RESUMEN
It is well-established that the beneficial properties of single phytonutrients can be better attained when they are taken with the complex of the molecules present in their natural milieu. Tomato, the fruit providing the most comprehensive complex of prostate-health-preserving micronutrients, has been shown to be superior to its single-nutrient counterparts in decreasing the incidence of age-related prostate diseases. Herein, we describe a novel tomato food supplement enriched with olive polyphenols, containing cis-lycopene concentrations far exceeding those present in industry-produced tomato commodities. The supplement, endowed with antioxidant activity comparable to that of N-acetylcysteine, significantly reduced, in experimental animals, the blood levels of prostate-cancer-promoting cytokines. In prospective, randomized, double-blinded, placebo-controlled studies performed on patients affected by benign prostatic hyperplasia, its uptake significantly improved urinary symptoms and quality of life. Therefore, this supplement can complement and, in some cases, be an alternative to current benign prostatic hyperplasia management. Furthermore, the product suppressed carcinogenesis in the TRAMP mouse model of human prostate cancer and interfered with prostate cancer molecular signaling. Thus, it may offer a step forward in exploring the potential of tomato consumption to delay or prevent the onset of age-related prostate diseases in high-risk individuals.
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Hiperplasia Prostática , Neoplasias de la Próstata , Solanum lycopersicum , Masculino , Ratones , Animales , Humanos , Hiperplasia Prostática/prevención & control , Próstata , Carotenoides , Estudios Prospectivos , Calidad de Vida , Dieta , Neoplasias de la Próstata/prevención & control , Neoplasias de la Próstata/epidemiología , HipertrofiaRESUMEN
BACKGROUND: Platelet dysfunctions are shared by cardiovascular diseases and a wide range of inflammatory diseases. AIMS: To determine the ability of a new whole tomato-based food supplement (WTBFS) containing carotenoid and olive polyphenols to inhibit platelet aggregation. METHODS: Aggregation was evaluated in platelet-rich plasma using microtiter plates and a plate reader. RESULTS: Platelets treated with WTBFS showed a >70% reduction of 5 µM adenosine diphosphate (ADP)-induced platelet aggregation; at 10 µM of ADP, the inhibitory effect of WTBFS was reduced of about 50%. Similarly, 78% and 48% reduction were obtained using 5 µg/mL and 10 µg /mL of collagen as an agonist. CONCLUSION: Since the compounds in WTBFS share the ability to inhibit STAT3, the inhibition of its signaling pathway may represent the mechanism underlying the antiplatelet activities. The activity of a lipophilic solution prepared from WTBS was in vitro tested on the platelet aggregation in response to ADP agonists and Collagen.
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Olea , Solanum lycopersicum , Humanos , Inhibidores de Agregación Plaquetaria/farmacología , Agregación Plaquetaria/fisiología , Colágeno/farmacología , Suplementos Dietéticos , Nutrientes , Adenosina Difosfato/farmacologíaRESUMEN
Trop-2 is a transmembrane signal transducer that is overexpressed in most human cancers, and drives malignant progression. To gain knowledge on the higher-order molecular mechanisms that drive Trop-2 signaling, we applied next-generation sequencing, proteomics, and high-resolution microscopy to models and primary cases of human colorectal cancer (CRC). We had previously shown that Trop-2 induces a Ca2+ signal. We reveal here that Trop-2 binds the cell membrane Na+/K+-ATPase, and that clustering of Trop-2 induces an intracellular Ca2+ rise followed by membrane translocation of PKCα, which in turn phosphorylates the Trop-2 cytoplasmic tail. This feed-forward signaling is promoted by the binding of Trop-2 to the PKCα membrane-anchor CD9. CRISPR-based inactivation of CD9 in CRC cells shows that CD9 is required by Trop-2 for recruiting PKCα and cofilin-1 to the cell membrane. This induces malignant progression through proteolytic cleavage of E-cadherin, remodeling of the ß-actin cytoskeleton, and activation of Akt and ERK. The interaction between Trop-2 and CD9 was validated in vivo in murine models of CRC growth and invasion. Overexpression of the components of this Trop-2-driven super-complex significantly worsened disease-free and overall survival of CRC patients, supporting a pivotal relevance in CRC malignant progression. Our findings demonstrate a previously unsuspected layer of cancer growth regulation, which is dormant in normal tissues, and is activated by Trop-2 in cancer cells.
