANNUBP and MPNST and to identify new therapies to treat existing tumors and to prevent disease progression.

scholarly journals CSIG-02. R-RAS SUBFAMILY PROTEINS ELICIT DISTINCT PHYSIOLOGIC EFFECTS AND PHOSPHOPROTEOME ALTERATIONS IN NEUROFIBROMIN-NULL MPNST CELLS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii27-ii28
Author(s):  
Shannon Weber ◽  
Nicole Brossier ◽  
Amanda Prechtl ◽  
Stephanie Brosius ◽  
Stephen Barnes ◽  
...  
Keyword(s):  
Genetic Disorder ◽  
Neurofibromatosis Type ◽  
Dominant Negative ◽  
Spectrometric Analysis ◽  
Ras Proteins ◽  
Nerve Sheath Tumors ◽  
Peripheral Nerve Sheath Tumors ◽  
And Migration ◽  
The Impact

Abstract Loss of the Ras GTPase-activating protein neurofibromin promotes the development of aggressive spindle cell neoplasms known as Malignant Peripheral Nerve Sheath Tumors (MPNSTs) in patients with the genetic disorder neurofibromatosis type 1 (NF1). Currently, the available chemotherapeutic regimens and radiotherapy are ineffective against MPNSTs, so the prognosis for patients with these neoplasms is poor. Neurofibromin loss dysregulates multiple Ras proteins in the classic (H-Ras, N-Ras, K-Ras) and R-Ras (R-Ras, R-Ras2/TC21, R-Ras3/M-Ras) subfamilies. Consequently, it is unclear which Ras proteins or pathways regulated by these Ras proteins should be therapeutically targeted in MPNSTs. We have previously shown that classic Ras proteins drive MPNST cell proliferation and survival. However, the role(s) of the R-Ras subfamily of proteins in MPNSTs have not been elucidated. To determine how R-Ras proteins contribute to the pathogenesis of neurofibromin-null MPNSTs, we introduced dominant negative (DN) R-Ras mutants, which are pan-inhibitors of the R-Ras subfamily, into MPNST cells and assessed the impact of R-Ras subfamily inhibition on mitogenesis, migration and the phosphoproteome. A panel of MPNST cell lines (STS-26T, YST-1, ST88-14, 90–8, NMS2, NMS-PC, S462, T265-2c) was used. Methodologies utilized include immunoblotting, PCR, Transwell migration, 3H-thymidine incorporation, and mass spectrometric analysis of phosphoprotein-enriched specimens. We found that R-Ras and R-Ras2 are widely expressed and can be activated in neurofibromin-null MPNST cells. In contrast to classic Ras proteins, we found that R-Ras proteins drive MPNST both mitogenesis and migration. Using mass spectrometry-based phosphoproteomics, we identified thirteen protein networks that were regulated by DN R-Ras, including networks affecting cellular movement via effects on microtubules. We chose to further study changes in ROCK1 phosphorylation and found that R-Ras subfamily proteins function, at least in some part, through the same pathways as ROCK1. We conclude that R-Ras proteins promote tumorigenesis by regulating distinct signaling pathways that regulate MPNST mitogenesis and migration.

Familial CNS Tumor Syndromes

2017 ◽  
Author(s):  
Ibrahim Hussain ◽  
David H. Gutmann
Keyword(s):  
Molecular Mechanisms ◽  
Neurofibromatosis Type ◽  
Genetically Engineered ◽  
Low Grade ◽  
Inherited Cancer ◽  
Cancer Predisposition Syndrome ◽  
Nerve Sheath Tumors ◽  
Peripheral Nerve Sheath Tumors ◽  
Nf1 Gene ◽  
New Treatments

Neurofibromatosis type 1 (NF1) is an inherited cancer predisposition syndrome affecting 1 in 2,500 to 3,000 individuals worldwide. Key clinical features of NF1 include pigmentary abnormalities, learning disabilities, and orthopedic problems. Individuals with NF1 are prone to the development of benign peripheral nerve sheath tumors, and 15% to 20% of affected children harbor low-grade gliomas of the optic pathway. Since the discovery of the NF1 gene and its protein neurofibromin, advances in understanding the molecular mechanisms of NF1 have resulted in the discovery of new treatments. In addition, genetically-engineered animal models of NF1-associated tumorigenesis have served as platforms for validating molecular targets for future medical therapies.

scholarly journals Oral plexiform schwannoma: A case report and relevant immunohistochemical investigation

2019 ◽  
Vol 7 ◽  
pp. 2050313X1983818 ◽  
Author(s):  
Johan Sergheraert ◽  
Dominique Zachar ◽  
Vincent Furon ◽  
Roman-Hossein Khonsari ◽  
Nicolas Ortonne ◽  
...  
Keyword(s):  
Peripheral Nerve ◽  
Plexiform Neurofibroma ◽  
Brain Magnetic Resonance Imaging ◽  
Neurofibromatosis Type ◽  
Neurofibromatosis Type 2 ◽  
Plexiform Schwannoma ◽  
Nerve Sheath Tumors ◽  
Peripheral Nerve Sheath Tumors ◽  
Nerve Sheath

Schwannomas are benign peripheral nerve sheath tumors originating from the Schwann cells. Most schwannomas in the head and neck region are solitary; however, multiple schwannomas affecting one or more nerves suggest a possible association with neurofibromatosis type 2 and schwannomatosis. Plexiform schwannoma is a rare variant of conventional schwannoma that is characterized by intraneural multinodular growth. This grow pattern has also been observed with other neural tumors which may make diagnosis more difficult. Herein, we report the case of a 28-year-old woman who presented a solitary plexiform schwannoma of great palatine nerve. In the present case, we focused on immunohistochemical analysis in daily practice for the differential diagnosis of schwannomas and their mainly morphological mimics, especially with plexiform neurofibroma, granular cell tumor and malignant peripheral nerve sheath tumors. We also discussed on SMARBC1/IN1 marker usefulness in combination with brain magnetic resonance imaging for the distinction of solitary schwannoma from neurofibromatosis type 2 or schwannomatosis.

