RESUMEN
The vertebrate adaptive immune systems (Agnatha and Gnathostomata) use sets of T and B lymphocyte lineages that somatically generate highly diverse repertoires of Ag-specific receptors and Abs. In Gnathostomata, cytokine networks regulate the activation of lymphoid and myeloid cells, whereas little is known about these components in Agnathans. Most gnathostome cytokines are four-helix bundle cytokines with poorly conserved primary sequences. In contrast, sequence conservation across bilaterians has been observed for cognate cytokine receptor chains, allowing their structural classification into two classes, and for downstream JAK/STAT signaling mediators. With conserved numbers among Gnathostomata, human cytokine receptor chains (comprising 34 class I and 12 class II) are able to interact with 28 class I helical cytokines (including most ILs) and 16 class II cytokines (including all IFNs), respectively. Hypothesizing that the arsenal of cytokine receptors and transducers may reflect homologous cytokine networks, we analyzed the lamprey genome and transcriptome to identify genes and transcripts for 23 class I and five class II cytokine receptors alongside one JAK signal mediator and four STAT transcription factors. On the basis of deduction of their respective orthologs, we predict that these receptors may interact with 16 class I and 3 class II helical cytokines (including IL-4, IL-6, IL-7, IL-12, IL-10, IFN-γ, and thymic stromal lymphoprotein homologs). On the basis of their respective activities in mammals, this analysis suggests the existence of lamprey cytokine networks that may regulate myeloid and lymphoid cell differentiation, including potential Th1/Th2 polarization. The predicted networks thus appear remarkably homologous to those of Gnathostomata, albeit reduced to essential functions.
Asunto(s)
Interleucina-10 , Receptores de Citocinas , Animales , Citocinas/metabolismo , Humanos , Interleucina-12 , Interleucina-4 , Interleucina-6 , Interleucina-7 , Lampreas , Mamíferos/metabolismo , Receptores de Citocinas/genética , Factores de Transcripción STAT , Vertebrados/metabolismoRESUMEN
In the present study we investigated the phosphorylation status of the 12 most important signaling cascades in glioblastomas. More than 60 tumor and control biopsies from tumor center and periphery (based on neuronavigation) were subjected to selective protein expression analysis using reverse-phase protein arrays (RPPA) incubated with antibodies against posttranslationally modified cancer pathway proteins. The ratio between phosphorylated (or modified) and non-phosphorylated protein was assessed. All samples were histopathologically validated and proteomic profiles correlated with clinical and survival data. By RPPA, we identified three distinct activation patterns within glioblastoma defined by the ratios of pCREB1/CREB1, NOTCH-ICD/NOTCH1, and pGSK3ß/GSK3ß, respectively. These subclasses demonstrated distinct overall survival patterns in a cohort of patients from a single-institution and in an analysis of publicly available data. In particular, a high pGSK3ß/GSK3ß-ratio was associated with a poor survival. Wnt-activation/GSK3ß-inhibition in U373 and U251 cell lines halted glioma cell proliferation and migration. Gene expression analysis was used as an internal quality control of baseline proteomic data. The protein expression and phosphorylation had a higher resolution, resulting in a better class-subdivision than mRNA based stratification data. Patients with different proteomic profiles from multiple biopsies showed a worse overall survival. The CREB1-, NOTCH1-, GSK3ß-phosphorylation status correlated with glioma grades. RPPA represent a fast and reliable tool to supplement morphological diagnosis with pathway-specific information in individual tumors. These data can be exploited for molecular stratification and possible combinatorial treatment planning. Further, our results may optimize current glioma grading algorithms.