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Neoplasias Colorrectales , Proteína Quinasa C-alfa , Factores Despolimerizantes de la Actina/metabolismo , Adenosina Trifosfatasas/metabolismo , Animales , Neoplasias Colorrectales/patología , Humanos , Ratones , Proteína Quinasa C-alfa/genética , Proteína Quinasa C-alfa/metabolismo , Transducción de Señal , Tetraspanina 29RESUMEN
We recently reported that activation of Trop-2 through its cleavage at R87-T88 by ADAM10 underlies Trop-2-driven progression of colon cancer. However, the mechanism of action and pathological impact of Trop-2 in metastatic diffusion remain unexplored. Through searches for molecular determinants of cancer metastasis, we identified TROP2 as unique in its up-regulation across independent colon cancer metastasis models. Overexpression of wild-type Trop-2 in KM12SM human colon cancer cells increased liver metastasis rates in vivo in immunosuppressed mice. Metastatic growth was further enhanced by a tail-less, activated ΔcytoTrop-2 mutant, indicating the Trop-2 tail as a pivotal inhibitory signaling element. In primary tumors and metastases, transcriptome analysis showed no down-regulation of CDH1 by transcription factors for epithelial-to-mesenchymal transition, thus suggesting that the pro-metastatic activity of Trop-2 is through alternative mechanisms. Trop-2 can tightly interact with ADAM10. Here, Trop-2 bound E-cadherin and stimulated ADAM10-mediated proteolytic cleavage of E-cadherin intracellular domain. This induced detachment of E-cadherin from ß-actin, and loss of cell-cell adhesion, acquisition of invasive capability, and membrane-driven activation of ß-catenin signaling, which were further enhanced by the ΔcytoTrop-2 mutant. This Trop-2/E-cadherin/ß-catenin program led to anti-apoptotic signaling, increased cell migration, and enhanced cancer-cell survival. In patients with colon cancer, activation of this Trop-2-centered program led to significantly reduced relapse-free and overall survival, indicating a major impact on progression to metastatic disease. Recently, the anti-Trop-2 mAb Sacituzumab govitecan-hziy was shown to be active against metastatic breast cancer. Our findings define the key relevance of Trop-2 as a target in metastatic colon cancer.
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Proteína ADAM10/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Antígenos CD/metabolismo , Antígenos de Neoplasias/metabolismo , Cadherinas/metabolismo , Moléculas de Adhesión Celular/metabolismo , Neoplasias del Colon/metabolismo , Transición Epitelial-Mesenquimal/fisiología , Perfilación de la Expresión Génica/métodos , Proteínas de la Membrana/metabolismo , Proteína ADAM10/genética , Secretasas de la Proteína Precursora del Amiloide/genética , Animales , Antígenos CD/genética , Antígenos de Neoplasias/genética , Cadherinas/genética , Moléculas de Adhesión Celular/genética , Neoplasias del Colon/genética , Femenino , Células HCT116 , Células HT29 , Humanos , Proteínas de la Membrana/genética , Ratones , Ratones Desnudos , Ratones Transgénicos , Tasa de Supervivencia/tendencias , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
BACKGROUND: Benign prostatic hyperplasia (BPH) is the most common urologic disease among elderly men. The diagnosis of BPH is usually driven by lower urinary tract symptoms (LUTS) that can significantly affect patients' quality of life. This phase II prospective, randomized double-blinded, placebo-controlled study aimed to determine the efficacy and safety of a novel whole tomato-based food supplement on LUTS of patients diagnosed with BPH. METHODS: Forty consecutive patients with histologically proved BPH were randomized 1:1 to receive daily for 2 months a sachet (5 g) of a newly developed whole tomato food supplement (WTFS) (treatment = Group A) or placebo (Group B). Patients were asked to fill the International Prostatic Symptom Score (IPSS) questionnaire before and after treatment. RESULTS: All but 1 patient in Group B successfully completed the scheduled regimen. No side effects were recorded. Unlike placebo, treatment significantly reduced (P < 0.0002) LUTS since mean IPSS decreased from 9.05 ± 1.15 to 7.15 ± 1.04 (paired t-test, two-tailed P-value < 0.001), and improved life quality (P < 0.0001). A trend toward a reduction of total PSA levels was observed in WTFS treated patients (8.98 ng/mL ± 1.52 vs 6.95 ± 0.76, P = 0.065), with changes being statistically significant only in the subgroup of patients with baseline levels above 10 ng/mL (18.5 ng/mL ± 2.7 vs 10.3 ± 2.1, P = 0.009). CONCLUSIONS: The new WTFS may represent a valid option for the treatment of symptomatic BPH patients. Unlike pharmacological treatments, the supplement is side effects free and highly accepted among patients.
