RESUMO
Cancer immunotherapy has transformed treatment possibilities, but its effectiveness differs significantly among patients, indicating the presence of alternative pathways for immune evasion. Here, we show that ITPRIPL1 functions as an inhibitory ligand of CD3ε, and its expression inhibits T cells in the tumor microenvironment. The binding of ITPRIPL1 extracellular domain to CD3ε on T cells significantly decreased calcium influx and ZAP70 phosphorylation, impeding initial T cell activation. Treatment with a neutralizing antibody against ITPRIPL1 restrained tumor growth and promoted T cell infiltration in mouse models across various solid tumor types. The antibody targeting canine ITPRIPL1 exhibited notable therapeutic efficacy against naturally occurring tumors in pet clinics. These findings highlight the role of ITPRIPL1 (or CD3L1, CD3ε ligand 1) in impeding T cell activation during the critical "signal one" phase. This discovery positions ITPRIPL1 as a promising therapeutic target against multiple tumor types.
Assuntos
Complexo CD3 , Ativação Linfocitária , Linfócitos T , Evasão Tumoral , Microambiente Tumoral , Animais , Complexo CD3/metabolismo , Complexo CD3/imunologia , Humanos , Camundongos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Microambiente Tumoral/imunologia , Cães , Neoplasias/imunologia , Linhagem Celular Tumoral , Feminino , Ligação Proteica , Proteína-Tirosina Quinase ZAP-70/metabolismo , Anticorpos Neutralizantes/imunologia , Camundongos Endogâmicos C57BLRESUMO
Malignant peripheral nerve sheath tumors (MPNSTs) originate from the neural crest lineage and are associated with the neurofibromatosis type I syndrome. MPNST is an unmet clinical need. In this review article, we summarize the knowledge and discuss research perspectives related to (1) the natural history of MPNST development; (2) the mouse models recapitulating the progression from precursor lesions to MPNST; (3) the role of the tumor microenvironment in MPNST development, and (4) the signaling pathways linked to MPNST development.
Assuntos
Neoplasias de Bainha Neural/metabolismo , Microambiente Tumoral , Animais , Humanos , Neoplasias de Bainha Neural/genética , Neoplasias de Bainha Neural/patologia , Transdução de SinaisRESUMO
Neurofibromatosis type 1 (NF1) is a hereditary tumour syndrome that predisposes to benign and malignant tumours originating from neural crest cells. Biallelic inactivation of the tumour-suppressor gene NF1 in glial cells in the skin, along a nerve plexus or in the brain results in the development of benign tumours: cutaneous neurofibroma, plexiform neurofibroma and glioma, respectively. Despite more than 40 years of research, only one medication was recently approved for treatment of plexiform neurofibroma and no drugs have been specifically approved for the management of other tumours. Work carried out over the past several years indicates that inhibiting different cellular signalling pathways (such as Hippo, Janus kinase/signal transducer and activator of transcription, mitogen-activated protein kinase and those mediated by sex hormones) in tumour cells or targeting cells in the microenvironment (nerve cells, macrophages, mast cells and T cells) might benefit NF1 patients. In this review, we outline previous strategies aimed at targeting these signalling pathways or cells in the microenvironment, agents that are currently in clinical trials, and the latest advances in basic research that could culminate in the development of novel therapeutics for patients with NF1.
Assuntos
Terapia de Alvo Molecular , Neurofibromatose 1/genética , Neurofibromina 1/genética , Microambiente Tumoral/genética , Genes Supressores de Tumor , Humanos , Mutação/genética , Neurofibroma Plexiforme/tratamento farmacológico , Neurofibroma Plexiforme/genética , Neurofibromatose 1/patologia , Transdução de Sinais/genética , Pesquisa Translacional BiomédicaRESUMO
Somatic cells of an organism virtually share the same DNA but it is the timely expression of specific genes that determine their phenotype and cellular identity. A series of complex molecular machinery allows for the regulated process of RNA transcription, splicing, and translation. In addition, microRNAs and specialized RNA binding proteins can trigger the degradation of mRNAs. Long non-coding RNAs can also regulate mRNA fate in multiple ways. In this chapter, we reviewed the RNA processing mechanisms directly regulating immune checkpoint genes. We also cover RNA-based therapeutic strategies aiming at restoring immunity by targeting immune checkpoint genes.
