RESUMEN
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, with proto-oncogene, receptor tyrosine kinase (c-kit), or PDGFRα mutations detected in around 85% of cases. GISTs without c-kit or platelet-derived growth factor receptor alpha (PDGFRα) mutations are considered wild-type (WT), and their diverse molecular alterations and biological behaviors remain uncertain. They are usually not sensitive to tyrosine kinase inhibitors (TKIs). Recently, some molecular alterations, including neurotrophic tyrosine receptor kinase (NTRK) fusions, have been reported in very few cases of WT GISTs. This novel finding opens the window for the use of tropomyosin receptor kinase (TRK) inhibitor therapy in these subtypes of GIST. Herein, we report a new case of NTRK-fused WT high-risk GIST in a female patient with a large pelvic mass (large dimension of 20 cm). The tumor was removed, and the histopathology displayed spindle-predominant morphology with focal epithelioid areas, myxoid stromal tissue, and notable lymphoid infiltration with tertiary lymphoid structures. Ten mitoses were quantified in 50 high-power fields without nuclear pleomorphism. DOG1 showed strong and diffuse positivity, and CD117 showed moderate positivity. Succinate dehydrogenase subunit B (SDHB) was retained, Pan-TRK was focal positive (nuclear pattern), and the proliferation index Ki-67 was 7%. Next-generation sequencing (NGS) detected an ETV6::NTRK3 fusion, and this finding was confirmed by fluorescence in situ hybridization (FISH), which showed NTRK3 rearrangement. In addition, an RB1 mutation was found by NGS. The follow-up CT scan revealed peritoneal nodules suggestive of peritoneal dissemination, and Entrectinib (a TRK inhibitor) was administered. After 3 months of follow-up, a new CT scan showed a complete response. Based on our results and the cases from the literature, GISTs with NTRK fusions are very uncommon so far; hence, further screening studies, including more WT GIST cases, may increase the possibility of finding additional cases. The present case may offer new insights into the potential introduction of TRK inhibitors as treatments for GISTs with NTRK fusions. Additionally, the presence of abundant lymphoid infiltration in the present case may prompt further research into immunotherapy as a possible additional therapeutic option.
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Tumores del Estroma Gastrointestinal , Estructuras Linfoides Terciarias , Femenino , Humanos , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/genética , Hibridación Fluorescente in Situ , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Inmunoterapia , Proteínas Proto-Oncogénicas c-kit , Proteínas Tirosina Quinasas ReceptorasRESUMEN
Synovial sarcoma (SS) is a rare soft-tissue tumor characterized by a monomorphic blue spindle cell histology and variable epithelial differentiation. Morphologically, SSs may be confused with other sarcomas. Systemic treatment is more effective for patients with high-risk SSs, patients with advanced disease, and younger patients. However, further studies are required to find new prognostic biomarkers. Herein, we describe the morphological, molecular, and clinical findings, using a wide immunohistochemical panel, of a series of SS cases. We studied 52 cases confirmed as SSs by morphological diagnosis and/or molecular studies. Clinical data (gender, age, tumor size, tumor location, resection margins, adjuvant treatment, recurrences, metastasis, and survival) were also retrieved for each patient. All the available H&E slides were examined by four pathologists. Three tissue microarrays (TMAs) were constructed for each of the tumors, and a wide immunohistochemical panel was performed. For time-to-event variables, survival analysis was performed using Kaplan-Meier curves and log-rank testing, or Cox regression. Statistical significance was considered at p < 0.05. The mean age of our patients was 40.33, and the median was 40.5 years. We found a predominance of males versus females (1.7:1). The most frequent morphological subtype was monophasic. TRPS1, SS18-SSX, and SSX-C-terminus were positive in 96% of cases. GLI1 expression was strong in six and focal (cytoplasmic) in twenty patients. Moreover, BCOR was expressed in more than half of SSs. Positive expression of both proteins, BCOR and GLI1, was correlated with a worse prognosis. Multivariate analysis was also performed, but only BCOR expression appeared to be significant. The combination of GLI1 and BCOR antibodies can be used to group SSs into three risk groups (low, intermediate, and high risk). We hypothesize that these findings could identify which patients would benefit from receiving adjuvant treatment and which would not. Moreover, these markers could represent therapeutic targets in advanced stages. However, further, larger series of SSs and molecular studies are necessary to corroborate our present findings.
