RESUMO
Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas that arise in connective tissue surrounding peripheral nerves. They occur sporadically in a subset of patients with neurofibromatosis type 1 (NF1). MPNSTs are highly aggressive, therapeutically resistant, and typically fatal. Using comparative transcriptome analysis, we identified CXCR4, a G-protein-coupled receptor, as highly expressed in mouse models of NF1-deficient MPNSTs, but not in nontransformed precursor cells. The chemokine receptor CXCR4 and its ligand, CXCL12, promote MPNST growth by stimulating cyclin D1 expression and cell-cycle progression through PI3-kinase (PI3K) and ß-catenin signaling. Suppression of CXCR4 activity either by shRNA or pharmacological inhibition decreases MPNST cell growth in culture and inhibits tumorigenesis in allografts and in spontaneous genetic mouse models of MPNST. We further demonstrate conservation of these activated molecular pathways in human MPNSTs. Our findings indicate a role for CXCR4 in NF1-associated MPNST development and identify a therapeutic target.
Assuntos
Comunicação Autócrina , Quimiocina CXCL12/metabolismo , Neoplasias de Bainha Neural/metabolismo , Neoplasias de Bainha Neural/patologia , Receptores CXCR4/metabolismo , Ciclo Celular , Proliferação de Células , Transformação Celular Neoplásica , Células Cultivadas , Técnicas de Silenciamento de Genes , Humanos , Neurofibromatose 1/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de SinaisRESUMO
Eighty percent of malignant tumors that develop in the central nervous system are malignant gliomas, which are essentially incurable. Here, we discuss how recent sequencing studies are identifying unexpected drivers of gliomagenesis, including mutations in isocitrate dehydrogenase 1 and the NF-κB pathway, and how genome-wide analyses are reshaping the classification schemes for tumors and enhancing prognostic value of molecular markers. We discuss the controversies surrounding glioma stem cells and explore how the integration of new molecular data allows for the generation of more informative animal models to advance our knowledge of glioma's origin, progression, and treatment.
Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/fisiopatologia , Glioma/genética , Glioma/fisiopatologia , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Modelos Animais de Doenças , Glioma/metabolismo , Glioma/patologia , Humanos , Camundongos , NF-kappa B/metabolismo , Células-Tronco Neoplásicas/patologia , Transdução de SinaisRESUMO
Clear cell renal cell carcinoma (ccRCC) is characterized by inactivation of the von Hippel-Lindau tumour suppressor gene (VHL). Because no other gene is mutated as frequently in ccRCC and VHL mutations are truncal, VHL inactivation is regarded as the governing event. VHL loss activates the HIF-2 transcription factor, and constitutive HIF-2 activity restores tumorigenesis in VHL-reconstituted ccRCC cells. HIF-2 has been implicated in angiogenesis and multiple other processes, but angiogenesis is the main target of drugs such as the tyrosine kinase inhibitor sunitinib. HIF-2 has been regarded as undruggable. Here we use a tumourgraft/patient-derived xenograft platform to evaluate PT2399, a selective HIF-2 antagonist that was identified using a structure-based design approach. PT2399 dissociated HIF-2 (an obligatory heterodimer of HIF-2α-HIF-1ß) in human ccRCC cells and suppressed tumorigenesis in 56% (10 out of 18) of such lines. PT2399 had greater activity than sunitinib, was active in sunitinib-progressing tumours, and was better tolerated. Unexpectedly, some VHL-mutant ccRCCs were resistant to PT2399. Resistance occurred despite HIF-2 dissociation in tumours and evidence of Hif-2 inhibition in the mouse, as determined by suppression of circulating erythropoietin, a HIF-2 target and possible pharmacodynamic marker. We identified a HIF-2-dependent gene signature in sensitive tumours. Gene expression was largely unaffected by PT2399 in resistant tumours, illustrating the specificity of the drug. Sensitive tumours exhibited a distinguishing gene expression signature and generally higher levels of HIF-2α. Prolonged PT2399 treatment led to resistance. We identified binding site and second site suppressor mutations in HIF-2α and HIF-1ß, respectively. Both mutations preserved HIF-2 dimers despite treatment with PT2399. Finally, an extensively pretreated patient whose tumour had given rise to a sensitive tumourgraft showed disease control for more than 11 months when treated with a close analogue of PT2399, PT2385. We validate HIF-2 as a target in ccRCC, show that some ccRCCs are HIF-2 independent, and set the stage for biomarker-driven clinical trials.