Assuntos
Regulação da Expressão Gênica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Animais , Pontos de Checagem do Ciclo Celular/genética , Pontos de Checagem do Ciclo Celular/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Splicing de RNA , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro/uso terapêutico , Proteínas de Ligação a RNA/metabolismoRESUMO
Pre-mRNA alternative splicing is modified in cancer, but the origin and specificity of these changes remain unclear. Here, we probed ovarian tumors to identify cancer-associated splicing isoforms and define the mechanism by which splicing is modified in cancer cells. Using high-throughput quantitative PCR, we monitored the expression of splice variants in laser-dissected tissues from ovarian tumors. Surprisingly, changes in alternative splicing were not limited to the tumor tissues but were also found in the tumor microenvironment. Changes in the tumor-associated splicing events were found to be regulated by splicing factors that are differentially expressed in cancer tissues. Overall, â¼20% of the alternative splicing events affected by the down-regulation of the splicing factors QKI and RBFOX2 were altered in the microenvironment of ovarian tumors. Together, our results indicate that the tumor microenvironment undergoes specific changes in alternative splicing orchestrated by a limited number of splicing factors.
Assuntos
Processamento Alternativo , Neoplasias Ovarianas/metabolismo , RNA Mensageiro/genética , Linhagem Celular Tumoral , Células Epiteliais/metabolismo , Feminino , Expressão Gênica , Humanos , Microdissecção e Captura a Laser , Especificidade de Órgãos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Sítios de Splice de RNA , Fatores de Processamento de RNA , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/fisiologia , Proteínas Repressoras/fisiologia , Células Estromais/metabolismo , Microambiente TumoralRESUMO
Ectopic modulators of alternative splicing are important tools to study the function of splice variants and for correcting mis-splicing events that cause human diseases. Such modulators can be bifunctional oligonucleotides made of an antisense portion that determines target specificity, and a non-hybridizing tail that recruits proteins or RNA/protein complexes that affect splice site selection (TOSS and TOES, respectively, for targeted oligonucleotide silencer of splicing and targeted oligonucleotide enhancer of splicing). The use of TOSS and TOES has been restricted to a handful of targets. To generalize the applicability and demonstrate the robustness of TOSS, we have tested this approach on more than 50 alternative splicing events. Moreover, we have developed an algorithm that can design active TOSS with a success rate of 80%. To produce bifunctional oligonucleotides capable of stimulating splicing, we built on the observation that binding sites for TDP-43 can stimulate splicing and improve U1 snRNP binding when inserted downstream from 5' splice sites. A TOES designed to recruit TDP-43 improved exon 7 inclusion in SMN2. Overall, our study shows that bifunctional oligonucleotides can redirect splicing on a variety of genes, justifying their inclusion in the molecular arsenal that aims to alter the production of splice variants.
Assuntos
Processamento Alternativo , Oligonucleotídeos/química , Algoritmos , Linhagem Celular , Proteínas de Ligação a DNA/metabolismo , Éxons , Células HeLa , Humanos , Oligonucleotídeos Antissenso/química , Sítios de Splice de RNA , Ribonucleoproteína Nuclear Pequena U1/metabolismoRESUMO
Neurofibromatosis Type I (NF1) is a rare genetic disorder. NF1 patients frequently develop a benign tumor in peripheral nerve plexuses called plexiform neurofibroma. In the past two decades, tissue-specific Nf1 knockout mouse models were developed using commercially available tissue-specific Cre recombinase and the Nf1 flox mice to mimic neurofibroma development. However, these models develop para-spinal neurofibroma, recapitulating a rare type of neurofibroma found in NF1 patients. The NPcis mouse model developed a malignant version of neurofibroma called malignant peripheral nerve sheath tumor (MPNST) within 3 to 6 months but intriguingly without apparent benign precursor lesion. Here, we revisited the NPcis model and discovered that about 20% display clinical signs similar to Nf1 tissue-specific knockout mice models. However, a systematic histological analysis could not explain the clinical signs we observed although we noticed lesions reminiscent of a neurofibroma in a peripheral nerve, a cutaneous neurofibroma, and para-spinal neurofibroma on rare occasions in NPcis mice. We also observed that 10% of the mice developed a malignant peripheral nerve sheath tumor (MPNST) spontaneously, coinciding with their earring tag identification. Strikingly, half of the sciatic nerves from NPcis mice developed plexiform neurofibroma within 1-6 months when intentionally injured. Thus, we provided a procedure to turn the widely used NPcis sarcoma model into a model recapitulating plexiform neurofibroma.