Asunto(s)
Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Transducción de Señal , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fosforilación , Análisis por Matrices de Proteínas , Proteómica , Análisis de SupervivenciaRESUMEN
Acquisition of IDH1 or IDH2 mutation (IDHmut) is among the earliest genetic events that take place in the development of most low-grade glioma (LGG). IDHmut has been associated with longer overall patient survival. However, its impact on malignant transformation (MT) remains to be defined. A collection of 210 archived adult LGG previously stratified by IDHmut, MGMT methylation (MGMTmet), 1p/19q combined loss of heterozygosity (1p19qloh) and TP53 immunopositivity (TP53pos) status was analyzed. We used multistate models to assess MT-free survival, considering one initial, one transient (MT), and one absorbing state (death). Missing explanatory variables were multiply imputed. Overall, although associated with a lower risk of death (HR(DEATH) = 0.35, P = 0.0023), IDHmut had a non-significantly higher risk of MT (HR(MT) = 1.84; P = 0.1683) compared to IDH wild type (IDHwt). The double combination of IDHmut and MGMTmet and the triple combination of IDHmut, MGMTmet and 1p/19qloh, despite significantly lower hazards for death (HR(DEATH) versus IDHwt: 0.35, P = 0.0194 and 0.15, P = 0.0008, respectively), had non-significantly different hazards for MT. Conversely, the triple combination of IDHmut/MGMTmet/TP53pos, with a non-significantly different hazard for death, had a significantly higher hazard for MT than IDHwt (HR(MT) versus IDHwt: 2.83; P = 0.0452). Although IDHmut status is associated with longer overall patient survival, all IDHmut/MGMTmet subsets consistently showed higher risks of MT than of death, compared to IDHwt LGG. This supports the findings that molecular events relevant to IDH mutations impact early glioma development prior to malignant transformation.
Asunto(s)
Neoplasias Encefálicas/patología , Transformación Celular Neoplásica/patología , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Glioma/patología , Isocitrato Deshidrogenasa/genética , Mutación/genética , Proteínas Supresoras de Tumor/genética , Adulto , Neoplasias Encefálicas/genética , Transformación Celular Neoplásica/genética , Metilación de ADN , Femenino , Estudios de Seguimiento , Glioma/genética , Humanos , Masculino , Estadificación de Neoplasias , Pronóstico , Tasa de SupervivenciaRESUMEN
In this issue, Bader et al.1 characterize the proteomes of diffuse glioma brain tumors by liquid chromatography mass spectrometry and classify isocitrate dehydrogenase (IDH)-mutant gliomas into two subtypes, which differ in oncogenic pathways and aerobic/anaerobic energy metabolism.
Asunto(s)
Neoplasias Encefálicas , Glioma , Humanos , Isocitrato Deshidrogenasa/genética , Proteoma/genética , Mutación , Glioma/genética , Glioma/patología , Neoplasias Encefálicas/genéticaRESUMEN
Malignant gliomas are among the most devastating tumors for which conventional therapies have not significantly improved patient outcome. Despite advances in imaging, surgery, chemotherapy and radiotherapy, survival is still less than 2 years from diagnosis and more targeted therapies are urgently needed. Notch signaling is central to the normal and neoplastic development of the central nervous system, playing important roles in proliferation, differentiation, apoptosis and cancer stem cell regulation. Notch is also involved in the regulation response to hypoxia and angiogenesis, which are typical tumor and more specifically glioblastoma multiforme (GBM) features. Targeting Notch signaling is therefore a promising strategy for developing future therapies for the treatment of GBM. In this review we give an overview of the mechanisms of Notch signaling, its networking pathways in gliomas, and discuss its potential for designing novel therapeutic approaches.
Asunto(s)
Glioblastoma/genética , Receptores Notch/genética , Receptores Notch/metabolismo , Transducción de Señal , Diferenciación Celular , Proliferación Celular , Glioblastoma/patología , Humanos , Hipoxia , Neovascularización PatológicaRESUMEN
Tumor-associated microglia (MG) and macrophages (MΦ) are important components of the glioblastoma (GBM) immune tumor microenvironment (iTME). From the recent advances in understanding how MG and GBM cells evolve and interact during tumorigenesis, we emphasize the cooperation of MG with other immune cell types of the GBM-iTME, mainly MΦ and T cells. We provide a comprehensive overview of current immunotherapeutic clinical trials and approaches for the treatment of GBM, which in general, underestimate the counteracting contribution of immunosuppressive MG as a main factor for treatment failure. Furthermore, we summarize new developments and strategies in MG reprogramming/re-education in the GBM context, with a focus on ways to boost MG-mediated tumor cell phagocytosis and associated experimental models and methods. This ultimately converges in our proposal of novel combinatorial regimens that locally modulate MG as a central paradigm, and therefore may lead to additional, long-lasting, and effective tumoricidal responses.