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/metabolismo , Indanos/farmacologia , Indanos/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/metabolismo , Sulfonas/farmacologia , Sulfonas/uso terapêutico , Animais , Translocador Nuclear Receptor Aril Hidrocarboneto/genética , Translocador Nuclear Receptor Aril Hidrocarboneto/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Sítios de Ligação , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Eritropoetina/antagonistas & inibidores , Eritropoetina/sangue , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Indanos/administração & dosagem , Indóis/farmacologia , Indóis/uso terapêutico , Neoplasias Renais/genética , Neoplasias Renais/patologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Terapia de Alvo Molecular , Mutação , Pirróis/farmacologia , Pirróis/uso terapêutico , Reprodutibilidade dos Testes , Sulfonas/administração & dosagem , Sunitinibe , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Subependymal nodules (SENs) and subependymal giant cell astrocytomas (SEGAs) are common brain lesions found in patients with tuberous sclerosis complex (TSC). These brain lesions present a mixed glioneuronal phenotype and have been hypothesized to originate from neural stem cells. However, this hypothesis has not been tested empirically. Here, we report that loss of Tsc1 in mouse subventricular zone (SVZ) neural stem/progenitor cells (NSPCs) results in formation of SEN- and SEGA-like structural abnormalities in the lateral ventricle, the consequence of abnormal migration of NSPCs following Tsc1 loss.
Assuntos
Ventrículos Laterais/patologia , Mutação/genética , Células-Tronco Neurais/patologia , Proteínas Supressoras de Tumor/genética , Animais , Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Diferenciação Celular , Movimento Celular/genética , Ventrículos Laterais/citologia , Camundongos , Camundongos Knockout , Células-Tronco Neurais/citologia , Esclerose Tuberosa/patologia , Proteína 1 do Complexo Esclerose TuberosaRESUMO
Glioblastoma multiforme is the most common primary malignant brain tumour, with a median survival of about one year. This poor prognosis is due to therapeutic resistance and tumour recurrence after surgical removal. Precisely how recurrence occurs is unknown. Using a genetically engineered mouse model of glioma, here we identify a subset of endogenous tumour cells that are the source of new tumour cells after the drug temozolomide (TMZ) is administered to transiently arrest tumour growth. A nestin-ΔTK-IRES-GFP (Nes-ΔTK-GFP) transgene that labels quiescent subventricular zone adult neural stem cells also labels a subset of endogenous glioma tumour cells. On arrest of tumour cell proliferation with TMZ, pulse-chase experiments demonstrate a tumour re-growth cell hierarchy originating with the Nes-ΔTK-GFP transgene subpopulation. Ablation of the GFP+ cells with chronic ganciclovir administration significantly arrested tumour growth, and combined TMZ and ganciclovir treatment impeded tumour development. Thus, a relatively quiescent subset of endogenous glioma cells, with properties similar to those proposed for cancer stem cells, is responsible for sustaining long-term tumour growth through the production of transient populations of highly proliferative cells.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Dacarbazina/análogos & derivados , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Animais , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Rastreamento de Células , Dacarbazina/farmacologia , Dacarbazina/uso terapêutico , Modelos Animais de Doenças , Progressão da Doença , Feminino , Ganciclovir/farmacologia , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/patologia , Temozolomida , Transgenes/genéticaRESUMO
Why different species are predisposed to different tumor spectra is not well understood. In particular, whether the physical location of tumor suppressor genes relative to one another influences tumor predisposition is unknown. Renal cancer presents a unique opportunity to explore this question. Renal cell carcinoma (RCC) of clear-cell type (ccRCC), the most common type, begins with an intragenic mutation in the von Hippel-Lindau (VHL) gene and loss of 3p (where VHL is located). Chromosome 3p harbors several additional tumor suppressor genes, including BRCA1-associated protein-1 (BAP1). In the mouse, Vhl is on a different chromosome than Bap1. Thus, whereas loss of 3p in humans simultaneously deletes one copy of BAP1, loss of heterozygosity in the corresponding Vhl region in the mouse would not affect Bap1. To test the role of BAP1 in ccRCC development, we generated mice deficient for either Vhl or Vhl together with one allele of Bap1 in nephron progenitor cells. Six2-Cre;Vhl(F/F);Bap1(F/+) mice developed ccRCC, but Six2-Cre;Vhl(F/F) mice did not. Kidneys from Six2-Cre;Vhl(F/F);Bap1(F/+) mice resembled kidneys from humans with VHL syndrome, containing multiple lesions spanning from benign cysts to cystic and solid RCC. Although the tumors were small, they showed nuclear atypia and exhibited features of human ccRCC. These results provide an explanation for why VHL heterozygous humans, but not mice, develop ccRCC. They also explain why a mouse model of ccRCC has been lacking. More broadly, our data suggest that differences in tumor predisposition across species may be explained, at least in part, by differences in the location of two-hit tumor suppressor genes across the genome.
