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Pathology of human peripheral nerve sheath tumors. A, neurofibroma composed of spindled and round cells and collagen bundles in a loose, myxoid background. B, Schwannoma with prominent, characteristic formation of Verocay bodies (arrows). C, cellular schwannoma, displaying moderate cellularity and nuclear pleomorphism and the absence of Verocay bodies. D, ultrastructural features of a schwannoma showing a Verocay body composed of intertwining of cytoplasmic processes surrounded by basal lamina. E, whorl formation and fascicles of spindle-shaped cells in a soft tissue perineurioma. F, diagnostic ultrastructural features of a perineurial cell include elongated cytoplasmic processes, a basal lamina (long arrow), and prominent pinocytotic vescicles (short arrow). G, malignant peripheral nerve sheath tumor composed of atypical spindle-shaped cells arranged in fascicles. H, large cells with abundant eosinophilic cytoplasm (arrow) represent skeletal muscle differentiation in a malignant peripheral nerve sheath tumor.
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Despite the progress made in our understanding of the biology of neurofibromatosis (NF), the long-term clinical outcome for affected patients has not changed significantly in the past decades, and both NF1 and NF2 are still associated with a significant morbidity and a decreased life span. A number of NF1 and NF2 murine models have been generated t...
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Neurofibromatosis (NF) is one of the most common genetic disorders. Inherited in an autosomal dominant fashion, this phacomatosis is classified into two genetically distinct subtypes characterized by multiple cutaneous lesions and tumors of the peripheral and central nervous system. Neurofibromatosis type 1 (NF1), also referred to as Recklinghausen...
Part 1 of this guideline addressed the differential diagnosis of the neurofibromatoses (NF): neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis (SCH). NF shares some features such as the genetic origin of the neural tumors and cutaneous manifestations, and affects nearly 80 thousand Brazilians. Increasing scientific...
Introduction. Neurofibromatosis (NF) is a generalized form of benign tumors of the peripheral nerves involving the skin, subcutaneous tissue, and bone. It comprises neurofibromatosis type 1 (NF-1), neurofibromatosis type 2 (NF-2), and schwannomatosis. Objective. To document the clinical and epidemiological features of patients with NF presenting at...
Neurofibromatosis type 1 (NF1) and type 2 both occur in mosaic (segmental) forms.1 When NF1 (and other autosomal dominant skin disorders)1,2 occurs in a linear, patchy, quadrant, or otherwise localised form, two different types of mosaicism can be distinguished.2 Type 1 segmental involvement reflects heterozygosity for a postzygotic mutation occurr...
Citations
... Vestibular schwannoma (VS) is a benign Schwann cell tumor that originates from the vestibulocochlear nerve [118]. In recent years, sporadic and neurofibromatosisrelated VS have been found to significantly overexpress CXCR4. ...
C-X-C motif chemokine receptor 4 (CXCR4) plays a key role in various physiological functions, such as immune processes and disease development, and can influence angiogenesis, proliferation, and distant metastasis in tumors. Recently, several radioligands, including peptides, small molecules, and nanoclusters, have been developed to target CXCR4 for diagnostic purposes, thereby providing new diagnostic strategies based on CXCR4. Herein, we focus on the recent research progress of CXCR4-targeting radioligands for tumor diagnosis. We discuss their application in the diagnosis of hematological tumors, such as lymphomas, multiple myelomas, chronic lymphocytic leukemias, and myeloproliferative tumors, as well as nonhematological tumors, including tumors of the esophagus, breast, and central nervous system. Additionally, we explored the theranostic applications of CXCR4-targeting radioligands in tumors. Targeting CXCR4 using nuclear medicine shows promise as a method for tumor diagnosis, and further research is warranted to enhance its clinical applicability.
... We performed histopathologic analysis of these tumors according to criteria established for mouse models of PNST 22 and criteria used for human nerve sheath tumors. 23 All five dermal tumors analyzed exhibited features typical of GEM-MPNST, comprising spindle cells forming interlacing fascicles and storiform formations with high cellularity and occasional pleomorphism and nuclear atypia ( Figure 1D, E). ...
Background
Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas. Somatic inactivation of NF1 and cooperating tumor suppressors, including CDKN2A/B , PRC2, and p53, is found in most MPNST. Inactivation of the LATS1/2 kinases of the Hippo pathway was recently shown to cause tumors resembling MPNST histologically, although Hippo pathway mutations are rarely found in MPNST. Because existing genetically engineered mouse (GEM) models of MPNST do not recapitulate some of the key genetic features of human MPNST, we aimed to establish a mouse MPNST model that recapitulated the human disease genetically, histologically, and molecularly.