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Hiperplasia Prostática , Solanum lycopersicum , Sistema Urinario , Anciano , Suplementos Dietéticos , Humanos , Hiperplasia , Masculino , Estudios Prospectivos , Hiperplasia Prostática/complicaciones , Hiperplasia Prostática/tratamiento farmacológico , Calidad de Vida , Resultado del TratamientoRESUMEN
BACKGROUND: Phospholipase Cγ1 (PLCγ1) is highly expressed in human tumours. Our previous studies reported that both stable and inducible PLCγ1 down-regulation can inhibit formation of breast-cancer-derived experimental lung metastasis. Further, high expression of PLCγ1 and its constitutively activated forms (i.e., PLCγ1-pY1253, PLCγ1-pY783) is associated with worse clinical outcome in terms of incidence of distant metastases, but not of local relapse in T1-T2, N0 breast cancer patients. METHODS: In the present retrospective study, we analysed the prognostic role of PLCγ1 in early breast cancer patients stratified according to the St. Gallen criteria and to their menopausal status. PLCγ1-pY1253 and PLCγ1-pY783 protein expression levels were determined by immunohistochemistry on tissue microarrays, and were correlated with patients' clinical data, using univariate and multivariate statistical analyses. RESULTS: In our series, the prognostic value of PLCγ1 overexpression was restricted to Luminal type tumours. From multivariate analyses, pY1253-PLCγ1High was an independent prognostic factor only in postmenopausal patients with Luminal-B tumours (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.1-5.3; P = 0.034). Conversely, PLCγ1-pY783High was a remarkably strong risk factor (HR, 20.1; 95% CI, 2.2-178.4; P = 0.003) for pre/perimenopausal patients with Luminal-A tumours. CONCLUSIONS: PLCγ1 overexpression is a strong predictive surrogate marker of development of metastases in early Luminal-A and -B breast cancer patients, being able to discriminate patients with high and low risk of metastases. Therefore, targeting the PLCγ1 pathway can be considered of potential benefit for prevention of metastatic disease.
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Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Fosfolipasa C gamma/metabolismo , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Anciano , Biomarcadores de Tumor/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Antígeno Ki-67/metabolismo , Menopausia/fisiología , Persona de Mediana Edad , Análisis Multivariante , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Fosforilación , Pronóstico , Modelos de Riesgos Proporcionales , Estudios RetrospectivosRESUMEN
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and is not a clinically homogeneous disease, but subsets of patients with distinct prognosis and response to therapy can be identified by genome-wide analyses. Mutations in major PDAC driver genes were associated with poor survival. By bioinformatics analysis, we identified protocadherins among the most frequently mutated genes in PDAC suggesting an important role of these genes in the biology of this tumor. Promoter methylation of protocadherins has been suggested as a prognostic marker in different tumors, but in PDAC this epigenetic modification has not been extensively studied. Thus, we evaluated whether promoter methylation of three frequently mutated protocadherins, PCDHAC2, PCDHGC5 and PCDH10 could be used as survival predictors in PDAC patients. METHODS: DNA extracted from 23 PDACs and adjacent non-neoplastic pancreatic tissues were bisulfite treated. Combined Bisulfite Restriction Analysis (COBRA) coupled to denaturing high-performance liquid chromatography (dHPLC) detection and bisulfite genomic sequencing (BGS) were used to determine the presence of methylated CpG dinucleotides in the promoter amplicons analyzed. RESULTS: In an exploratory analysis, two protocadherins showed the same pattern of CpG methylation in PDAC and adjacent non-neoplastic pancreatic tissues: lack of methylation for PCDHAC2, complete methylation for PCDHGC5. Conversely, the third protocadherin analyzed, PCDH10, showed a variable degree of CpG methylation in PDAC and absence of methylation in adjacent non-neoplastic pancreatic tissues. At Kaplan-Meier analysis, high levels of PCDH10 methylation defined according to the receiver operating characteristic (ROC) curve analysis were significantly associated with worse progression-free survival (PFS) rates (P = 0.008), but not with overall survival (OS). High levels of PCDH10 methylation were a prognostic factor influencing PFS (HR = 4.0: 95% CI, 1.3-12.3; P = 0.016), but not the OS. CONCLUSIONS: In this study, we show for the first time that the methylation status of PCDH10 can predict prognosis in PDAC patients with a significant impact on the outcome in terms of progression-free survival. High levels of PCDH10 promoter methylation could be useful to identify patients at high risk of disease progression, contributing to a more accurate stratification of PDAC patients for personalized clinical management.