Assuntos
Modelos Animais de Doenças , Neurofibroma Plexiforme , Animais , Neurofibroma Plexiforme/patologia , Camundongos , Nervo Isquiático/patologia , Camundongos Knockout , Neurofibromatose 1/patologia , Neurofibromatose 1/genética , Neurofibromina 1/genéticaRESUMO
Animal models represent the workhorse of the neuroscience field. Despite this, today, there is still no step-by-step protocol to dissect a complete rodent nervous system, nor is there a complete schematic representing it that is freely available. Only methods to harvest the brain, the spinal cord, a specific dorsal root ganglion, and the sciatic nerve (separately) are available. Here, we provide detailed pictures and a schematic of the central and peripheral murine nervous system. More importantly, we outline a robust procedure to perform its dissection. The 30 min pre-dissection step allows isolating the intact nervous system within the vertebra with muscles free of viscera and skin. A 2-4 h dissection follows it under a micro-dissection microscope to expose the spinal cord and the thoracic nerves, and finally peel the whole central and peripheral nervous system off the carcass. This protocol represents a significant step forward in studying the anatomy and pathophysiology of the nervous system globally. For example, the dissected dorsal root ganglions from a neurofibromatosis type I mice model can be further processed for histology to unravel changes in tumor progression.
Assuntos
Sistema Nervoso Periférico , Medula Espinal , Camundongos , Animais , Gânglios Espinais/cirurgia , Gânglios Espinais/patologia , Nervo Isquiático/cirurgia , EncéfaloRESUMO
Most human messenger RNAs (mRNAs) are alternatively spliced and many exhibit disease-specific splicing patterns. However, the contribution of most splicing events to the development and maintenance of human diseases remains unclear. As the contribution of alternative splicing events to diagnosis and prognosis is becoming increasingly recognized, it becomes important to develop precise methods to quantify the abundance of these isoforms in clinical samples. Here we present a pipeline for real-time PCR annotation of splicing events (RASE) that allows accurate identification of a large number of splicing isoforms in human tissues. The RASE automatically designed specific primer pairs for 81% of all alternative splicing events in the NCBI build 36 database. Experimentally, the majority of the RASE designed primers resulted in isoform-specific amplification suitable for quantification in human cell lines or in formalin-fixed, paraffin-embedded (FFPE) RNA extract. Using this pipeline it is now possible to rapidly identify splicing isoform signatures in different types of human tissues or to validate complete sets of data generated by microarray expression profiling and deep sequencing techniques.
Assuntos
Processamento Alternativo , Reação em Cadeia da Polimerase/métodos , RNA Mensageiro/análise , RNA Mensageiro/genética , Sequência de Bases , Primers do DNA/genética , Humanos , Sítios de Splice de RNARESUMO
Neurofibromatosis Type I (NF1) is a neurocutaneous genetic syndrome characterized by a wide spectrum of clinical presentations, including benign peripheral nerve sheath tumor called neurofibroma. These tumors originate from the Schwann cell lineage but other cell types as well as extracellular matrix (ECM) in the neurofibroma microenvironment constitute the majority of the tumor mass. In fact, collagen accounts for up to 50% of the neurofibroma's dry weight. Although the presence of collagens in neurofibroma is indisputable, the exact repertoire of ECM genes and ECM-associated genes (i.e. the matrisome) and their functions are unknown. Here, transcriptome profiling by single-cell RNA sequencing reveals the matrisome of human cutaneous neurofibroma (cNF). We discovered that classic pro-fibrogenic collagen I myofibroblasts are rare in neurofibroma. In contrast, collagen VI, a pro-tumorigenic ECM, is abundant and mainly secreted by neurofibroma fibroblasts. This study also identified potential cell type-specific markers to further elucidate the biology of the cNF microenvironment.