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Biomarcadores de Tumor , Inmunohistoquímica , Proteínas Proto-Oncogénicas , Proteínas Represoras , Sarcoma Sinovial , Proteína con Dedos de Zinc GLI1 , Humanos , Sarcoma Sinovial/metabolismo , Sarcoma Sinovial/patología , Sarcoma Sinovial/genética , Masculino , Femenino , Proteínas Represoras/metabolismo , Proteínas Represoras/genética , Adulto , Persona de Mediana Edad , Pronóstico , Biomarcadores de Tumor/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteína con Dedos de Zinc GLI1/metabolismo , Proteína con Dedos de Zinc GLI1/genética , Anciano , Adulto Joven , Adolescente , Estimación de Kaplan-MeierRESUMEN
BACKGROUND: Ovarian clear cell carcinomas (OCCCs) are rare, aggressive and chemoresistant tumors. Geographical and ethnic differences in the incidence of OCCC have been reported with a higher incidence in Asiatic countries. There is a paucity of information regarding OCCC in Latin America (LA) and other countries. METHODS: Here, we characterized two cohorts of 33 patients with OCCC from LA (24 from Brazil and 9 from Costa Rica) and a cohort of 27 patients from Spain. Genomic analysis was performed for 26 OCCC using the OncoScan platform. Tumors were classified according to their genomic landscapes into subgroups. Clinical parameters were related to the frequency of genomic aberrations. RESULTS: The median overall survival (OS) was not significantly different between the cohorts. Genomic landscapes were characterized by different homologous recombination deficiency (HRD) levels. No difference in the distribution of genomic landscapes profiles was detected between patients from the different cohorts. OCCCs with MYC-amplified tumors harboring a concomitant loss of a region in chromosome 13q12-q13 that includes the BRCA2 gene had the longest OS. In contrast, patients carrying a high number (> 30) of total copy number (CN) aberrations with no concomitant alterations in MYC and BRCA2 genes presented the shortest OS. Furthermore, amplification of the ASH1L gene was also associated with a shorter OS. Initial-stage OCCCs with early progression were characterized by gains in the JNK1 and MKL1 genes. CONCLUSIONS: Our results provide new data from understudied OCCC populations and reveal new potential markers for OCCCs.
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Adenocarcinoma de Células Claras , Carcinoma , Neoplasias Ováricas , Femenino , Humanos , Neoplasias Ováricas/patología , Genómica , Brasil , Adenocarcinoma de Células Claras/patologíaRESUMEN
Merkel cell carcinoma (MCC) is an infrequent, aggressive cutaneous neoplasm, that typically affects the photodamaged skin of elderly individuals, and immunosuppressed patients. Because a subset of MCC is closely related to UV radiation, MCC can develop concurrently with other tumors, most commonly, as a combined tumor with squamous cell carcinoma (SCC). These combined tumors appear to represent a distinct disease process from pure MCC, as they are mostly Merkel cell polyomavirus (MCPyV) negative, and show a more aggressive behavior. We present two additional cases of combined MCC and SCC with nodal metastases, one of which was MCPyV positive. Two different subtypes of MCC have been proposed based on their origin: a true neuroendocrine carcinoma, that is MCPyV positive and has a dermal origin, and a UV-related SCC with neuroendocrine differentiation. This theory could explain why MCC can develop concurrently with SCC, and why these combined cases are generally MCPyV negative. However, it fails to explain the minority of combined MCC and SCC tumors that are MCPyV positive. Because both our patients had a history of chronic UV exposure, we hypothesize that UV radiation probably played a major role in the pathogenesis of these tumors, while MCPyV integration probably acted as an additional trigger.