Methods
We combined two genetically modified alleles, an Nf1 ; Trp53 cis -conditional allele and an inducible Plp-CreER allele (NP-Plp), to model the somatic, possibly postnatal, mutational events in human MPNST. We also generated conditional Lats1 ; Lats2 knockout mice. We performed histopathologic analysis of mouse MPNST models and transcriptomic comparison of mouse models and human nerve sheath tumors.
Results
Postnatal Nf1;Trp53 cis -deletion resulted in GEM-MPNST that was histologically more similar to human MPNST than the widely used germline Nf1;Trp53 cis -heterozygous (NPcis) model and showed partial loss of H3K27me3. At the transcriptome level, Nf1;p53- driven GEM-MPNST were distinct from Lats -driven GEM-MPNST and resembled human MPNST more closely than do Lats- driven tumors.
Conclusions
The NP-Plp model recapitulates human MPNST genetically, histologically, and molecularly.
Key Points
Postnatal Nf1;p53 cis -deletion in NP-Plp mice results in tumors similar to MPNST.
The transcriptomes of Nf1;p53- driven and Lats -driven MPNST models are distinct.
NP-Plp model resembles human MPNST genetically, histologically, and molecularly.
Importance of the Study
Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas with a poor prognosis and limited treatment options. Existing genetically engineered mouse (GEM) models of MPNST do not recapitulate some of the key genetic features of human MPNST. To model the somatic, possibly postnatal, mutational events seen in MPNST patients, we generated a GEM-MPNST model by combining two genetically modified alleles, an Nf1 ; Trp53 cis -conditional allele and a Plp-CreER allele. Our histologic and transcriptomic analyses showed that this NP-Plp model resembles human MPNST genetically, histologically, and molecularly—more so than the widely used NPcis model and the recently published Lats -driven model. The NP-Plp model is genetically simple, making it easy to maintain and an ideal platform for preclinical studies. Given its tamoxifen-inducible nature, this model can be used to study the time/stage dependency of the tumorigenic potential of Schwann cells.
... Vestibular schwannomas (VS) are benign nerve sheath tumors of the vestibular nerve that arise from neoplastic Schwann cells (1,2). These tumors usually appear sporadically, but in rare cases (1:33,000) they are part of a genetic disorder, called neurofibromatosis type 2. NF2 is associated with the loss of the NF2 gene on chromosome 22, which encodes for merlin, a tumor suppressor protein (3,4). ...
A disintegrin and metalloproteinase 9 (ADAM9) is a member of the transmembrane ADAM family. It is expressed in different types of solid cancer and promotes tumor invasiveness. To the best of our knowledge, the present study was the first to examine ADAM9 expression in vestibular schwannomas (VS) from patients with and without neurofibromatosis type 2 (NF2) and to associate the data with clinical parameters of the patients. The aim of the present study was to evaluate if ADAM9 could be used as prognostic marker or therapeutic target. ADAM9 mRNA and protein levels were measured in VS samples (n=60). A total of 30 of them were from patients with neurofibromatosis. Healthy peripheral nerves from autopsies (n=10) served as controls. ADAM9 mRNA levels were measured by PCR, and protein levels were determined by immunohistochemistry (IHC) and western blotting (WB). The Hannover Classification was used to categorize tumor extension and hearing loss. ADAM9 mRNA levels were 8.8-fold higher in VS compared with in controls. The levels were 5.6-fold higher in patients with NF2 and 12-fold higher in patients with sporadic VS. WB revealed two mature isoforms of the protein, and according to IHC ADAM9 was mainly expressed by S100-positive Schwann cells. There was a strong correlation between ADAM9 mRNA expression and the level of functional impairment (r~1, p=0.01). Particularly, the secreted isoform of ADAM9 was expressed in patients with higher hearing impairment. ADAM9 mRNA was overexpressed in the tumor samples relative to healthy vestibular nerves, and there was an association between higher ADAM9 expression levels and greater hearing impairment. Therefore, ADAM9 may be a prognostic marker for VS, and ADAM9 inhibition might have the potential as a systemic approach for the treatment of VS.
... To study JHU395 in MPNST in vivo, a flank tumor model was utilized with cells harvested from tumor originating in the NPcis mouse (29). Cells injected subcutaneously to B6 mice developed into tumors that had characteristics of high-grade human peripheral nerve sheath tumors (38), including high cellularity and marked nuclear pleomorphism (Fig. 3A). Tumors also exhibited many Ki67 positive cells, and tumor cells were positive for phospho-ERK (Fig. 3A). ...