Asunto(s)
Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Inmunoterapia/métodos , Microglía/fisiología , Animales , Neoplasias Encefálicas/inmunología , Reprogramación Celular , Ensayos Clínicos como Asunto , Glioblastoma/inmunología , Humanos , Fagocitosis , Microambiente TumoralRESUMEN
BACKGROUND: Malignant gliomas are frequent primary brain tumors associated with poor prognosis and very limited response to conventional chemo- and radio-therapies. Besides sharing common growth features with other types of solid tumors, gliomas are highly invasive into adjacent brain tissue, which renders them particularly aggressive and their surgical resection inefficient. Therefore, insights into glioma formation are of fundamental interest in order to provide novel molecular targets for diagnostic purposes and potential anti-cancer drugs. Human Tripartite motif protein 3 (TRIM3) encodes a structural homolog of Drosophila brain tumor (brat) implicated in progenitor cell proliferation control and cancer stem cell suppression. TRIM3 is located within the loss of allelic heterozygosity (LOH) hotspot of chromosome segment 11p15.5, indicating a potential role in tumor suppression. METHODS: Here we analyze 70 primary human gliomas of all types and grades and report somatic deletion mapping as well as single nucleotide polymorphism analysis together with quantitative real-time PCR of chromosome segment 11p15.5. RESULTS: Our analysis identifies LOH in 17 cases (24%) of primary human glioma which defines a common 130 kb-wide interval within the TRIM3 locus as a minimal area of loss. We further detect altered genomic dosage of TRIM3 in two glioma cases with LOH at 11p15.5, indicating homozygous deletions of TRIM3. CONCLUSION: Loss of heterozygosity of chromosome segment 11p15.5 in malignant gliomas suggests TRIM3 as a candidate brain tumor suppressor gene.
Asunto(s)
Neoplasias Encefálicas/genética , Proteínas Portadoras/genética , Glioma/genética , Pérdida de Heterocigocidad , Mapeo Cromosómico , Cromosomas Humanos Par 11 , Dosificación de Gen , Genes Supresores de Tumor , Humanos , Reacción en Cadena de la Polimerasa , Polimorfismo de Nucleótido Simple , Lugares Marcados de SecuenciaRESUMEN
PURPOSE: High-grade gliomas are difficult to treat due to their location behind the blood-brain barrier and to inherent radioresistance and chemoresistance. EXPERIMENTAL DESIGN: Because tumorigenesis is considered a multistep process of accumulating mutations affecting distinct signaling pathways, combinations of compounds, which inhibit nonoverlapping pathways, are being explored to improve treatment of gliomas. Histone deacetylase inhibitors (HDI) have proven antitumor activity by blocking cell proliferation, promoting differentiation, and inducing tumor cell apoptosis. RESULTS: In this report, we show that the HDIs trichostatin A, sodium butyrate, and low nanomolar doses of LAQ824 combined with the glycolysis inhibitor 2-deoxy-d-glucose induce strong apoptosis in cancer cell lines of brain, breast, and cervix in a p53-independent manner. HDIs up-regulate p21, which is blocked by concomitant administration of 2-deoxy-d-glucose. CONCLUSIONS: We propose simultaneous blockade of histone deacetylation and glycolysis as a novel therapeutic strategy for several major cancers.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis/efectos de los fármacos , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Glucólisis/efectos de los fármacos , Inhibidores de Histona Desacetilasas , Butiratos/farmacología , Línea Celular Tumoral , Desoxiglucosa/farmacología , Sinergismo Farmacológico , Inhibidores Enzimáticos/farmacología , Histona Desacetilasas/efectos de los fármacos , Humanos , Ácidos Hidroxámicos/farmacologíaRESUMEN
BACKGROUND: Gliomas are the most frequent and aggressive malignancies of the central nervous system. Decades of molecular analyses have demonstrated that gliomas accumulate genetic alterations that culminate in enhanced activity of receptor tyrosine kinases and downstream mediators. While the genetic alterations, like gene amplification or loss, have been well characterized, little information exists about changes in the proteome of gliomas of different grades. METHODS: We performed unbiased quantitative proteomics of human glioma biopsies by mass spectrometry followed by bioinformatic analysis. FINDINGS: Various pathways were found to be up- or downregulated. In particular, endocytosis as pathway was affected by a vast and concomitant reduction of multiple machinery components involved in initiation, formation, and scission of endocytic carriers. Both clathrin-dependent and -independent endocytosis were changed, since not only clathrin, AP-2 adaptins, and endophilins were downregulated, but also dynamin that is shared by both pathways. The reduction of endocytic machinery components caused increased receptor cell surface levels, a prominent phenotype of defective endocytosis. Analysis of additional biopsies revealed that depletion of endocytic machinery components was a common trait of various glioma grades and subclasses. INTERPRETATION: We propose that impaired endocytosis creates a selective advantage in glioma tumor progression due to prolonged receptor tyrosine kinase signaling from the cell surface. FUND: This work was supported by Grants 316030-164105 (to P. Jenö), 31003A-162643 (to M. Spiess) and PP00P3-176974 (to G. Hutter) from the Swiss National Science Foundation. Further funding was received by the Department of Surgery from the University Hospital Basel.