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Carcinoma de Células de Merkel , Carcinoma de Células Escamosas , Poliomavirus de Células de Merkel , Infecciones por Polyomavirus , Neoplasias Cutáneas , Infecciones Tumorales por Virus , Humanos , Anciano , Carcinoma de Células de Merkel/patología , Carcinoma de Células Escamosas/patología , Neoplasias Cutáneas/patología , Metástasis Linfática , Piel/patologíaRESUMEN
Intimal sarcomas (IS) are rare malignant mesenchymal tumors arising in large blood vessels of the systemic and pulmonary circulation and also in the heart. They are morphologically similar to other spindle cell, poorly differentiated sarcomas. The prognosis is poor and depends mainly on surgical options. Three cases of IS were collected from two institutions. Clinical data were retrieved and histological study was performed. A wide immunohistochemical panel was analyzed. FISH of MDM2 gene was performed, and a molecular study with NGS was implemented in all cases. The mean age of our cases was 54 years. Histologically, the tumors presented a diffuse growth pattern with heterogeneous atypical epithelioid or spindle cells and extensive thrombosed areas. All cases presented intense immunoexpression for MDM2, CDK4, CD117, c-myc, PDGFRA, and p16. PDGFRA, HTERT, and pan-TRK gained expression, while p16 lost intensity, being weaker in both the local recurrences and xenografts. The three cases showed amplification of MDM2 by FISH. NGS analysis revealed amplifications in the CDK4, PDGFRA, and KIT genes, together with BRAF mutation and KRAS amplification. P16 was expressed in all cases, losing intensity in local recurrence and xenografts. Two new alterations, a BRAF mutation and a KRAS amplification, were detected by NGS in different tumors, opening up new therapeutic options for these patients.
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Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Xenoinjertos , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Sarcoma/patología , Mutación , Neoplasias de los Tejidos Blandos/genética , Proteínas Tirosina Quinasas Receptoras/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Amplificación de Genes , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Quinasa 4 Dependiente de la Ciclina/genética , Quinasa 4 Dependiente de la Ciclina/metabolismoRESUMEN
Early stages are under-represented in studies on the molecular and immune features of high-grade serous ovarian carcinoma (HGSOC), and specific studies focused on early-stage HGSOC are required for a better prognostic stratification and to personalize chemotherapy. The aim of this study was to determine the prognostic significance of CD8+ and CD4+ tumor-infiltrating lymphocytes (TILs), tumoral cell PD-L1 expression, BRCA mutational status and tumor mutation burden (TMB) in early-stage HGSOC. A retrospective study was performed on stage I and II HGSOC from the Molecular Reclassification of Early Stages of Ovarian Cancer (RECLAMO) cohort from the Spanish Group of Ovarian Cancer Research (GEICO). Centralized histological typing was performed based on morphological and immunohistochemical features. Intraepithelial (i) and stromal (s) CD8+ and CD4+ T cells and PD-L1 were evaluated on tissue microarrays by immunohistochemistry. BRCA1 and BRCA2 mutation status and TMB were analyzed in tumor DNA using next-generation sequencing. The study included 124 tumors. High iCD8+ (>20 TILs/core), low/intermediate CD4+ (<20 TILs/core) and high CD8+/CD4+ ratio (>35/core) were associated with favorable outcomes. Tumor cell PD-L1 expression (TPS ≥ 1) was present in only 8% of tumors. In total, 11 (16%) and 6 (9%) out of 69 HGSOC tested carried pathogenic or likely pathogenic BRCA1 or BRCA2 mutations, respectively. Median TMB of 40 tumors analyzed was 5.04 mutations/Mb and only 6 tumors had 10 or more mutations/Mb. BRCA status and TMB were not associated with TILs or prognosis. When compared with studies on advanced HGSOC, our results suggested that prognostic variables differed according to stage and that more studies focused on early stages of HGSOC are needed to better stratify these tumors.
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Linfocitos Infiltrantes de Tumor , Neoplasias Ováricas , Humanos , Femenino , Pronóstico , Estudios Retrospectivos , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Neoplasias Ováricas/patología , MutaciónRESUMEN
Herpes simplex virus type 1 (HSV-1) is a neurotropic virus that occasionally may spread to the central nervous system (CNS), being the most common cause of sporadic encephalitis. One of the main neurovirulence factors of HSV-1 is the protein ICP34.5, which although it initially seems to be relevant only in neuronal infections, it can also promote viral replication in non-neuronal cells. New ICP34.5 functions have been discovered during recent years, and some of them have been questioned. This review describes the mechanisms of ICP34.5 to control cellular antiviral responses and debates its most controversial functions. One of the most discussed roles of ICP34.5 is autophagy inhibition. Although autophagy is considered a defense mechanism against viral infections, current evidence suggests that this antiviral function is only one side of the coin. Different types of autophagic pathways interact with HSV-1 impairing or enhancing the infection, and both the virus and the host cell modulate these pathways to tip the scales in its favor. In this review, we summarize the recent progress on the interplay between autophagy and HSV-1, focusing on the intricate role of ICP34.5 in the modulation of this pathway to fight the battle against cellular defenses.