Assuntos
Fibroblastos Associados a Câncer/metabolismo , Matriz Extracelular/genética , Neurofibroma/genética , Neoplasias Cutâneas/genética , Células Apresentadoras de Antígenos/metabolismo , Colágeno Tipo VI/genética , Colágeno Tipo VI/metabolismo , Células Endoteliais/metabolismo , Matriz Extracelular/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Humanos , Neurofibroma/metabolismo , Pericitos/metabolismo , RNA-Seq , Análise de Célula Única , Neoplasias Cutâneas/metabolismo , Transcriptoma , Microambiente Tumoral/genéticaRESUMO
Programmed cell death protein 1 (PD-1) is a crucial anticancer target, but the relatively low response rate and acquired resistance to existing antibody drugs highlight an urgent need to develop alternative targeting strategies. Here, we report the palmitoylation of PD-1, discover the main DHHC enzyme for this modification, reveal the mechanism of its effect on PD-1 protein stability, and rationally develop a peptide for targeting PD-1 expression. Palmitoylation promoted the trafficking of PD-1 to the recycling endosome, thus preventing its lysosome-dependent degradation. Palmitoylation of PD-1, but not of PD-L1, promoted mTOR signaling and tumor cell proliferation, and targeting palmitoylation displayed significant anti-tumor effects in a three-dimensional culture system. A peptide was designed to competitively inhibit PD-1 palmitoylation and expression, opening a new route for developing PD-1 inhibitors and combinatorial cancer immunotherapy.
RESUMO
Cancer immunotherapy using immune-checkpoint blockade has displayed promising clinical effects, but prevalent antibody-based inhibitors face multiple challenges such as low response rate, acquired resistance, and adverse effects. The intracellular expression of PD-1/PD-L1 in recycling endosomes and their active trafficking to membrane highlight the importance of depleting rather than interfering with checkpoint proteins. Preclinical investigations on the therapeutic effects of lead compounds that function by degrading immune checkpoint ligands and receptors have reported highly promising results. By harnessing the degradation capabilities of the lysosome, proteasome and autophagosomes, different small molecules and peptides potently induced degradation of checkpoint proteins and enhanced anti-tumor immunity. Both in vitro and in vivo experiments support the therapeutic efficacy of these molecules. Thus, targeted degradation through endo-lysosomal, autophagic, proteasomal, or endoplasmic reticulum-related pathways may provide promising strategies for tackling the challenges in cancer immunotherapy.
Assuntos
Proteínas de Checkpoint Imunológico/metabolismo , Imunoterapia/métodos , Terapia de Alvo Molecular/métodos , Neoplasias/imunologia , Neoplasias/terapia , Proteólise/efeitos dos fármacos , Animais , Humanos , Neoplasias/metabolismoRESUMO
Schwannomas are tumors of the Schwann cells that cause chronic pain, numbness, and potentially life-threatening impairment of vital organs. Despite the identification of causative genes, including NF2 (Merlin), INI1/SMARCB1, and LZTR1, the exact molecular mechanism of schwannoma development is still poorly understood. Several studies have identified Merlin as a key regulator of the Hippo, MAPK, and PI3K signaling pathways; however, definitive evidence demonstrating the importance of these pathways in schwannoma pathogenesis is absent. Here, we provide direct genetic evidence that dysregulation of the Hippo pathway in the Schwann cell lineage causes development of multiple schwannomas in mice. We found that canonical Hippo signaling through the effectors YAP/TAZ is required for schwannomagenesis and that MAPK signaling modifies schwannoma formation. Furthermore, cotargeting YAP/TAZ transcriptional activity and MAPK signaling demonstrated a synergistic therapeutic effect on schwannomas. Our new model provides a tractable platform to dissect the molecular mechanisms underpinning schwannoma formation and the role of combinatorial targeted therapy in schwannoma treatment.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Perda de Heterozigosidade/genética , Neurilemoma/genética , Neurofibromina 2/genética , Animais , Regulação Neoplásica da Expressão Gênica/genética , Fator de Crescimento de Hepatócito/genética , Humanos , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Neurilemoma/patologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Proteína SMARCB1/genética , Transdução de Sinais/genética , Fatores de Transcrição/genética , Proteínas de Sinalização YAP , Proteínas ras/genéticaRESUMO
Hereditary cancer syndromes are typically caused by mutations of a tumor suppressor gene that lead to the early development of multifocal benign neoplasms followed by their malignant progression. However, the term 'hereditary cancer syndrome' may be misleading, as a large subgroup of syndromes are characterized by highly penetrant benign tumors. The reason why these cardinal tumors rarely progress to malignancy has been an elusive question in cancer biology. In this opinion article, we propose a framework where a heterozygous tumor suppressor gene microenvironment has antagonistic roles in tumorigenesis, by accelerating development of benign tumors while restraining further progression to malignant cancers.