Asunto(s)
Endocitosis , Glioma/metabolismo , Proteoma , Proteómica , Biopsia , Biología Computacional/métodos , Glioma/genética , Glioma/patología , Humanos , Espectrometría de Masas , Clasificación del Tumor , Estadificación de Neoplasias , Células Neoplásicas Circulantes , Proteómica/métodosRESUMEN
Diffuse gliomas progress by invading neighboring brain tissue to promote postoperative relapse. Transcription factor SOX2 is highly expressed in invasive gliomas and maps to chromosome region 3q26 together with the genes for PI3K/AKT signaling activator PIK3CA and effector molecules of mitochondria fusion and cell invasion, MFN1 and OPA1. Gene copy number analysis at 3q26 from 129 glioma patient biopsies revealed mutually exclusive SOX2 amplifications (26%) and OPA1 losses (19%). Both forced SOX2 expression and OPA1 inactivation increased LN319 glioma cell invasion in vitro and promoted cell dispersion in vivo in xenotransplanted D. rerio embryos. While PI3 kinase activity sustained SOX2 expression, pharmacological PI3K/AKT pathway inhibition decreased invasion and resulted in SOX2 nucleus-to-cytoplasm translocation in an mTORC1-independent manner. Chromatin immunoprecipitation and luciferase reporter gene assays together demonstrated that SOX2 trans-activates PIK3CA and OPA1. Thus, SOX2 activates PI3K/AKT signaling in a positive feedback loop, while OPA1 deletion is interpreted to counteract OPA1 trans-activation. Remarkably, neuroimaging of human gliomas with high SOX2 or low OPA1 genomic imbalances revealed significantly larger necrotic tumor zone volumes, corresponding to higher invasive capacities of tumors, while autologous necrotic cells are capable of inducing higher invasion in SOX2 overexpressing or OPA1 knocked-down relative to parental LN319. We thus propose necrosis volume as a surrogate marker for the assessment of glioma invasive potential. Whereas glioma invasion is activated by a PI3K/AKT-SOX2 loop, it is reduced by a cryptic invasion suppressor SOX2-OPA1 pathway. Thus, PI3K/AKT-SOX2 and mitochondria fission represent connected signaling networks regulating glioma invasion.