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Herpes Simple , Herpesvirus Humano 1 , Humanos , Herpesvirus Humano 1/fisiología , Proteínas Virales/metabolismo , Autofagia/fisiología , Replicación Viral , Antivirales/metabolismo , Herpes Simple/metabolismoRESUMEN
Myelin and lymphocyte protein (MAL) is a tetraspan integral membrane protein that resides in detergent-insoluble membrane fractions enriched in condensed membranes. MAL is expressed in oligodendrocytes, in Schwann cells, where it is essential for the stability of myelin, and at the apical membrane of epithelial cells, where it has a critical role in transport. In T lymphocytes, MAL is found at the immunological synapse and plays a crucial role in exosome secretion. However, no involvement of MAL in viral infections has been reported so far. Here, we show that herpes simplex virus 1 (HSV-1) virions travel in association with MAL-positive structures to reach the end of cellular processes, which contact uninfected oligodendrocytes. Importantly, the depletion of MAL led to a significant decrease in infection, with a drastic reduction in the number of lytic plaques in MAL-silenced cells. These results suggest a significant role for MAL in viral spread at cell contacts. The participation of MAL in the cell-to-cell spread of HSV-1 may shed light on the involvement of proteolipids in this process.IMPORTANCE Herpes simplex virus 1 (HSV-1) is a neurotropic pathogen that can infect many types of cells and establish latent infections in neurons. HSV-1 may spread from infected to uninfected cells by two main routes: by cell-free virus or by cell-to-cell spread. In the first case, virions exit into the extracellular space and then infect another cell from the outside. In the second case, viral transmission occurs through cell-to-cell contacts via a mechanism that is still poorly understood. A third mode of spread, using extracellular vesicles, also exists. In this study, we demonstrate the important role for a myelin protein, myelin and lymphocyte protein (MAL), in the process of cell-to-cell viral spread in oligodendrocytes. We show that MAL is involved in trafficking of virions along cell processes and that MAL depletion produces a significant alteration in the viral cycle, which reduces cell-to cell spread of HSV-1.
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Herpes Simple/metabolismo , Herpesvirus Humano 1/metabolismo , Proteínas Proteolipídicas Asociadas a Mielina y Linfocito/metabolismo , Línea Celular Tumoral , Membrana Celular/metabolismo , Células Epiteliales/metabolismo , Herpes Simple/virología , Herpesvirus Humano 1/patogenicidad , Humanos , Linfocitos/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de la Mielina/metabolismo , Proteínas Proteolipídicas Asociadas a Mielina y Linfocito/química , Proteínas Proteolipídicas Asociadas a Mielina y Linfocito/fisiología , Neuronas/metabolismo , Neuronas/virología , Oligodendroglía/metabolismo , Oligodendroglía/virología , Proteolípidos/química , Proteolípidos/metabolismo , Linfocitos T/metabolismoRESUMEN
BACKGROUND: Because of their specific and biologically relevant cargo, urine extracellular vesicles (EVs) constitute a valuable source of potential non-invasive biomarkers that could support the clinical decision-making to improve the management of prostate cancer (PCa) patients. Different EV isolation methods differ in terms of complexity and yield, conditioning, as consequence, the analytical result. METHODS: The aim of this study was to compare three different isolation methods for urine EVs: ultracentrifugation (UC), size exclusion chromatography (SEC), and a commercial kit (Exolute® Urine Kit). Urine samples were collected from 6 PCa patients and 4 healthy donors. After filtered through 0.22 µm filters, urine was divided in 3 equal volumes to perform EVs isolation with each of the three approaches. Isolated EVs were characterized by spectrophotometric protein quantification, nanoparticle tracking analysis, transmission electron microscopy, AlphaScreen Technology, and whole miRNA Transcriptome. RESULTS: Our results showed that UC and SEC provided better results in terms of EVs yield and purity than Exolute®, non-significant differences were observed in terms of EV-size. Interestingly, luminescent AlphaScreen assay demonstrated a significant enrichment of CD9 and CD63 positive microvesicles in SEC and UC methods compared with Exolute®. This heterogeneity was also demonstrated in terms of miRNA content indicating that the best correlation was observed between UC and SEC. CONCLUSIONS: Our study highlights the importance of standardizing the urine EV isolation methods to guaranty the analytical reproducibility necessary for their implementation in a clinical setting.