The carbon and nitrogen components of glutamine are used for multiple biosynthetic processes by tumors. Glutamine metabolism and the therapeutic potential of glutamine antagonists (GA), however, are incompletely understood in malignant peripheral nerve sheath tumor (MPNST), an aggressive soft tissue sarcoma observed in patients with neurofibromatosis type I. We investigated glutamine dependence of MPNST using JHU395, a novel orally-bioavailable GA prodrug designed to circulate inert in plasma, but permeate and release active GA within target tissues. Human MPNST cells, compared to Schwann cells derived from healthy peripheral nerve, were selectively susceptible to both glutamine deprivation and GA dose-dependent growth inhibition. In vivo, orally administered JHU395 delivered active GA to tumors with over two-fold higher tumor-to-plasma exposure, and significantly inhibited tumor growth in a murine flank MPNST model without observed toxicity. Global metabolomics studies and stable isotope labeled flux analyses in tumors identified multiple glutamine dependent metabolites affected, including prominent effects on purine synthesis. These data demonstrate that glutamine antagonism is a potential antitumor strategy for MPNST.
... Vestibular schwannomas (VS) are benign nerve sheath tumors that arise from Schwann cells of the vestibulocochlear nerve (1,2). VS regularly cause hypoacusis, dizziness, and tinnitus. ...
We have recently demonstrated CXCR4 overexpression in vestibular schwannomas (VS). This study investigated the feasibility of CXCR4-directed positron emission tomography/computed tomography (PET/CT) imaging of VS using the radiolabeled chemokine ligand [⁶⁸Ga]Pentixafor.
Methods: 4 patients with 6 primarily diagnosed or pre-treated/observed VS were enrolled. All subjects underwent [⁶⁸Ga]Pentixafor PET/CT prior to surgical resection. Images were analyzed visually and semi-quantitatively for CXCR4 expression including calculation of tumor-to-background ratios (TBR). Immunohistochemistry served as standard of reference in three patients.
Results: [⁶⁸Ga]Pentixafor PET/CT was visually positive in all cases. SUVmean and SUVmax were 3.0 ± 0.3 and 3.8 ± 0.4 and TBRmean and TBRmax were 4.0 ± 1.4 and 5.0 ± 1.7, respectively. Histological analysis confirmed CXCR4 expression in tumors.
Conclusion: Non-invasive imaging of CXCR4 expression using [⁶⁸Ga]Pentixafor PET/CT of VS is feasible and could prove useful for in vivo assessment of CXCR4 expression.
... The results of each pathology committee group were published in refereed journals. 29,30,31,32,33,34,35,36,37,38 These publications report the comparative pathology for organ-specific carcinogenesis for the purpose of developing mouse models of cancer. ...
The need for international collaboration in rodent pathology has evolved since the 1970s and was initially driven by the new field of toxicologic pathology. First initiated by the World Health Organization's International Agency for Research on Cancer for rodents, it has evolved to include pathology of the major species (rats, mice, guinea pigs, nonhuman primates, pigs, dogs, fish, rabbits) used in medical research, safety assessment, and mouse pathology. The collaborative effort today is driven by the needs of the regulatory agencies in multiple countries, and by needs of research involving genetically engineered animals, for "basic" research and for more translational preclinical models of human disease. These efforts led to the establishment of an international rodent pathology nomenclature program. Since that time, multiple collaborations for standardization of laboratory animal pathology nomenclature and diagnostic criteria have been developed, and just a few are described herein. Recently, approaches to a nomenclature that is amenable to sophisticated computation have been made available and implemented for large-scale programs in functional genomics and aging. Most terminologies continue to evolve as the science of human and veterinary pathology continues to develop, but standardization and successful implementation remain critical for scientific communication now as ever in the history of veterinary nosology.
... Deux modèles ont été utilisés dans ce travail. Tout d'abord in vitro le modèle choisi a été la lignée 08031-9 établie à partir d'un schwannome spontané d'une souris P0-SCH-∆(39-121).30,31 Ce choix a été orienté vers la possibilité d'utiliser dans le future le modèle murin P0-SCH-∆(39-121) finement caractérisé et dont la sensibilité à l'inhibition de mTOR a été démontrée.31 ...