Asunto(s)
Cromosomas Humanos Par 3 , Fosfatidilinositol 3-Quinasa Clase I/genética , GTP Fosfohidrolasas/genética , Glioma/genética , Factores de Transcripción SOXB1/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Variaciones en el Número de Copia de ADN , GTP Fosfohidrolasas/metabolismo , Glioma/metabolismo , Glioma/patología , Células HEK293 , Humanos , Necrosis/genética , Invasividad Neoplásica , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factores de Transcripción SOXB1/metabolismo , Transducción de SeñalRESUMEN
The oncogenic epidermal growth factor receptor (EGFR) pathway triggers downstream phosphatidylinositol 3-kinase (PI3K)/RAS-mediated signaling cascades. In transgenic mice, glioblastoma cannot develop on single but only on simultaneous activation of the EGFR signaling mediators RAS and AKT. However, complete blockade of EGFR activation does not result in apoptosis in human glioblastoma cells, suggesting additional cross-talk between downstream pathways. Based on these observations, we investigated combination therapies using protein kinase inhibitors against EGFR, platelet-derived growth factor receptor, and mammalian target of rapamycin, assessing glioblastoma cell survival. Clinically relevant doses of AEE788, Gleevec (imatinib), and RAD001 (everolimus), alone or in combinations, did not induce glioblastoma cell apoptosis. In contrast, simultaneous inactivation of the EGFR downstream targets mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase and PI3K by U0126 and wortmannin triggered rapid tumor cell death. Blocking EGFR with AEE788 in combination with sublethal concentrations of the microtubule stabilizer patupilone also induced apoptosis and reduced cell proliferation in glioblastoma cells, accompanied by reduced AKT and ERK activity. These data underline the critical role of the PI3K/AKT and the RAS/RAF/mitogen-activated protein/ERK kinase/ERK signaling cascades in the cell-intrinsic survival program of sensitive glioblastoma cell lines. We conclude that drug combinations, which down-regulate both ERK and protein kinase B/AKT activity, may prove effective in overcoming cell resistance in a subgroup of glioblastoma.
Asunto(s)
Apoptosis/efectos de los fármacos , Receptores ErbB/antagonistas & inhibidores , Glioblastoma/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Transducción de Señal/efectos de los fármacos , Benzamidas , Western Blotting , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Epotilonas/farmacología , Receptores ErbB/metabolismo , Everolimus , Glioblastoma/metabolismo , Humanos , Mesilato de Imatinib , Inmunosupresores/farmacología , MAP Quinasa Quinasa 1/metabolismo , Microtúbulos/efectos de los fármacos , Microtúbulos/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Ésteres del Forbol/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Piperazinas/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Purinas/farmacología , Pirimidinas/farmacología , Sirolimus/análogos & derivados , Sirolimus/farmacología , Células Tumorales Cultivadas/efectos de los fármacosRESUMEN
BACKGROUND: Although tumor size affects survival of patients with lower-grade glioma, a prognostic effect on patients with glioblastoma remains to be established. METHODS: We performed a retrospective analysis of 61 patients using volumetric data of tumor compartments of 61 patients obtained by preoperative magnetic resonance images using the visual ABC/2 method. Preoperative enhancing, nonenhancing, necrosis, and edema volume, the preoperative tumor area (TA) as a product of the 2 largest tumor diameters perpendicular to each other on axial T1-weighted postcontrast images, as well as postoperative enhancing residual volumes, were measured. Multivariable Cox proportional hazard models were used to associate these parameters with overall survival, adjusting for potential confounders. RESULTS: The median preoperative enhancing tumor volume was 18.2 mL (interquartile range, 8.2-41.7 mL); the median remnant tumor volume was 1.3% (interquartile range, 0.0%-42.9%). During follow-up, 59 patients (92%) died; median survival time and median follow-up time were both 404 days. We found a statistically significant multiplicative effect of TA on survival: the hazard ratio (HR) was increased by 1.096 per unit increase of 200 mm2 (95% confidence interval [CI], 1.027-1.170; P < 0.01). The effect of remnant tumor on HR increased multiplicatively by 1.013 (95% CI, 1.001-1.026; P = 0.04) per unit increase of 1 log (day) and 1% in tumor remnant. HR associated with age at surgery increased by 1.503 per 5 years of age (95% CI, 1.243-1.817; P < 0.01). CONCLUSIONS: Preoperative TA proved to be the only glioblastoma size parameter that affects patient survival.