Assuntos
Carcinoma de Células Renais/genética , Modelos Animais de Doenças , Genes Supressores de Tumor , Falência Renal Crônica/genética , Neoplasias Renais/genética , Proteínas Supressoras de Tumor/fisiologia , Ubiquitina Tiolesterase/fisiologia , Proteína Supressora de Tumor Von Hippel-Lindau/fisiologia , Idade de Início , Alelos , Animais , Linhagem da Célula , Mapeamento Cromossômico , Feminino , Genes Reporter , Genes Sintéticos , Predisposição Genética para Doença , Humanos , Doenças Renais Císticas/genética , Doenças Renais Císticas/patologia , Falência Renal Crônica/sangue , Falência Renal Crônica/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Modelos Genéticos , Células-Tronco Multipotentes/metabolismo , Células-Tronco Multipotentes/patologia , Mutação , Fenótipo , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia , Especificidade da Espécie , Proteínas Supressoras de Tumor/antagonistas & inibidores , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/antagonistas & inibidores , Ubiquitina Tiolesterase/genética , Proteína Supressora de Tumor Von Hippel-Lindau/antagonistas & inibidores , Proteína Supressora de Tumor Von Hippel-Lindau/genéticaRESUMO
Neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), are associated with the physiology of the striatum and the loss of its normal functioning under pathological conditions. The role of BDNF and its downstream signaling in regulating the development of the striatum has not been fully investigated, however. Here we report that ablation of Bdnf in both the cortex and substantia nigra depletes BDNF in the striatum, and leads to impaired striatal development, severe motor deficits, and postnatal lethality. Furthermore, striatal-specific ablation of TrkB, the gene encoding the high-affinity receptor for BDNF, is sufficient to elicit an array of striatal developmental abnormalities, including decreased anatomical volume, smaller neuronal nucleus size, loss of dendritic spines, reduced enkephalin expression, diminished nigral dopaminergic projections, and severe deficits in striatal dopamine signaling through DARPP32. In addition, TrkB ablation in striatal neurons elicits a non-cell-autonomous reduction of tyrosine hydroxylase protein level in the axonal projections of substantia nigral dopaminergic neurons. Thus, our results establish an essential function for TrkB in regulating the development of striatal neurons.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Corpo Estriado/metabolismo , Regulação da Expressão Gênica , Neurônios/metabolismo , Receptor trkB/metabolismo , Transdução de Sinais , Animais , Axônios/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Biológicos , Substância Negra/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Neurofibromatosis type 1 (NF1) is caused by mutations in the NF1 gene that encodes neurofibromin, a RAS GTPase-activating protein. Inactivating NF1 mutations cause hyperactivation of RAS-mediated signaling, resulting in the development of multiple neoplasms, including malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are an aggressive tumor and the main cause of mortality in patients with NF1. MPNSTs are difficult to resect and refractory to chemo- and radiotherapy, and no molecular therapies currently exist. Immune checkpoint blockade (ICB) is an approach to treat inoperable, undruggable cancers like MPNST, but successful outcomes require an immune cell-rich tumor microenvironment. While MPNSTs are noninflamed "cold" tumors, here, we converted MPNSTs into T cell-inflamed "hot" tumors by activating stimulator of IFN genes (STING) signaling. Mouse genetic and human xenograft MPNST models treated with a STING agonist plus ICB exhibited growth delay via increased apoptotic cell death. This strategy offers a potential treatment regimen for MPNSTs.