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Cadherinas/genética , Carcinoma Ductal Pancreático/genética , Metilación de ADN , Neoplasias Pancreáticas/genética , Adulto , Anciano , Islas de CpG , Epigénesis Genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Regiones Promotoras Genéticas , Protocadherinas , Curva ROC , Análisis de Secuencia de ADN , Análisis de SupervivenciaRESUMEN
Galectin-3-binding protein (Gal-3BP) has been identified as a cancer and metastasis-associated, secreted protein that is expressed by the large majority of cancers. The present study describes a special type of non-internalizing antibody-drug-conjugates that specifically target Gal-3BP. Here, we show that the humanized 1959 antibody, which specifically recognizes secreted Gal-3BP, selectively localized around tumor but not normal cells. A site specific disulfide linkage with thiol-maytansinoids to unpaired cysteine residues of 1959, resulting in a drug-antibody ratio of 2, yielded an ADC product, which cured A375m melanoma bearing mice. ADC products based on the non-internalizing 1959 antibody may be useful for the treatment of several human malignancies, as the cognate antigen is abundantly expressed and secreted by several cancers, while being present at low levels in most normal adult tissues.
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Antígenos de Neoplasias/inmunología , Biomarcadores de Tumor/inmunología , Inmunoconjugados/uso terapéutico , Neoplasias/terapia , Animales , Línea Celular Tumoral , Femenino , Humanos , Inmunoconjugados/farmacocinética , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias/inmunología , Neoplasias/metabolismo , Neoplasias/patología , ConejosRESUMEN
Purpose: Non-muscle-invasive bladder cancer (NMIBC) is a malignant disease characterized by high heterogeneity, which corresponds to dysregulated gene expression and alternative splicing (AS) profiles. Bioinformatics analyses of splicing factors potentially linked to bladder cancer progression identified the heterogeneous nuclear ribonucleoprotein I (i.e., PTBP1) as candidate. This study aimed at investigating whether PTBP1 expression associates with clinical outcome in patients with NMIBC.Experimental Design: A cohort of 152 patients presenting with primary NMIBC (pTa-pT1) was enrolled. Primary NMIBCs were assessed for PTBP1 expression by IHC, and the results were correlated with clinical data using Kaplan-Meier curves and Cox regression analyses. Cell proliferation and survival assays were performed to assess the function of PTBP1. Furthermore, the impact of PTBP1 on the AS pattern of specific bladder cancer-related genes was investigated in cancer cell lines and in patients' specimens.Results: Public datasets querying highlighted a positive correlation between PTBP1 expression and NMIBC progression, which was then confirmed by IHC analysis. High PTBP1 expression was associated with worse clinical outcome in terms of incidence of tumor relapse and survival in patients with NMIBC. Interestingly, downregulation of PTBP1 in bladder cancer cell lines affected prosurvival features. Accordingly, PTBP1 modulated AS of bladder cancer-related genes in cell lines and patient's specimens.Conclusions: PTBP1 expression correlates with disease progression, poor prognosis, and worse survival in patients with NMIBC. Downregulation of PTBP1 expression affects prosurvival features of bladder cancer cells and modulates AS of genes with relevance for bladder cancer, suggesting its role as an outcome-predictor in this disease. Clin Cancer Res; 24(21); 5422-32. ©2018 AACR.