Asunto(s)
Neoplasias Encefálicas/mortalidad , Glioblastoma/mortalidad , Recurrencia Local de Neoplasia/patología , Neoplasia Residual/patología , Anciano , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/cirugía , Femenino , Glioblastoma/patología , Glioblastoma/cirugía , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Neoplasia Residual/mortalidad , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Carga TumoralRESUMEN
Microsatellite instability (MSI) is the phenotypic hallmark of a deficient DNA mismatch-repair system, observed in 10-20% of sporadic colorectal cancers (CRC). Since the prognostic and predictive value of this genetic alteration has been assessed mainly in non-randomised, uncontrolled studies, we investigated the potential of MSI to predict patient survival and response to adjuvant chemotherapy in tumour specimens from a randomised trial of the Swiss Group for Clinical Cancer Research (SAKK) that tested the value of 5-fluorouracil/mitomycin adjuvant chemotherapy. MSI status was determined in matched normal and tumour tissue samples from 160 patients using a panel of 9 microsatellite markers. There was no correlation between high frequency MSI (MSI-H) and overall (OS) or disease-free survival (DFS) in the untreated control group of patients (HR=1.13, p=0.80; and HR=0.89, p=0.81, respectively). Furthermore, MSI-H phenotype did not predict for a larger benefit of adjuvant chemotherapy on OS or DFS (HR=0.49, p=0.41; HR=0.49, p=0.41, respectively), making a potential value of this molecular marker as a predictive factor in CRC unlikely. Our data do not confirm the prognostic relevance of MSI-H status in colorectal cancer patients found in some other studies. In addition, microsatellite instability did not correlate with the extent of chemotherapy benefit, although we observed a statistically non-significant favourable impact of 5-FU-based treatment in the MSI-H group compared to MSI-L/MSS patients. Larger prospective randomised trials are required to conclusively establish a potential clinical significance of MSI in colorectal cancer.
Asunto(s)
Neoplasias Colorrectales/patología , Repeticiones de Microsatélite/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia Adyuvante , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , ADN de Neoplasias/análisis , ADN de Neoplasias/genética , Femenino , Fluorouracilo/administración & dosificación , Humanos , Masculino , Metaanálisis como Asunto , Persona de Mediana Edad , Mitomicina/administración & dosificación , Análisis Multivariante , Pronóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Literatura de Revisión como Asunto , Análisis de SupervivenciaRESUMEN
In the brain, Notch signaling maintains normal neural stem cells, but also brain cancer stem cells, indicating an oncogenic role. Here, we identify an unexpected tumor suppressor function for Notch in forebrain tumor subtypes. Genetic inactivation of RBP-Jκ, a key Notch mediator, or Notch1 and Notch2 receptors accelerates PDGF-driven glioma growth in mice. Conversely, genetic activation of the Notch pathway reduces glioma growth and increases survival. In humans, high Notch activity strongly correlates with distinct glioma subtypes, increased patient survival, and lower tumor grade. Additionally, simultaneous inactivation of RBP-Jκ and p53 induces primitive neuroectodermal-like tumors in mice. Hence, Notch signaling cooperates with p53 to restrict cell proliferation and tumor growth in mouse models of human brain tumors.
Asunto(s)
Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Células Madre Neoplásicas/metabolismo , Células-Madre Neurales/metabolismo , Prosencéfalo/metabolismo , Receptores Notch/metabolismo , Transducción de Señal , Proteínas Supresoras de Tumor/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Proliferación Celular , Bases de Datos Genéticas , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Técnicas de Transferencia de Gen , Glioma/genética , Glioma/mortalidad , Glioma/patología , Humanos , Proteína de Unión a la Señal Recombinante J de las Inmunoglobulinas/genética , Proteína de Unión a la Señal Recombinante J de las Inmunoglobulinas/metabolismo , Infusiones Intraventriculares , Estimación de Kaplan-Meier , Ratones Noqueados , Clasificación del Tumor , Células Madre Neoplásicas/patología , Células-Madre Neurales/patología , Fenotipo , Factor de Crecimiento Derivado de Plaquetas/administración & dosificación , Prosencéfalo/patología , Proteínas Proto-Oncogénicas c-sis/genética , Proteínas Proto-Oncogénicas c-sis/metabolismo , Receptor Notch1/genética , Receptor Notch1/metabolismo , Receptor Notch2/genética , Receptor Notch2/metabolismo , Receptores Notch/genética , Proteínas Recombinantes/administración & dosificación , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Factores de Tiempo , Carga Tumoral , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor/genéticaRESUMEN
BACKGROUND: Improved risk stratification of early colorectal cancer might help to better select patients for adjuvant treatment. Alterations in the transforming growth factor-beta (TGF-beta) pathway have frequently been found in colorectal cancer, but their impact on prognosis remains controversial. We therefore analyzed two transcriptional corepressors of the TGF-beta signaling pathway with respect to prognosis and prediction of chemotherapy benefit in early colorectal cancer. METHODS: The gene copy status of SKI and SNON was analyzed by use of quantitative real-time polymerase chain reaction in 179 colorectal tumor biopsies, which had been collected from a randomized multicenter trial of the Swiss Group for Clinical Cancer Research (SAKK). RESULTS: Partial or complete allelic loss was found in 41.5% and 55.2% for SKI and SNON, whereas amplification was found in 10.1% and 15.1%, respectively. Multivariate Cox analysis showed that gene amplification of SKI independently predicted reduced relapse-free [hazard ratio (HR) for relapse 2.08, P =.049] and overall survival (HR for death 2.62, P =.012). In contrast, deletion of SKI and the gene copy status of SNON were not significantly correlated with prognosis. CONCLUSION: Amplification of SKI is a negative prognostic marker in early-stage colorectal cancer. This marker should help to improve risk stratification to better select patients for adjuvant therapy. Confirmatory investigations are warranted.