scholarly journals Malignant triton tumor of the left thoracic cavity: a case report

2019 ◽  
Vol 2019 (8) ◽  
Author(s):  
Masashi Ishikawa ◽  
Hiroyuki Chou ◽  
Naoto Imamura ◽  
Yumeta Shimazu ◽  
Kazuo Ono
Keyword(s):  
Tumor Resection ◽  
Neurofibromatosis Type ◽  
Large Mass ◽  
Surgical Removal ◽  
Thoracic Cavity ◽  
Left Hemithorax ◽  
Malignant Triton Tumor ◽  
Nerve Sheath Tumors ◽  
Peripheral Nerve Sheath Tumors ◽  
Failure Investigation

Abstract Malignant triton tumor (MTT) is a rare subtype of malignant peripheral nerve sheath tumors with rhabdomyoblastic differentiation. Although the condition may manifest sporadically, it typically affects adult patients with neurofibromatosis type 1. In this article, an extremely rare case of MTT with chest wall origin, which expanded into the left thoracic cavity, is reported. A 64-year-old male was admitted to the institution with sudden shortness of breath. Radiological examination revealed a large mass with massive pleural effusion occupying the patient’s left hemithorax. A percutaneous needle biopsy was performed and the patient underwent subtotal tumor resection with left pleuropneumonectomy. Immunohistochemical study of postsurgical pathologic specimens confirmed the diagnosis of MTT. Despite extensive surgical removal, tumor recurrence was reported soon after resection, leading to patient’s death 20 days after surgery due to acute respiratory failure. Investigation of rare MTT cases is necessary for understanding this condition.

scholarly journals Oral Metastasis of Metaplastic Breast Carcinoma in a Patient with Neurofibromatosis 1

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Ana Paula Molina Vivas ◽  
Luana Eschholz Bomfin ◽  
Clovis Antonio Lopes Pinto ◽  
Ulisses Ribaldo Nicolau ◽  
Fabio Abreu Alves
Keyword(s):  
Breast Cancer ◽  
Breast Carcinoma ◽  
English Literature ◽  
Neurofibromatosis Type ◽  
Nerve Sheath Tumors ◽  
Peripheral Nerve Sheath Tumors ◽  
Increased Risk ◽  
Multiple Metastases ◽  
Metaplastic Breast Carcinoma ◽  
Oral Metastasis

Neurofibromatosis type 1 (NF1) has been associated with an increased risk for development of malignancy, especially malignant peripheral nerve sheath tumors. In addition, recently, literature has demonstrated an increased risk of breast cancer in women with NF1. The present paper shows a 53-year-old woman with NF1 who presented with metaplastic breast carcinoma and developed multiple metastases, including mandible. Furthermore, we reviewed the English literature, found 63 cases showing the association between NF1 and breast cancer, and added one more case. The present study demonstrated an important association between NF1 and breast cancer. Until the present time, there has been only one case of metaplastic breast carcinoma associated with NF1. Curiously, in our case the oral metastasis corresponded to sarcomatous component of metaplastic breast carcinoma.

scholarly journals New Model Systems and the Development of Targeted Therapies for the Treatment of Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors

Genes ◽  
2020 ◽  
Vol 11 (5) ◽  
pp. 477 ◽  
Author(s):  
Kyle B. Williams ◽  
David A. Largaespada
Keyword(s):  
Schwann Cell ◽  
Peripheral Nerve ◽  
Neurofibromatosis Type 1 ◽  
Single Agent ◽  
Neurofibromatosis Type ◽  
Mek Inhibitors ◽  
Nerve Sheath Tumors ◽  
Peripheral Nerve Sheath Tumors ◽  
Nerve Sheath

Neurofibromatosis Type 1 (NF1) is a common genetic disorder and cancer predisposition syndrome (1:3000 births) caused by mutations in the tumor suppressor gene NF1. NF1 encodes neurofibromin, a negative regulator of the Ras signaling pathway. Individuals with NF1 often develop benign tumors of the peripheral nervous system (neurofibromas), originating from the Schwann cell linage, some of which progress further to malignant peripheral nerve sheath tumors (MPNSTs). Treatment options for neurofibromas and MPNSTs are extremely limited, relying largely on surgical resection and cytotoxic chemotherapy. Identification of novel therapeutic targets in both benign neurofibromas and MPNSTs is critical for improved patient outcomes and quality of life. Recent clinical trials conducted in patients with NF1 for the treatment of symptomatic plexiform neurofibromas using inhibitors of the mitogen-activated protein kinase (MEK) have shown very promising results. However, MEK inhibitors do not work in all patients and have significant side effects. In addition, preliminary evidence suggests single agent use of MEK inhibitors for MPNST treatment will fail. Here, we describe the preclinical efforts that led to the identification of MEK inhibitors as promising therapeutics for the treatment of NF1-related neoplasia and possible reasons they lack single agent efficacy in the treatment of MPNSTs. In addition, we describe work to find targets other than MEK for treatment of MPNST. These have come from studies of RAS biochemistry, in vitro drug screening, forward genetic screens for Schwann cell tumors, and synthetic lethal screens in cells with oncogenic RAS gene mutations. Lastly, we discuss new approaches to exploit drug screening and synthetic lethality with NF1 loss of function mutations in human Schwann cells using CRISPR/Cas9 technology.

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