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Vesículas Extracelulares , Neoplasias de la Próstata/orina , Cromatografía en Gel , Humanos , Masculino , Ultracentrifugación , UrinálisisRESUMEN
Herpes simplex virus type 1 (HSV-1) is a neurotropic alphaherpesvirus that can infect the peripheral and central nervous systems, and it has been implicated in demyelinating and neurodegenerative processes. Transposable elements (TEs) are DNA sequences that can move from one genomic location to another. TEs have been linked to several diseases affecting the central nervous system (CNS), including multiple sclerosis (MS), a demyelinating disease of unknown etiology influenced by genetic and environmental factors. Exogenous viral transactivators may activate certain retrotransposons or class I TEs. In this context, several herpesviruses have been linked to MS, and one of them, HSV-1, might act as a risk factor by mediating processes such as molecular mimicry, remyelination, and activity of endogenous retroviruses (ERVs). Several herpesviruses have been involved in the regulation of human ERVs (HERVs), and HSV-1 in particular can modulate HERVs in cells involved in MS pathogenesis. This review exposes current knowledge about the relationship between HSV-1 and human ERVs, focusing on their contribution as a risk factor for MS.
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Enfermedades Desmielinizantes/etiología , Susceptibilidad a Enfermedades , Retrovirus Endógenos/fisiología , Herpes Simple/complicaciones , Herpes Simple/virología , Herpesvirus Humano 1 , Animales , Evolución Biológica , Elementos Transponibles de ADN , Enfermedades Desmielinizantes/metabolismo , Enfermedades Desmielinizantes/patología , Retrovirus Endógenos/clasificación , Humanos , Esclerosis Múltiple/etiología , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , RetroelementosRESUMEN
Prostate cancer (PCa) is the most commonly diagnosed cancer in men. The diagnosis is currently based on PSA levels, which are associated with overdiagnosis and overtreatment. Moreover, most PCas are localized tumours; hence, many patients with low-/very low-risk PCa could benefit from active surveillance (AS) programs instead of more aggressive, active treatments. Heterogeneity within inclusion criteria and follow-up strategies are the main controversial issues that AS presently faces. Many biomarkers are currently under investigation in this setting; however, none has yet demonstrated enough diagnostic ability as an independent predictor of pathological or clinical progression. This work aims to review the currently available literature on tissue, blood and urine biomarkers validated in clinical practice for the management of AS patients.
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Biomarcadores/análisis , Neoplasias de la Próstata/diagnóstico , Espera Vigilante/estadística & datos numéricos , Progresión de la Enfermedad , Humanos , Masculino , Neoplasias de la Próstata/prevención & control , Espera Vigilante/métodosRESUMEN
BACKGROUND: Solitary fibrous tumour is an ultra-rare sarcoma, which encompasses different clinicopathological subgroups. The dedifferentiated subgroup shows an aggressive course with resistance to pazopanib, whereas in the malignant subgroup, pazopanib shows higher activity than in previous studies with chemotherapy. We designed a trial to test pazopanib activity in two different cohorts of solitary fibrous tumour: the malignant-dedifferentiated cohort, which was previously published, and the typical cohort, which is presented here. METHODS: In this single-arm, phase 2 trial, adult patients (aged ≥18 years) diagnosed with confirmed metastatic or unresectable typical solitary fibrous tumour of any location, who had progressed in the previous 6 months (by Choi criteria or Response Evaluation Criteria in Solid Tumors [RECIST]) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were enrolled at 11 tertiary hospitals in Italy, France, and Spain. Patients received pazopanib 800 mg once daily, taken orally, until progression, unacceptable toxicity, withdrawal of consent, non-compliance, or a delay in pazopanib administration of longer than 3 weeks. The primary endpoint was proportion of patients achieving an overall response measured by Choi criteria in patients who received at least 1 month of treatment with at least one radiological assessment. All patients who received at least one dose of the study drug were included in the safety analyses. This study is registered in ClinicalTrials.gov, NCT02066285, and with the European Clinical Trials Database, EudraCT 2013-005456-15. FINDINGS: From June 26, 2014, to Dec 13, 2018, of 40 patients who were assessed, 34 patients were enrolled and 31 patients were included in the response analysis. Median follow-up was 18 months (IQR 14-34), and 18 (58%) of 31 patients had a partial response, 12 (39%) had stable disease, and one (3%) showed progressive disease according to Choi criteria and central review. The proportion of overall response based on Choi criteria was 58% (95% CI 34-69). There were no deaths caused by toxicity, and the most frequent adverse events were diarrhoea (18 [53%] of 34 patients), fatigue (17 [50%]), and hypertension (17 [50%]). INTERPRETATION: To our knowledge, this is the first prospective trial of pazopanib for advanced typical solitary fibrous tumour. The manageable toxicity and activity shown by pazopanib in this cohort suggest that this drug could be considered as first-line treatment for advanced typical solitary fibrous tumour. FUNDING: Spanish Group for Research on Sarcomas (GEIS), Italian Sarcoma Group (ISG), French Sarcoma Group (FSG), GlaxoSmithKline, and Novartis.