Assuntos
Imunoterapia , Proteínas de Membrana , Neurofibromatose 1 , Neurofibromina 1 , Microambiente Tumoral , Animais , Microambiente Tumoral/imunologia , Humanos , Camundongos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas de Membrana/imunologia , Neurofibromatose 1/genética , Neurofibromatose 1/patologia , Neurofibromatose 1/imunologia , Neurofibromatose 1/terapia , Neurofibromatose 1/metabolismo , Neurofibromina 1/genética , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias de Bainha Neural/genética , Neoplasias de Bainha Neural/patologia , Neoplasias de Bainha Neural/terapia , Neoplasias de Bainha Neural/imunologia , Neoplasias de Bainha Neural/metabolismo , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Transdução de Sinais/imunologiaRESUMO
Neurogenesis persists in the rodent dentate gyrus (DG) throughout adulthood but declines with age and stress. Neural progenitor cells (NPCs) residing in the subgranular zone of the DG are regulated by an array of growth factors and respond to the microenvironment, adjusting their proliferation level to determine the rate of neurogenesis. Here we report that genetic deletion of neurofibromin (Nf1), a tumor suppressor with RAS-GAP activity, in adult NPCs enhanced DG proliferation and increased generation of new neurons in mice. Nf1 loss-associated neurogenesis had the functional effect of enhancing behavioral responses to subchronic antidepressants and, over time, led to spontaneous antidepressive-like behaviors. Thus, our findings establish an important role for the Nf1-Ras pathway in regulating adult hippocampal neurogenesis, and demonstrate that activation of adult NPCs is sufficient to modulate depression- and anxiety-like behaviors.
Assuntos
Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Hipocampo/fisiologia , Neurofibromina 1/fisiologia , Neurogênese/fisiologia , Neurônios/fisiologia , Fatores Etários , Animais , Antidepressivos/uso terapêutico , Ansiedade/tratamento farmacológico , Ansiedade/patologia , Células Cultivadas , Depressão/patologia , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurogênese/efeitos dos fármacos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Regulação para Cima/genéticaRESUMO
Adult neurogenesis persists throughout life in restricted brain regions in mammals and is affected by various physiological and pathological conditions. The tumor suppressor gene Pten is involved in adult neurogenesis and is mutated in a subset of autism patients with macrocephaly; however, the link between the role of PTEN in adult neurogenesis and the etiology of autism has not been studied before. Moreover, the role of hippocampus, one of the brain regions where adult neurogenesis occurs, in development of autism is not clear. Here, we show that ablating Pten in adult neural stem cells in the subgranular zone of hippocampal dentate gyrus results in higher proliferation rate and accelerated differentiation of the stem/progenitor cells, leading to depletion of the neural stem cell pool and increased differentiation toward the astrocytic lineage at later stages. Pten-deleted stem/progenitor cells develop into hypertrophied neurons with abnormal polarity. Additionally, Pten mutant mice have macrocephaly and exhibit impairment in social interactions and seizure activity. Our data reveal a novel function for PTEN in adult hippocampal neurogenesis and indicate a role in the pathogenesis of abnormal social behaviors.
Assuntos
Células-Tronco Adultas/fisiologia , Giro Denteado/citologia , Regulação da Expressão Gênica/genética , Neurogênese/genética , Neurônios/fisiologia , PTEN Fosfo-Hidrolase/deficiência , Adaptação Ocular/genética , Células-Tronco Adultas/efeitos dos fármacos , Fatores Etários , Animais , Bromodesoxiuridina/metabolismo , Diferenciação Celular/genética , Movimento Celular/genética , Células Cultivadas , Relação Dose-Resposta a Droga , Eletroencefalografia , Eletromiografia , Comportamento Exploratório/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Proteínas de Filamentos Intermediários/genética , Relações Interpessoais , Ventrículos Laterais/citologia , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Memória/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação/genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Nestina , Neurogênese/efeitos dos fármacos , Neurônios/citologia , Propanolaminas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
Cutaneous neurofibromas (cNFs) are tumors that develop in more than 99% of individuals with neurofibromatosis type 1 (NF1). They develop in the dermis and can number in the thousands. cNFs can be itchy and painful and negatively impact self-esteem. There is no US Food and Drug Administration (FDA)-approved drug for their treatment. Here, we screen a library of FDA-approved drugs using a cNF cell model derived from human induced pluripotent stem cells (hiPSCs) generated from an NF1 patient. We engineer an NF1 mutation in the second allele to mimic loss of heterozygosity, differentiate the NF1+/- and NF1-/- hiPSCs into Schwann cell precursors (SCPs), and use them to screen a drug library to assess for inhibition of NF1-/- but not NF1+/- cell proliferation. We identify econazole nitrate as being effective against NF1-/- hiPSC-SCPs. Econazole cream selectively induces apoptosis in Nf1-/- murine nerve root neurosphere cells and human cNF xenografts. This study supports further testing of econazole for cNF treatment.