Contexte : Le schwannome vestibulaire (SV) est une tumeur bénigne de la gaine du nerf vestibulaire. La plupart des SV présentent une inactivation somatique bi-allèlique du gène suppresseur de tumeur NF2. L’inactivation congénitale du gène NF2 est impliquée dans le développement de la Neurofibromatose de type 2, une maladie génétique autosomique dominante prédisposant au développement de tumeurs multiples du système nerveux central et en particulier de schwannomes vestibulaires bilatéraux. Le traitement des schwannomes vestibulaires repose sur la chirurgie ou la radiothérapie délivrée en conditions stéréotaxiques. La réduction de la dose d’irradiation des schwannomes vestibulaires a permis d’améliorer le pronostic fonctionnel auditif tout en garantissant un taux de réponse satisfaisant. Pourtant de nombreux patients présenteront une surdité neurosensorielle progressive. Afin de poursuivre cette réduction de dose d’irradiation, des modèles biologiques fidèles récapitulant le statut d’inactivation du gène NF2 et la surdité neurosensorielle sont nécessaires à l’élaboration d’une approche préclinique.Problématique : Nous avons proposé de développer des systèmes modèles in-vitro et in-vivo compatibles avec l’étude de la radiosensibilité des schwannomes vestibulaires en combinaison avec des thérapies ciblant les voies de signalisation spécifiquement activées par la perte de fonction NF2.Méthodes : Les lignées cellulaires humaines de schwannomes vestibulaires NF2 (HEI_193, HEI_182), et de cellules de Schwann vestibulaire contrôle (HEI_286) ont été cultivées en essai clonogénique afin de déterminer le nombre d’unité formatrices de colonies à doses croissantes d’inhibiteur mTOR (Rapamycine), PI3K (GDC_0941), mTOR et PI3K (BEZ_235) pour déterminer le 50% d’inhibition de croissance (GI50%) puis en combinaison à doses croissantes de radiation gamma (Co60). La lignée cellulaire murine inactivée pour nf2 (SC4#9) a été utilisée pour réaliser des greffes syngéniques orthotopiques. La croissance des tumeurs a été suivie par IRM et bioluminescence et l’audition déterminée par potentiels évoqués auditifs. L’analyse histologique des cochlées a été réalisée par coloration en hématoxyline et éosine puis par fluorescence après clarification cochléaire. Des volumes complets ont été obtenus par microscopie confocale à balayage laser.Résultats : Les essais clonogéniques réalisés en Agarose ont identifié une radiorésistance relative des lignées humaines de schwannomes mutées pour NF2 par comparaison au contrôle humain non muté. Cette résistance identifiée en réponse à l’exposition à une dose unique d’irradiation gamma peut être contournée par l’inhibition de la voie mTOR au moment de l’irradiation restituant une sensibilité comparable au contrôle humain non muté. Une tendance à un bénéfice de l’association d’une inhibition mTOR à un inhibiteur PI3 kinase a été retrouvée à une dose maximum d’irradiation. Un modèle murin de schwannome vestibulaire qui récapitule la croissance dans l’angle ponto-cérébelleux et la perte d’audition a été développé par injection stéréotaxique dans le paquet acoustico faciale. Le suivi de croissance de ce schwannome a été caractérisé par IRM et bio-luminescence in-vivo. Enfin un protocole de clarification cochléaire a été adapté aux mammifères murins pour permettre l’étude histologique de cochlées intactes compatible avec l’étude de l’otoxicité des schwannomes et/ou de leur traitement .Conclusion : Les modèles décrits dans cette thèse permettent l’évaluation pré-clinique de stratégies thérapeutiques combinant thérapie ciblée et irradiation gamma en dose unique. L’amélioration des connaissances des mécanismes participant à l’ototoxicité des schwannomes et de leur traitement permettra d’améliorer le ciblage moléculaire afin de réduire les effets auditifs secondaires de la radiochirurgie.
... Slow SC proliferation is later maintained in cNFs, as immunolabelling of cNFs from 10-month-old Nf1-KO mutants against the mitotic marker phospho-histone-H3 (PHH3) indicates that a small proportion of traced cells undergo mitosis (Fig. S3K). This is in line with clinical observations demonstrating rare mitoses in human NFs (12). Overall, our data suggests that inactivation of Nf1 provides a small proliferative advantage to neonatal mutant SCs. ...
Patients carrying an inactive NF1 allele develop tumors of Schwann cell origin called neurofibromas (NF). Genetically engineered mouse models have significantly enriched our understanding of plexiform forms of NFs (pNF). However, this has not been the case for cutaneous neurofibromas (cNF), observed in all NF1 patients, as no previous model recapitulates their development. Here, we show that conditional Nf1 inactivation in Prss56-positive boundary cap cells leads to bona fide pNFs and cNFs. This work identifies subepidermal glia as a likely candidate for the cellular origin of cNFs and provides insights on disease mechanisms, revealing a long, multistep pathologic process in which inflammation-related signals play a pivotal role. This new mouse model is an important asset for future clinical and therapeutic investigations of NF1-associated neurofibromas.