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Ribonucleoproteínas Nucleares Heterogéneas/metabolismo , Oncogenes , Proteína de Unión al Tracto de Polipirimidina/metabolismo , Empalme del ARN , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/metabolismo , Biomarcadores de Tumor , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Ribonucleoproteínas Nucleares Heterogéneas/genética , Humanos , Receptores de Hialuranos/metabolismo , Inmunohistoquímica , Informática/métodos , Masculino , Invasividad Neoplásica , Estadificación de Neoplasias , Proteína de Unión al Tracto de Polipirimidina/genética , Pronóstico , Neoplasias de la Vejiga Urinaria/mortalidad , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
Targeting different members of the Akt pathways is a promising therapeutic chance in solid tumors including breast cancer. The variable expression levels of Akt isoforms with opposite effects on tumor growth and metastasis, however, make it difficult to select the inhibitors to be used for specific breast tumor subtypes. Using in vitro and in vivo models, we demonstrated here that Vav1, ectopically expressed in invasive breast tumors derived cells, downmodulates Akt acting at expression and/or activation levels depending on tumor subtype. The decreased p-Akt1 (Ser473) levels are a common effect of Vav1 upmodulation, suggesting that, in breast tumor-derived cells and independently of their phenotype, Vav1 interferes with signaling pathways ended to specifically recruit Akt1. Only in ER-negative cell lines, the silencing of Vav1 induced the expression but not the activation of Akt2. A retrospective analysis of early invasive breast tumors allowed to establish the prognostic significance of the p-Akt/Vav1 relationship. In particular, low Vav1 levels negatively influence the follow-up of patients with low p-Akt in their primary tumors and subjected to adjuvant chemotherapy. As the use of specific or pan Akt inhibitors may not be sufficient or may even be detrimental, increasing the levels of Vav1 could be a new approach to improve breast cancer outcomes. This might be particularly relevant for tumors with a triple-negative phenotype, for which target-based therapies are not currently available.
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Neoplasias de la Mama/clasificación , Neoplasias de la Mama/metabolismo , Regulación hacia Abajo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-vav/metabolismo , Anciano , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Femenino , Silenciador del Gen , Humanos , Persona de Mediana Edad , Invasividad Neoplásica , Fenotipo , Fosforilación , Pronóstico , Resultado del Tratamiento , Neoplasias de la Mama Triple Negativas/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Breast cancer, the most common malignancy among women, is usually detected at an early stage and has a low risk of relapse. Nevertheless, a significant number of patients cannot be cured solely by local treatment. Distinguishing between patients who are of low risk of relapse from those who are of high risk may have important implications to improve treatment outcomes. The PLC-γ1 signaling pathway promotes many physiological processes, including cell migration and invasion. Increasing evidence shows aberrant PLC-γ1 signaling implication in carcinogenesis including breast cancer. In this review, the role of PLC-γ1 in breast cancer and its clinical implications will be discussed, as well as its potential as a prognostic factor and a therapeutic target.