Assuntos
Células-Tronco Pluripotentes Induzidas , Neurofibroma , Neurofibromatose 1 , Neoplasias Cutâneas , Estados Unidos , Humanos , Animais , Camundongos , Neurofibromatose 1/tratamento farmacológico , Neurofibromatose 1/genética , Neurofibromatose 1/metabolismo , Econazol , Células-Tronco Pluripotentes Induzidas/metabolismo , Neurofibroma/genética , Neurofibroma/metabolismo , Neurofibroma/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Apoptose/genéticaRESUMO
Neurofibromatosis type 1 (NF1) is one of the most common tumor-predisposing genetic disorders. Neurofibromas are NF1-associated benign tumors. A hallmark feature of neurofibromas is an abundant collagen-rich extracellular matrix (ECM) that constitutes more than 50% of the tumor dry weight. However, little is known about the mechanism underlying ECM deposition during neurofibroma development and treatment response. We performed a systematic investigation of ECM enrichment during plexiform neurofibroma (pNF) development and identified basement membrane (BM) proteins, rather than major collagen isoforms, as the most upregulated ECM component. Following MEK inhibitor treatment, the ECM profile displayed an overall downregulation signature, suggesting ECM reduction as a therapeutic benefit of MEK inhibition. Through these proteomic studies, TGF-ß1 signaling was identified as playing a role in ECM dynamics. Indeed, TGF-ß1 overexpression promoted pNF progression in vivo. Furthermore, by integrating single-cell RNA sequencing, we found that immune cells including macrophages and T cells produce TGF-ß1 to induce Schwann cells to produce and deposit BM proteins for ECM remodeling. Following Nf1 loss, neoplastic Schwann cells further increased BM protein deposition in response to TGF-ß1. Our data delineate the regulation governing ECM dynamics in pNF and suggest that BM proteins could serve as biomarkers for disease diagnosis and treatment response.
Assuntos
Neurofibroma , Neurofibromatose 1 , Humanos , Neurofibromatose 1/tratamento farmacológico , Neurofibromatose 1/genética , Neurofibromatose 1/complicações , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Proteínas de Membrana/metabolismo , Proteômica , Neurofibroma/tratamento farmacológico , Neurofibroma/genética , Inibidores de Proteínas Quinases , Colágeno/metabolismo , Membrana Basal/metabolismo , Membrana Basal/patologia , Matriz Extracelular/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno , Células de Schwann/patologiaRESUMO
Neurofibromatosis type 1 is one of the most common genetic disorders of the nervous system and predisposes patients to develop benign and malignant tumors. Cutaneous neurofibromas (cNFs) are NF1-associated benign tumors that affect nearly 100% of patients with NF1. cNFs dramatically reduce patients' QOL owing to their unaesthetic appearance, physical discomfort, and corresponding psychological burden. There is currently no effective drug therapy option, and treatment is restricted to surgical removal. One of the greatest hurdles for cNF management is the variability of clinical expressivity in NF1, resulting in intrapatient and interpatient cNF tumor burden heterogeneity, that is, the variability in the presentation and evolution of these tumors. There is growing evidence that a wide array of factors are involved in the regulation of cNF heterogeneity. Understanding the mechanisms underlying this heterogeneity of cNF at the molecular, cellular, and environmental levels can facilitate the development of innovative and personalized treatment regimens.