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Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Tumores Fibrosos Solitarios/tratamiento farmacológico , Sulfonamidas/uso terapéutico , Anciano , Femenino , Estudios de Seguimiento , Humanos , Indazoles , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Pronóstico , Estudios Prospectivos , Criterios de Evaluación de Respuesta en Tumores Sólidos , Tumores Fibrosos Solitarios/patología , Tasa de SupervivenciaRESUMEN
Prostate cancer (PCa) is a hormone-dependent tumor characterized by an extremely heterogeneous prognosis. Despite recent advances in partially uncovering some of the biological processes involved in its progression, there is still an urgent need for identifying more accurate and specific prognostic procedures to differentiate between disease stages. In this context, targeted approaches, focused on mapping dysregulated metabolic pathways, could play a critical role in identifying the mechanisms driving tumorigenesis and metastasis. In this study, a targeted analysis of the nuclear magnetic resonance-based metabolomic profile of PCa patients with different tumor grades, guided by transcriptomics profiles associated with their stages, was performed. Serum and urine samples were collected from 73 PCa patients. Samples were classified according to their Gleason score (GS) into low-GS (GS < 7) and high-GS PCa (GS ≥ 7) groups. A total of 36 metabolic pathways were found to be dysregulated in the comparison between different PCa grades. Particularly, the levels of glucose, glycine and 1-methlynicotinamide, metabolites involved in energy metabolism and nucleotide synthesis were significantly altered between both groups of patients. These results underscore the potential of targeted metabolomic profiling to characterize relevant metabolic changes involved in the progression of this neoplastic process.
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Neoplasias de la Próstata , Humanos , Masculino , Metabolómica , Clasificación del Tumor , Pronóstico , Neoplasias de la Próstata/diagnósticoRESUMEN
It is being increasingly demonstrated that extracellular vesicles (EVs) are deeply involved in the physiology of the central nervous system (CNS). Processes such as synaptic activity, neuron-glia communication, myelination and immune response are modulated by EVs. Likewise, these vesicles may participate in many pathological processes, both as triggers of disease or, on the contrary, as mechanisms of repair. EVs play relevant roles in neurodegenerative disorders such as Alzheimer's or Parkinson's diseases, in viral infections of the CNS and in demyelinating pathologies such as multiple sclerosis (MS). This review describes the involvement of these membrane vesicles in major demyelinating diseases, including MS, neuromyelitis optica, progressive multifocal leukoencephalopathy and demyelination associated to herpesviruses.
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Sistema Nervioso Central/patología , Enfermedades Desmielinizantes/patología , Vesículas Extracelulares/metabolismo , Animales , Retrovirus Endógenos/fisiología , Humanos , Modelos BiológicosRESUMEN
Herpes simplex type 1 (HSV-1) is a neurotropic virus that infects the peripheral and central nervous systems. After primary infection in epithelial cells, HSV-1 spreads retrogradely to the peripheral nervous system (PNS), where it establishes a latent infection in the trigeminal ganglia (TG). The virus can reactivate from the latent state, traveling anterogradely along the axon and replicating in the local surrounding tissue. Occasionally, HSV-1 may spread trans-synaptically from the TG to the brainstem, from where it may disseminate to higher areas of the central nervous system (CNS). It is not completely understood how HSV-1 reaches the CNS, although the most accepted idea is retrograde transport through the trigeminal or olfactory tracts. Once in the CNS, HSV-1 may induce demyelination, either as a direct trigger or as a risk factor, modulating processes such as remyelination, regulation of endogenous retroviruses, or molecular mimicry. In this review, we describe the current knowledge about the involvement of HSV-1 in demyelination, describing the pathways used by this herpesvirus to spread throughout the CNS and discussing the data that suggest its implication in demyelinating processes.