Asunto(s)
Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Proteínas de Unión al ADN/genética , Amplificación de Genes/genética , Proteínas Proto-Oncogénicas/genética , Adulto , Anciano , Biomarcadores de Tumor , Diagnóstico Precoz , Femenino , Humanos , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
BACKGROUND: Molecular predictors for the effectiveness of adjuvant chemotherapy in colorectal cancer are of considerable clinical interest. To this aim, we analyzed the serine threonine receptor-associated protein (STRAP), an inhibitor of TGF-beta signaling, with regard to prognosis and prediction of adjuvant 5-FU chemotherapy benefit. METHODS: The gene copy status of STRAP was determined using quantitative real-time polymerase chain reaction in 166 colorectal tumor biopsies, which had been collected from a randomized multicenter trial of 5-fluorouracil (5-FU)/mitomycin C (MMC) adjuvant chemotherapy of the Swiss Group for Clinical Cancer Research (SAKK). RESULTS: Amplification of STRAP was found in 22.8% of the tumors. When left without adjuvant chemotherapy, patients bearing tumors with a STRAP amplification had a significantly better prognosis (hazard ratio for death: 0.26; P=.004). Interestingly, these patients, when receiving adjuvant treatment, had a worse survival (hazard ratio for death: 3.48; P=.019) than without chemotherapy, whereas patients carrying tumors with diploidy or deletion of STRAP benefited from the treatment (hazard ratio for death: 0.44; P=.052). This suggests the amplification of STRAP as a strong predictor of an unfavorable effect of 5-FU-based adjuvant chemotherapy. CONCLUSION: If confirmed, the STRAP gene copy status might provide a parameter to decide about the use of 5-FU-based adjuvant chemotherapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/análisis , Proteínas Portadoras/biosíntesis , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Antimetabolitos Antineoplásicos/uso terapéutico , Proteínas Portadoras/genética , Quimioterapia Adyuvante , Neoplasias Colorrectales/mortalidad , Femenino , Fluorouracilo/uso terapéutico , Dosificación de Gen , Humanos , Masculino , Persona de Mediana Edad , Mitomicina/uso terapéutico , Reacción en Cadena de la Polimerasa , PronósticoRESUMEN
The objective of the present project was to design and validate a method for teleoperating (from an expert site) an echographic examination in an isolated site. A dedicated robotic arm holding a real ultrasound (US) probe is remotely controlled from the expert site with a fictive probe, and reproduces on the real probe all the movements of the expert hand. The isolated places, defined as areas with reduced medical facilities, could be secondary hospitals 20 to 50 km from the university hospital, or dispensaries in Africa or Amazonia, or a moving structure like a rescue vehicle or the International Space Station (ISS). These sites are linked to the expert one by ISDN (numeric) telephone or satellite lines. At the expert center, the US medical expert moves a fictive probe, connected to a computer (no. 1) that sends the coordinate changes of this probe via an ISDN or satellite line to a second computer (no. 2), located at the isolated site, that applies them to the robotic arm holding the real echographic probe. The system was tested on 20 patients. In all cases, the expert was able to perform the main views (longitudinal, transverse) of the liver, gallbladder, kidneys, aorta, pancreas, bladder, prostate and uterus as during direct examination on the patient. The heart and spleen were not visualized in 2 and 4 of the 20 cases, respectively. The mean duration of the robotized echography (27 +/- 7 min for three to four organs) was approximately 50% longer than direct echography of the patient.