Assuntos
Carcinogênese/genética , Genes Supressores de Tumor , Síndromes Neoplásicas Hereditárias/genética , Microambiente Tumoral/genética , Carcinogênese/patologia , Progressão da Doença , Humanos , Mutação , Síndromes Neoplásicas Hereditárias/patologiaRESUMO
In the version of this Article originally published, 'palmitoyltransferase ZDHHC3 (DHHC3)' was incorrectly referred to as an 'acetyltransferase' rather than an as an 'acyltransferase'; this has now been corrected in five instances. In Fig. 3a, the label for the bottom row of the blots was mistakenly written as 'GAPHD'; it should have read 'GAPDH'. In the two right-most panels of Fig. 4j, the antibody labels 'α-PD-L1' for the reciprocal co-immunoprecipitation of DHHC3 were incorrect; they should have been 'α-DHHC3'. These errors have been corrected in all versions of the Article.
RESUMO
Checkpoint blockade therapy targeting the programmed-death ligand 1 (PD-L1) and its receptor programmed cell death 1 promotes T-cell-mediated immunosurveillance against tumours, and has been associated with marked clinical benefit in cancer patients. Antibodies against PD-L1 function by blocking PD-L1 on the cell surface, but intracellular storage of PD-L1 and its active redistribution to the cell membrane can minimize the therapeutic benefits, which highlights the importance of targeting PD-L1 throughout the whole cell. Here, we show that PD-L1 is palmitoylated in its cytoplasmic domain, and that this lipid modification stabilizes PD-L1 by blocking its ubiquitination, consequently suppressing PD-L1 degradation by lysosomes. We identified palmitoyltransferase ZDHHC3 (DHHC3) as the main acetyltransferase required for the palmitoylation of PD-L1, and show that the inhibition of PD-L1 palmitoylation via 2-bromopalmitate, or the silencing of DHHC3, activates antitumour immunity in vitro and in mice bearing MC38 tumour cells. We also designed a competitive inhibitor of PD-L1 palmitoylation that decreases PD-L1 expression in tumour cells to enhance T-cell immunity against the tumours. These findings suggest new strategies for overcoming PD-L1-mediated immune evasion in cancer.
Assuntos
Antígeno B7-H1/metabolismo , Lipoilação , Neoplasias/imunologia , Linfócitos T/imunologia , Aciltransferases/metabolismo , Animais , Linhagem Celular Tumoral , Humanos , Lisossomos/metabolismo , Camundongos , Peptídeos/metabolismo , UbiquitinaçãoRESUMO
Neurofibromatosis type 1 (NF1) is a cancer predisposition disorder that results from inactivation of the tumor suppressor neurofibromin, a negative regulator of RAS signaling. Patients with NF1 present with a wide range of clinical manifestations, and the tumor with highest prevalence is cutaneous neurofibroma (cNF). Most patients harboring cNF suffer greatly from the burden of those tumors, which have no effective medical treatment. Ironically, none of the numerous NF1 mouse models developed so far recapitulate cNF. Here, we discovered that HOXB7 serves as a lineage marker to trace the developmental origin of cNF neoplastic cells. Ablating Nf1 in the HOXB7 lineage faithfully recapitulates both human cutaneous and plexiform neurofibroma. In addition, we discovered that modulation of the Hippo pathway acts as a "modifier" for neurofibroma tumorigenesis. This mouse model opens the doors for deciphering the evolution of cNF to identify effective therapies, where none exist today. SIGNIFICANCE: This study provides insights into the developmental origin of cNF, the most common tumor in NF1, and generates the first mouse model that faithfully recapitulates both human cutaneous and plexiform neurofibroma. The study also demonstrates that the Hippo pathway can modify neurofibromagenesis, suggesting that dampening the Hippo pathway could be an attractive therapeutic target.This article is highlighted in the In This Issue feature, p. 1.