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Sistema Nervioso Central/virología , Enfermedades Desmielinizantes/virología , Herpes Simple/complicaciones , Herpesvirus Humano 1/fisiología , Animales , Sistema Nervioso Central/patología , Enfermedades Desmielinizantes/etiología , Enfermedades Desmielinizantes/patología , Herpes Simple/patología , Herpes Simple/virología , Interacciones Huésped-Patógeno , HumanosRESUMEN
The purpose of this study is to clinically validate a series of circulating miRNAs that distinguish between the 4 most prevalent tumor types (lung cancer (LC); breast cancer (BC); colorectal cancer (CRC); and prostate cancer (PCa)) and healthy donors (HDs). A total of 18 miRNAs and 3 housekeeping miRNA genes were evaluated by qRT-PCR on RNA extracted from serum of cancer patients, 44 LC, 45 BC, 27 CRC, and 40 PCa, and on 45 HDs. The cancer detection performance of the miRNA expression levels was evaluated by studying the area under the curve (AUC) of receiver operating characteristic (ROC) curves at univariate and multivariate levels. miR-21 was significantly overexpressed in all cancer types compared with HDs, with accuracy of 67.5% (p = 0.001) for all 4 tumor types and of 80.8% (p < 0.0001) when PCa cases were removed from the analysis. For each tumor type, a panel of miRNAs was defined that provided cancer-detection accuracies of 91%, 94%, 89%, and 77%, respectively. In conclusion, we have described a series of circulating miRNAs that define different tumor types with a very high diagnostic performance. These panels of miRNAs would constitute the basis of different approaches of cancer-detection systems for which clinical utility should be validated in prospective cohorts.
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Neoplasias de la Mama/genética , MicroARN Circulante/sangre , Neoplasias Colorrectales/genética , Neoplasias Pulmonares/genética , Neoplasias de la Próstata/genética , Adulto , Anciano , Anciano de 80 o más Años , Área Bajo la Curva , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/patología , Estudios de Casos y Controles , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/patología , Detección Precoz del Cáncer , Femenino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/patología , Curva ROCRESUMEN
Epithelial ovarian cancer (EOC) is a heterogeneous group of diseases with distinct biological and clinical behaviour. Despite the differences between them, the capability of tumour cells to continuously proliferate and avoid death is maintained among histotypes. This ability is the result of alterations at different levels, causing the deregulation of cell cycle and proliferative-related pathways. Even if the leading role is played by RB and TP53, changes in other molecular pathways are involved in the development of EOC. This ability can be exploited to generate in vitro and in vivo models resembling the conditions of tumour development in a patient. In vivo models, such as patient-derived xenografts (PDX) or genetically engineered mouse models (GEMM), represent a fundamental tool in the study of the molecular mechanisms implicated in each EOC biotype for testing new therapeutic approaches. Herein we describe the major proliferation-related pathways and its disruption found in EOC and how these features can be used to establish in vivo models for translational research.
RESUMEN
Herpes simplex virus 1 (HSV-1) is a neurotropic pathogen that can infect many types of cells and establishes latent infections in the neurons of sensory ganglia. In some cases, the virus spreads into the central nervous system, causing encephalitis or meningitis. Cells infected with several different types of viruses may secrete microvesicles (MVs) containing viral proteins and RNAs. In some instances, extracellular microvesicles harboring infectious virus have been found. Here we describe the features of shedding microvesicles released by the human oligodendroglial HOG cell line infected with HSV-1 and their participation in the viral cycle. Using transmission electron microscopy, we detected for the first time microvesicles containing HSV-1 virions. Interestingly, the Chinese hamster ovary (CHO) cell line, which is resistant to infection by free HSV-1 virions, was susceptible to HSV-1 infection after being exposed to virus-containing microvesicles. Therefore, our results indicate for the first time that MVs released by infected cells contain virions, are endocytosed by naive cells, and lead to a productive infection. Furthermore, infection of CHO cells was not completely neutralized when virus-containing microvesicles were preincubated with neutralizing anti-HSV-1 antibodies. The lack of complete neutralization and the ability of MVs to infect nectin-1/HVEM-negative CHO-K1 cells suggest a novel way for HSV-1 to spread to and enter target cells. Taken together, our results suggest that HSV-1 could spread through microvesicles to expand its tropism and that microvesicles could shield the virus from neutralizing antibodies as a possible mechanism to escape the host immune response.IMPORTANCE Herpes simplex virus 1 (HSV-1) is a neurotropic pathogen that can infect many types of cells and establishes latent infections in neurons. Extracellular vesicles are a heterogeneous group of membrane vesicles secreted by most cell types. Microvesicles, which are extracellular vesicles which derive from the shedding of the plasma membrane, isolated from the supernatant of HSV-1-infected HOG cells were analyzed to find out whether they were involved in the viral cycle. The importance of our investigation lies in the detection, for the first time, of microvesicles containing HSV-1 virions. In addition, virus-containing microvesicles were endocytosed into CHO-K1 cells and were able to actively infect these otherwise nonpermissive cells. Finally, the infection of CHO cells with these virus-containing microvesicles was not completely neutralized by anti-HSV-1 antibodies, suggesting that these extracellular vesicles might shield the virus from neutralizing antibodies as a possible mechanism of immune evasion.