Asunto(s)
Robótica , Telemetría/métodos , Ultrasonografía/métodos , Diseño de Equipo , Humanos , Consulta Remota , Sensibilidad y Especificidad , Telemetría/instrumentación , Teléfono , Ultrasonografía/instrumentaciónRESUMEN
BACKGROUND: Low-grade gliomas (LGGs) are rare brain neoplasms, with survival spanning up to a few decades. Thus, accurate evaluations on how biomarkers impact survival among patients with LGG require long-term studies on samples prospectively collected over a long period. METHODS: The 210 adult LGGs collected in our databank were screened for IDH1 and IDH2 mutations (IDHmut), MGMT gene promoter methylation (MGMTmet), 1p/19q loss of heterozygosity (1p19qloh), and nuclear TP53 immunopositivity (TP53pos). Multivariate survival analyses with multiple imputation of missing data were performed using either histopathology or molecular markers. Both models were compared using Akaike's information criterion (AIC). The molecular model was reduced by stepwise model selection to filter out the most critical predictors. A third model was generated to assess for various marker combinations. RESULTS: Molecular parameters were better survival predictors than histology (ΔAIC = 12.5, P< .001). Forty-five percent of studied patients died. MGMTmet was positively associated with IDHmut (P< .001). In the molecular model with marker combinations, IDHmut/MGMTmet combined status had a favorable impact on overall survival, compared with IDHwt (hazard ratio [HR] = 0.33, P< .01), and even more so the triple combination, IDHmut/MGMTmet/1p19qloh (HR = 0.18, P< .001). Furthermore, IDHmut/MGMTmet/TP53pos triple combination was a significant risk factor for malignant transformation (HR = 2.75, P< .05). CONCLUSION: By integrating networks of activated molecular glioma pathways, the model based on genotype better predicts prognosis than histology and, therefore, provides a more reliable tool for standardizing future treatment strategies.
Asunto(s)
Metilación de ADN , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Glioblastoma/mortalidad , Isocitrato Deshidrogenasa/genética , Mutación/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor/genética , Adolescente , Adulto , Anciano , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/clasificación , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidad , Núcleo Celular/metabolismo , Terapia Combinada , ADN de Neoplasias/genética , Femenino , Estudios de Seguimiento , Glioblastoma/clasificación , Glioblastoma/genética , Humanos , Técnicas para Inmunoenzimas , Pérdida de Heterocigocidad , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Regiones Promotoras Genéticas/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Tasa de Supervivencia , Adulto JovenRESUMEN
Loss of heterozygosity (LOH) of the entire chromosome 10 is the most frequent genetic alteration in human glioblastoma (GBM). In addition to PTEN/MMAC1 on 10q23.3, clustering of partial deletion break-points on 10q25.3-26.1 points to a second suppressor locus. The proposed target gene DMBT1 was not confirmed. By somatic deletion mapping of this region, we identified the complementary DNA encoding the human homologue of rat orphan G protein-coupled receptor GPR26. GPR26 is highly expressed in fetal and adult brain, but frequently reduced or absent in glioma cells and biopsies, due to de novo methylation of its 5' CpG island. Silencing of GPR26 was reversed with 5-aza-deoxycytidine and the histone deacetylase inhibitor trichostatin A. Furthermore, overexpression of GPR26 in HEK and in U87 glioma cells increased intracellular cAMP concentration which is considered to induce astrocytic differentiation. Interestingly, we observed concomitant silencing of GPR26 with O6-methylguanine-DNA methyl transferase (MGMT), a DNA repair gene co-localized on 10q25.3-26.1 (p=0.0001). We conclude that epigenetic silencing is a common mechanism in malignant gliomas that simultaneously inactivates MGMT and GPR26. The 10q25.3-26.1 region may contain an important epigenetic pathway in brain tumorigenesis.