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Frizzled receptors mediate Wnt ligand signalling, which is crucially involved in regulating tissue development and differentiation, and is often deregulated in cancer. In this study, we found that the gene encoding the Wnt receptor frizzled 6 (FZD6) is frequently amplified in breast cancer, with an increased incidence in the triple-negative breast cancer (TNBC) subtype. Ablation of FZD6 expression in mammary cancer cell lines: (1) inhibited motility and invasion; (2) induced a more symmetrical shape of organoid three-dimensional cultures; and (3) inhibited bone and liver metastasis in vivo. Mechanistically, FZD6 signalling is required for the assembly of the fibronectin matrix, interfering with the organization of the actin cytoskeleton. Ectopic delivery of fibronectin in FZD6-depleted, triple-negative MDA-MB-231 cells rearranged the actin cytoskeleton and restored epidermal growth factor-mediated invasion. In patients with localized, lymph node-negative (early) breast cancer, positivity of tumour cells for FZD6 protein identified patients with reduced distant relapse-free survival. Multivariate analysis indicated an independent prognostic significance of FZD6 expression in TNBC tumours, predicting distant, but not local, relapse. We conclude that the FZD6-fibronectin actin axis identified in our study could be exploited for drug development in highly metastatic forms of breast cancer, such as TNBC. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/metabolismo , Receptores Frizzled/genética , Recurrencia Local de Neoplasia/genética , Neoplasias de la Mama/genética , Línea Celular Tumoral , Movimiento Celular/genética , Femenino , Receptores Frizzled/metabolismo , Genómica/métodos , Humanos , Pronóstico , Transducción de Señal/genéticaRESUMEN
BACKGROUND: Traditional prognostic indicators of breast cancer, i.e. lymph node diffusion, tumor size, grading and estrogen receptor expression, are inadequate predictors of metastatic relapse. Thus, additional prognostic parameters appear urgently needed. Individual oncogenic determinants have largely failed in this endeavour. Only a few individual tumor growth drivers, e.g. mutated p53, Her-2, E-cadherin, Trops, did reach some prognostic/predictive power in clinical settings. As multiple factors are required to drive solid tumor progression, clusters of such determinants were expected to become stronger indicators of tumor aggressiveness and malignant progression than individual parameters. To identify such prognostic clusters, we went on to coordinately analyse molecular and histopathological determinants of tumor progression of post-menopausal breast cancers in the framework of a multi-institutional case series/case-control study. METHODS: A multi-institutional series of 217 breast cancer cases was analyzed. Twenty six cases (12 %) showed disease relapse during follow-up. Relapsed cases were matched with a set of control patients by tumor diameter, pathological stage, tumor histotype, age, hormone receptors and grading. Histopathological and molecular determinants of tumor development and aggressiveness were then analyzed in relapsed versus non-relapsed cases. Stepwise analyses and model structure fitness assessments were carried out to identify clusters of molecular alterations with differential impact on metastatic relapse. RESULTS: p53, Bcl-2 and cathepsin D were shown to be coordinately associated with unique levels of relative risk for disease relapse. As many Ras downstream targets, among them matrix metalloproteases, are synergistically upregulated by mutated p53, whole-exon sequence analyses were performed for TP53, Ki-RAS and Ha-RAS, and findings were correlated with clinical phenotypes. Notably, TP53 insertion/deletion mutations were only detected in relapsed cases. Correspondingly, Ha-RAS missense oncogenic mutations were only found in a subgroup of relapsing tumors. CONCLUSIONS: We have identified clusters of specific molecular alterations that greatly improve prognostic assessment with respect to singularly-analysed indicators. The combined analysis of these multiple tumor-relapse risk factors promises to become a powerful approach to identify patients subgroups with unfavourable disease outcome.
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Neoplasias de la Mama/patología , Catepsina D/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteína p53 Supresora de Tumor/genética , Anciano , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Estudios de Casos y Controles , Femenino , Redes Reguladoras de Genes , Humanos , Persona de Mediana Edad , Mutación , Pronóstico , Recurrencia , Análisis de Secuencia de ADNRESUMEN
In Apc(Min) mice (an animal model of colorectal carcinogenesis) fed a high-fat diet, low doses of resveratrol suppress intestinal adenoma development more potently than high doses do; however, these findings appear affected by multiple confounding factors, as resveratrol alone added to a standard diet has opposite outcomes.
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Adenoma , Estilbenos , Animales , Quimioprevención , Dieta Alta en Grasa , Humanos , Ratones , Ratones Endogámicos C57BL , ResveratrolRESUMEN
The present study aimed to investigate the expression of human epidermal growth factor receptors (HERs) (HER1/HER2/HER3/HER4) and their phosphorylated forms (p-HER1/p-HER2/p-HER3/p-HER4) in pulmonary carcinoids (PCs). HER and p-HER protein expression was assessed by immunohistochemistry on tissue microarrays in 37 specimens of sporadic PCs, 29 typical carcinoids (TCs) and 8 atypical carcinoids (ACs). When compared with the ACs, the TCs did not exhibit any differences in terms of HER/p-HER expression. The tumors of this study have previously been characterized for the expression of menin and the mutational status of menin 1 (MEN1), a gene strongly implicated in the pathogenesis of PCs. In the present study, it was found that the cytoplasmic ('disarrayed'), but not nuclear ('arrayed') expression of menin was positively correlated with HER3 (P=0.004), HER4 (P=0.015), p-HER1 (P=0.005), p-HER3 (P<0.001), and p-HER4 (P=0.001) expression. Moreover, HER3 and p-HER3 were found to be significantly more expressed in PCs with MEN1 variants, than in tumors with MEN1 wild-type (P=0.000 and P=0.025, respectively). These findings suggest the potential clinical use of HER inhibitors in the treatment of patients with PCs, particularly for individuals with p-HER3-positive PCs harboring MEN1 gene variants.