Assuntos
Neurofibroma/metabolismo , Neurofibromatose 1/metabolismo , Neurofibromina 1/genética , Proteínas Serina-Treonina Quinases/metabolismo , Células de Schwann/metabolismo , Transdução de Sinais , Neoplasias Cutâneas/metabolismo , Animais , Linhagem da Célula , Modelos Animais de Doenças , Feminino , Via de Sinalização Hippo , Masculino , Camundongos , Camundongos Knockout , Mutação , Neurofibroma/etiologia , Neurofibroma/genética , Neurofibroma/fisiopatologia , Neurofibroma Plexiforme/etiologia , Neurofibroma Plexiforme/genética , Neurofibroma Plexiforme/metabolismo , Neurofibroma Plexiforme/fisiopatologia , Neurofibromatose 1/complicações , Neurofibromatose 1/genética , Neurofibromatose 1/fisiopatologia , Células de Schwann/fisiologia , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/fisiopatologiaRESUMO
OBJECTIVE: A group of experts in dermatology, genetics, neuroscience, and regenerative medicine collaborated to summarize current knowledge on the defined factors contributing to cutaneous neurofibroma (cNF) development and to provide consensus recommendations for future research priorities to gain an improved understanding of the biology of cNF. METHODS: The group members reviewed published and unpublished data on cNF and related diseases via literature search, defined a set of key topic areas deemed critical in cNF pathogenesis, and developed recommendations in a series of consensus meetings. RESULTS: Five specific topic areas were identified as being relevant to providing an enhanced understanding of the biology of cNF: (1) defining the human cells of origin; (2) understanding the role of the microenvironment, focusing on neurons, mast cells, and fibroblasts; (3) defining the genetic and molecular differences between the cNFs, focusing on size and number; (4) understanding if sex hormones are critical for cNF development or progression; and (5) identifying challenges in establishing in vitro and in vivo models representing human cNF. CONCLUSIONS: The complexity of cNF biology stems from its heterogeneity at multiple levels including genetic, spatial involvement, temporal development, and cellular composition. We propose a unified working model for cNF that builds a framework to address the key questions about cNF that, when answered, will provide the necessary understanding of cNF biology to allow meaningful development of therapies.
Assuntos
Neurofibroma/fisiopatologia , Neurofibromatose 1/fisiopatologia , Neoplasias Cutâneas/fisiopatologia , Animais , Conferências de Consenso como Assunto , Humanos , Neurofibroma/complicações , Neurofibroma/genética , Neurofibromatose 1/complicações , Neurologia , Pesquisa , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/genética , Microambiente TumoralRESUMO
Neurofibromatosis type 1 (NF1) is an autosomal genetic disorder. Patients with NF1 are associated with mono-allelic loss of the tumor suppressor gene NF1 in their germline, which predisposes them to develop a wide array of benign lesions. Intriguingly, recent sequencing efforts revealed that the NF1 gene is frequently mutated in multiple malignant tumors not typically associated with NF1 patients, suggesting that NF1 heterozygosity is refractory to at least some cancer types. In two orthogonal mouse models representing NF1- and non-NF1-related tumors, we discover that an Nf1+/- microenvironment accelerates the formation of benign tumors but impairs further progression to malignancy. Analysis of benign and malignant tumors commonly associated with NF1 patients, as well as those with high NF1 gene mutation frequency, reveals an antagonistic role for NF1 heterozygosity in tumor initiation and malignant transformation and helps to reconciliate the role of the NF1 gene in both NF1 and non-NF1 patient contexts.
Assuntos
Carcinogênese/genética , Carcinogênese/patologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Neurofibromina 1/genética , Animais , Proliferação de Células , Modelos Animais de Doenças , Progressão da Doença , Heterozigoto , Humanos , Queratinócitos/metabolismo , Queratinócitos/patologia , Camundongos Endogâmicos C57BL , Neurofibroma/patologia , Neurofibromina 1/metabolismo , Fenótipo , Neoplasias Cutâneas/patologia , Linfócitos T/metabolismo , Microambiente TumoralRESUMO
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. In the present study, we use new, genetically engineered Scf mice to decipher the contributions of tumor-derived SCF and mast cells to neurofibroma development. 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. Furthermore, we show that plexiform neurofibromas are highly associated with injury-prone spinal nerves that are close to flexible vertebras. In summary, 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.