Assuntos
Neurofibroma , Neurofibromatose 1 , Neoplasias Cutâneas , Humanos , Neurofibromatose 1/genética , Neurofibromatose 1/terapia , Qualidade de Vida , Carga Tumoral , Neurofibroma/genética , Neoplasias Cutâneas/genéticaRESUMO
Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disease and one of the most common inherited tumor predisposition syndromes, affecting 1 in 3000 individuals worldwide. The NF1 gene encodes neurofibromin, a large protein with RAS GTP-ase activating (RAS-GAP) activity, and loss of NF1 results in increased RAS signaling. Neurofibromin contains many other domains, and there is considerable evidence that these domains play a role in some manifestations of NF1. Investigating the role of these domains as well as the various signaling pathways that neurofibromin regulates and interacts with will provide a better understanding of how neurofibromin acts to suppress tumor development and potentially open new therapeutic avenues. In this review, we discuss what is known about the structure of neurofibromin, its interactions with other proteins and signaling pathways, its role in development and differentiation, and its function as a tumor suppressor. Finally, we discuss the latest research on potential therapeutics for neurofibromin-deficient neoplasms.
Assuntos
Neurofibromina 1RESUMO
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, invasive cancer that comprise around 10% of all soft tissue sarcomas and develop in about 8-13% of patients with Neurofibromatosis Type 1. They are associated with poor prognosis and are the leading cause of mortality in NF1 patients. MPNSTs can also develop sporadically or following exposure to radiation. There is currently no effective targeted therapy to treat MPNSTs and surgical removal remains the mainstay treatment. Unfortunately, surgery is not always possible due to the size and location of the tumor, thus, a better understanding of MPNST initiation and development is required to design novel therapeutics. Here, we provide an overview of MPNST biology and genetics, discuss findings regarding the developmental origin of MPNST, and summarize the various model systems employed to study MPNST. Finally, we discuss current management strategies for MPNST, as well as recent developments in translating basic research findings into potential therapies.
Assuntos
Neoplasias de Bainha Neural , Neurofibromatose 1 , Neurofibrossarcoma , Sarcoma , Biologia , Humanos , Neoplasias de Bainha Neural/genética , Neoplasias de Bainha Neural/terapia , Neurofibromatose 1/complicações , Neurofibromatose 1/genética , Neurofibromatose 1/terapia , Neurofibrossarcoma/complicações , Neurofibrossarcoma/genética , Neurofibrossarcoma/terapiaRESUMO
Active surveillance (AS) may be used in the management of metastatic renal cell carcinoma (mRCC), but consensus regarding its application is lacking. We report an exploratory analysis of prospectively collected specimens prespecified in the only modern clinical trial evaluating AS in mRCC. Whole-exome and RNA sequencing were performed for patients providing consent to identify putative biomarkers associated with time on AS (TAS), the primary endpoint. Log-rank tests and multivariable Cox proportional-hazards models were used for analyses. Patients with mutations in either TP53 or SMARCA4 tumor suppressor genes had shorter TAS (7.5 vs 14.2 mo; log-rank p = 0.004). While these patients exhibited features of aggressive disease clinically, the two-gene model was independently predictive in multivariable analyses (hazard ratio 3.30, 95% confidence interval 1.07-10.18; p = 0.038). In conclusion, insight into the underlying RCC biology improves patient selection for AS. If validated, this two-gene model could help in stratifying patients with mRCC and identifying those who are poor candidates for AS. PATIENT SUMMARY: In this study, we analyzed tumors from patients with metastatic kidney cancer enrolled in a clinical trial of imaging surveillance. We found that tumors with mutations in either the TP53 or SMARCA4 gene progressed faster than tumors without these mutations. Thus, patients harboring mutations in these genes may not be good candidates for AS.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/terapia , DNA Helicases/genética , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Biologia Molecular , Proteínas Nucleares/genética , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Transcrição/genética , Conduta ExpectanteRESUMO
Neurofibromatosis Type 1 (NF1) is one of the most common inherited neurological disorders and predisposes patients to develop benign and malignant tumors. Neurofibromas are NF1-associated benign tumors but can cause substantial discomfort and disfigurement. Numerous studies have shown that neurofibromas arise from the Schwann cell lineage but both preclinical mouse models and clinical trials have demonstrated that the neurofibroma tumor microenvironment contributes significantly to tumorigenesis. This offers the opportunity for targeting new therapeutic vulnerabilities to treat neurofibromas. However, a translational gap exists between deciphering the contribution of the neurofibroma tumor microenvironment and clinically applying this knowledge to treat neurofibromas. Here, we discuss the key cellular and molecular components in the neurofibroma tumor microenvironment that can potentially be targeted therapeutically to advance neurofibroma treatment.