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PURPOSE: Inhibition of AKT is a key target area for personalized cancer medicine. However, predictive markers of response to AKT inhibitors are lacking. Correspondingly, the AKT-dependent chain of command for tumor growth, which will mediate AKT-dependent therapeutic responses, remains unclear. EXPERIMENTAL DESIGN: Proteomic profiling was utilized to identify nodal hubs of the Trop-2 cancer growth-driving network. Kinase-specific inhibitors were used to dissect Trop-2-dependent from Trop-2-independent pathways. In vitro assays, in vivo preclinical models, and case series of primary human breast cancers were utilized to define the mechanisms of Trop-2-driven growth and the mode of action of Trop-2-predicted AKT inhibitors. RESULTS: Trop-2 and AKT expression was shown to be tightly coordinated in human breast cancers, with virtual overlap with AKT activation profiles at T308 and S473, consistent with functional interaction in vivo AKT allosteric inhibitors were shown to only block the growth of Trop-2-expressing tumor cells, both in vitro and in preclinical models, being ineffective on Trop-2-null cells. Consistently, AKT-targeted siRNA only impacted on Trop-2-expressing cells. Lentiviral downregulation of endogenous Trop-2 abolished tumor response to AKT blockade, indicating Trop-2 as a mandatory activator of AKT. CONCLUSIONS: Our findings indicate that the expression of Trop-2 is a stringent predictor of tumor response to AKT inhibitors. They also support the identification of target-activatory pathways, as efficient predictors of response in precision cancer therapy. Clin Cancer Res; 22(16); 4197-205. ©2016 AACR.
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Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Resistencia a Antineoplásicos , Neoplasias/genética , Neoplasias/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Animales , Apoptosis/efectos de los fármacos , Biomarcadores , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Ratones , Neoplasias/patología , Unión Proteica , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
It is now well established that the enzymes phosphoinositide 3-kinases (PI3Ks) have a key role in the development and progression of many cancer types and indeed PI3Ks inhibitors are currently being tested in clinical trials. Although eight distinct PI3K isoforms exist, grouped into three classes, most of the evidence currently available are focused on one specific isoform with very little known about the potential role of the other members of this family in cancer. Here we demonstrate that the class II enzyme PI3K-C2ß is overexpressed in several human breast cancer cell lines and in human breast cancer specimens. Our data indicate that PI3K-C2ß regulates breast cancer cell growth in vitro and in vivo and that PI3K-C2ß expression in breast tissues is correlated with the proliferative status of the tumor. Specifically we show that downregulation of PI3K-C2ß in breast cancer cell lines reduces colony formation, induces cell cycle arrest and inhibits tumor growth, in particular in an estrogen-dependent in vivo xenograft. Investigation of the mechanism of the PI3K-C2ß-dependent regulation of cell cycle progression and cell growth revealed that PI3K-C2ß regulates cyclin B1 protein levels through modulation of microRNA miR-449a levels. Our data further demonstrate that downregulation of PI3K-C2ß inhibits breast cancer cell invasion in vitro and breast cancer metastasis in vivo. Consistent with this, PI3K-C2ß is highly expressed in lymph-nodes metastases compared to matching primary tumors. These data demonstrate that PI3K-C2ß plays a pivotal role in breast cancer progression and in metastasis development. Our data indicate that PI3K-C2ß may represent a key molecular switch that regulates a rate-limiting step in breast tumor progression and therefore it may be targeted to limit breast cancer spread.