Significance
Patients affected by NF1 develop numerous cNFs. We present a mouse model that faithfully recapitulates cNFs, identify a candidate cell type at their origin, analyze the steps involved in their formation, and show that their development is dramatically accelerated by skin injury. These findings have important clinical/therapeutic implications.
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... Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive nerve-associated sarcomas with strong metastatic proclivity and resistance to radiation and chemotherapy (Farid et al., 2014;Stemmer-Rachamimov et al., 2004) that account for the leading cause of death in adult neurofibromatosis type 1 (NF1) patients. MPNSTs either occur independently or in ...
... Pathological classification revealed that whereas tumors were all PNST, those in the dermis were largely low-grade (grade I PNST) (Figure 2A), but did not precisely resemble benign human neurofibroma or schwannoma due to their highly cellular and invasive features. Tumors from paraspinal regions, including nerve roots or dorsal root ganglia, and peripheral nerves were classified as aggressive, rapidly growing high-grade (grade III) genetically engineered mouse (GEM)-PNSTs ( Figures 2B-2E, S2A, and S2B), resembling MPNSTs in humans (Stemmer-Rachamimov et al., 2004). The high-grade PNSTs consisted of densely packed cells with high cellularity entrapping muscle fibers, indicating strong invasiveness of tumor cells (Figures 2B and 2E). ...
Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann cell (SC)-lineage-derived sarcomas. Molecular events driving SC-to-MPNST transformation are incompletely understood. Here, we show that human MPNSTs exhibit elevated HIPPO-TAZ/YAP expression, and that TAZ/YAP hyperactivity in SCs caused by Lats1/2 loss potently induces high-grade nerve-associated tumors with full penetrance. Lats1/2 deficiency reprograms SCs to a cancerous, progenitor-like phenotype and promotes hyperproliferation. Conversely, disruption of TAZ/YAP activity alleviates tumor burden in Lats1/2-deficient mice and inhibits human MPNST cell proliferation. Moreover, genome-wide profiling reveals that TAZ/YAP-TEAD1 directly activates oncogenic programs, including platelet-derived growth factor receptor (PDGFR) signaling. Co-targeting TAZ/YAP and PDGFR pathways inhibits tumor growth. Thus, our findings establish a previously unrecognized convergence between Lats1/2-TAZ/YAP signaling and MPNST pathogenesis, revealing potential therapeutic targets in these untreatable tumors.
... Vestibular schwannomas are benign nerve sheath tumors of the vestibulocochlear nerve that are composed entirely of neoplastic Schwann cells [1,2]. These tumors may arise sporadically, but they are also associated with a rare (1:33,000) genetic disorder, neurofibromatosis type 2 (NF2). ...
Background
CXCR4 is a chemokine receptor that recruits blood stem cells and increases tumor cell growth and invasiveness. We examined CXCR4 expression in vestibular schwannomas (VS) from patients with and without neurofibromatosis type 2 (NF2) and correlated the levels with the patients’ clinical characteristics. The aim was to determine whether CXCR4 can be used as a prognostic marker and as a target for systemic therapy.
Results
Overall, CXCR4 mRNA levels were 4.6-fold higher in VS versus control; the levels were 4.9-fold higher in NF2 patients and 4.2-fold higher in sporadic VS patients. IHC and WB showed heterogeneous protein expression, and CXCR4 was expressed mainly in S100-positive Schwann cells. There was no correlation between the CXCR4 protein levels and tumor extension. However, there was a trend towards correlation between higher expression levels and greater hearing loss.
Materials and Methods
CXCR4 mRNA and protein levels were determined in VS samples (n = 60); of these, 30 samples were from patients with NF2. Healthy nerves from autopsies served as controls. CXCR4 mRNA levels were measured by PCR, and protein levels were measured by immunohistochemistry (IHC) and Western blotting (WB). Tumor extension and hearing loss were categorized according to the Hannover Classification as clinical parameters.
Conclusions
CXCR4 mRNA was overexpressed in VS relative to healthy vestibular nerves, and there was a trend towards higher CXCR4 expression levels being correlated with greater functional impairment. Thus, CXCR4 may be a prognostic marker of VS, and CXCR4 inhibition has potential as a systemic approach for the treatment of VS.