Assuntos
Neurofibromatose 1 , Animais , Carcinogênese , Transformação Celular Neoplásica , Genótipo , Camundongos , Neurofibroma , Células de Schwann , Microambiente TumoralRESUMO
Neurofibromatosis type 1 (NF1) is one of the most common neurocutaneous genetic disorders, presenting with different cutaneous features such as café-au-lait macules, intertriginous skin freckling, and neurofibromas. Although most of the disease manifestations are benign, patients are at risk for a variety of malignancies, including malignant transformation of plexiform neurofibromas. Numerous studies have investigated the mechanisms by which these characteristic neurofibromas develop, with progress made toward unraveling the various players involved in their complex pathogenesis. In this review, we summarize the current understanding of the cells that give rise to NF1 neoplasms as well as the molecular mechanisms and cellular changes that confer tumorigenic potential. We also discuss the role of the tumor microenvironment and the key aspects of its various cell types that contribute to NF1-associated tumorigenesis. An increased understanding of these intrinsic and extrinsic components is critical for developing novel therapeutic approaches for affected patients.
RESUMO
Dry eye disease affects over 16 million adults in the US, and the majority of cases are due to Meibomian gland dysfunction. Unfortunately, the identity of the stem cells involved in Meibomian gland development and homeostasis is not well elucidated. Here, we report that loss of Krox20, a zinc finger transcription factor involved in the development of ectoderm-derived tissues, or deletion of KROX20-expressing epithelial cells disrupted Meibomian gland formation and homeostasis, leading to dry eye disease secondary to Meibomian gland dysfunction. Ablation of Krox20-lineage cells in adult mice also resulted in dry eye disease, implicating Krox20 in homeostasis of the mature Meibomian gland. Lineage-tracing and expression analyses revealed a restricted KROX20 expression pattern in the ductal areas of the Meibomian gland, although Krox20-lineage cells generate the full, mature Meibomian gland. This suggests that KROX20 marks a stem/progenitor cell population that differentiates to generate the entire Meibomian gland. Our Krox20 mouse models provide a powerful system that delineated the identity of stem cells required for Meibomian gland development and homeostasis and can be used to investigate the factors underlying these processes. They are also robust models of Meibomian gland dysfunction-related dry eye disease, with a potential for use in preclinical therapeutic screening.
Assuntos
Síndromes do Olho Seco/fisiopatologia , Células Epiteliais/metabolismo , Disfunção da Glândula Tarsal/fisiopatologia , Células-Tronco/metabolismo , Animais , Homeostase , CamundongosRESUMO
PURPOSE: Intratumoral heterogeneity (ITH) challenges the molecular characterization of clear cell renal cell carcinoma (ccRCC) and is a confounding factor for therapy selection. Most approaches to evaluate ITH are limited by two-dimensional ex vivo tissue analyses. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can noninvasively assess the spatial landscape of entire tumors in their natural milieu. To assess the potential of DCE-MRI, we developed a vertically integrated radiogenomics colocalization approach for multi-region tissue acquisition and analyses. We investigated the potential of spatial imaging features to predict molecular subtypes using histopathologic and transcriptome correlatives. EXPERIMENTAL DESIGN: We report the results of a prospective study of 49 patients with ccRCC who underwent DCE-MRI prior to nephrectomy. Surgical specimens were sectioned to match the MRI acquisition plane. RNA sequencing data from multi-region tumor sampling (80 samples) were correlated with percent enhancement on DCE-MRI in spatially colocalized regions of the tumor. Independently, we evaluated clinical applicability of our findings in 19 patients with metastatic RCC (39 metastases) treated with first-line antiangiogenic drugs or checkpoint inhibitors. RESULTS: DCE-MRI identified tumor features associated with angiogenesis and inflammation, which differed within and across tumors, and likely contribute to the efficacy of antiangiogenic drugs and immunotherapies. Our vertically integrated analyses show that angiogenesis and inflammation frequently coexist and spatially anti-correlate in the same tumor. Furthermore, MRI contrast enhancement identifies phenotypes with better response to antiangiogenic therapy among patients with metastatic RCC. CONCLUSIONS: These findings have important implications for decision models based on biopsy samples and highlight the potential of more comprehensive imaging-based approaches.