Asunto(s)
Micropartículas Derivadas de Células/virología , Herpes Simple/transmisión , Herpesvirus Humano 1/fisiología , Oligodendroglía/virología , Replicación Viral/fisiología , Animales , Anticuerpos Antivirales/inmunología , Células CHO , Línea Celular , Membrana Celular/metabolismo , Chlorocebus aethiops , Cricetulus , Endocitosis , Células HeLa , Herpes Simple/virología , Herpesvirus Humano 1/crecimiento & desarrollo , Humanos , Microscopía Electrónica de Transmisión , Oligodendroglía/citología , Células Vero , Internalización del VirusRESUMEN
BACKGROUND: Approximately 5 to 10% of all cancers are caused by inherited germline mutations, many of which are associated with different Hereditary Cancer Syndromes (HCS). In the context of the Program of Hereditary Cancer of the Valencia Community, individuals belonging to specific HCS and their families receive genetic counselling and genetic testing according to internationally established guidelines. The current diagnostic approach is based on sequencing a few high-risk genes related to each HCS; however, this method is time-consuming, expensive and does not achieve a confirmatory genetic diagnosis in many cases. This study aims to test the level of improvement offered by a Next Generation Sequencing (NGS) gene-panel compared to the standard approach in a diagnostic reference laboratory setting. METHODS: A multi-gene NGS panel was used to test a total of 91 probands, previously classified as non-informative by analysing the high-risk genes defined in our guidelines. RESULTS: Nineteen deleterious mutations were detected in 16% of patients, some mutations were found in already-tested high-risk genes (BRCA1, BRCA2, MSH2) and others in non-prevalent genes (RAD51D, PALB2, ATM, TP53, MUTYH, BRIP1). CONCLUSIONS: Overall, our findings reclassify several index cases into different HCS, and change the mutational status of 14 cases from non-informative to gene mutation carriers. In conclusion, we highlight the necessity of incorporating validated multi-gene NGS panels into the HCSs diagnostic routine to increase the performance of genetic diagnosis.
RESUMEN
BACKGROUND: Prostate cancer (PCa) is characterized by clinical and biological heterogeneity and has differential outcomes and mortality rates. Therefore, it is necessary to identify molecular alterations to define new therapeutic strategies based on the risk of progression. In this study, the prognostic relevance of the insulin-like growth factor (IGF) system was examined in molecular subtypes defined by TMPRSS2-ERG (T2E) gene fusion within a series of patients with primary localized PCa. METHODS: A cohort of 270 formalin-fixed and paraffin-embedded (FFPE) primary PCa samples from patients with more than 5 years' follow-up was collected. IGF-1R, IGF-1, IGFBP-3 and INSR expression was analyzed using quantitative RT-PCR. The T2E status and immunohistochemical ERG findings were considered in the analyses. The association with both biochemical and clinical progression-free survival (BPFS and PFS, respectively) was evaluated for the different molecular subtypes using the Kaplan-Meier proportional risk log-rank test and the Cox proportional hazards model. RESULTS: An association between IGF-1R overexpression and better BPFS was found in T2E-negative patients (35.3% BPFS, p-value = 0.016). Multivariate analysis demonstrated that IGF-1R expression constitutes an independent variable in T2E-negative patients [HR: 0.41. CI 95% (0.2-0.82), p = 0.013]. These data were confirmed using immunohistochemistry of ERG as subrogate of T2E. High IGF-1 expression correlated with prolonged BPFS and PFS independent of the T2E status. CONCLUSIONS: IGF-1R, a reported target of T2E, constitutes an independent factor for good prognosis in T2E-negative PCa. Quantitative evaluation of IGF-1/IGF-1R expression combined with molecular assessment of T2E status or ERG protein expression represents a useful marker for tumor progression in localized PCa.