Asunto(s)
Neoplasias de la Mama/enzimología , Fosfatidilinositol 3-Quinasas Clase II/metabolismo , Animales , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/fisiología , Fosfatidilinositol 3-Quinasas Clase II/genética , Progresión de la Enfermedad , Femenino , Xenoinjertos , Humanos , Células MCF-7 , Ratones , Ratones Desnudos , Transducción de SeñalRESUMEN
BACKGROUND: A previous report has shown that LGALS3BP (also known as 90K or Mac-2 BP) has antitumor activity in colorectal cancer (CRC) via suppression of Wnt signalling with a novel mechanism of ISGylation-dependent ubiquitination of ß-catenin. The role of LGALS3BP in CRC prognosis was investigated. METHODS: The role of LGALS3BP on CRC progression and clinical prognosis was analyzed by combining cell cultures, in vitro assays, and immunohistochemistry. RESULTS: Silencing of LGALS3BP in HCT-116 human colon cancer cells resulted in enhanced ß-catenin expression that was reversed by addition of human recombinant LGALS3BP. Moreover, intra-tumor delivery of LGALS3BP reduced tumor growth of xenografts originating from LGALS3BP-silenced HCT-116 cells. Finally, in a series of 196 CRC patients, LGALS3BP expression in tumor tissue associated with clinical outcome. Patients with high LGALS3BP expression had lower risk of relapse and a longer overall survival time than those with low LGALS3BP expression. Multivariate analyses confirmed LGALS3BP expression status as the only independent prognostic factor of survival. CONCLUSIONS: These results provide evidence that low expression of LGALS3BP participates in malignant progression of CRC and implicates poor prognosis, highlighting its augmentation as a potential therapeutic approach.
Asunto(s)
Antígenos de Neoplasias/metabolismo , Biomarcadores de Tumor/metabolismo , Proteínas Portadoras/metabolismo , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Glicoproteínas/metabolismo , Animales , Proliferación Celular , Regulación hacia Abajo , Femenino , Técnicas de Silenciamiento del Gen , Silenciador del Gen , Células HCT116 , Células HEK293 , Humanos , Inmunohistoquímica , Inyecciones Intralesiones , Estimación de Kaplan-Meier , Ratones Desnudos , Análisis Multivariante , Pronóstico , Resultado del Tratamiento , Ensayos Antitumor por Modelo de Xenoinjerto , beta Catenina/metabolismoRESUMEN
Amyloid-ß (Aß) deposition and tau-dependent pathology are key features of Alzheimer's disease (AD). However, to date, approaches aimed at counteracting these two pathogenic factors have produced only modest therapeutic outcomes. More effective therapies should therefore consider additional pathogenic factors like energy production failure, hyperexcitability and excitotoxicity, oxidative stress, deregulation of metal ion homeostasis, and neuroinflammation. Pyruvate is an energy substrate associated with neuroprotective properties. In this study, we evaluated protective effects of long-term administration of pyruvate in 3xTg-AD mice, a preclinical AD model that develops amyloid-ß- and tau-dependent pathology. Chronic (9 months) treatment with pyruvate inhibited short and long-term memory deficits in 6 and 12 months old 3xTg-AD mice as assessed with the Morris water maze test. Pyruvate had no effects on intraneuronal amyloid-ß accumulation and, surprisingly, the molecule increased deposition of phosphorylated tau. Pyruvate did not change aerobic or anaerobic metabolisms but decreased lipid peroxidation, counteracted neuronal hyperexcitability, decreased baseline levels of oxidative stress, and also reduced reactive oxygen species-driven elevations of intraneuronal Zn(2+) as well as glutamate receptor-mediated deregulation of intraneuronal Ca(2+). Thus, pyruvate promotes beneficial cognitive effects without affecting Aß and tau pathology. The molecule mainly promotes a reduction of hyperexcitability, oxidative stress while favors the regulation of intraneuronal Ca(2+) and Zn(2+) homeostasis rather than acting as energy substrate. Pyruvate can be therefore a valuable, safe, and affordable pharmacological tool to be associated with classical anti-Aß and tau drugs to counteract the development and progression of AD-related cognitive deficits and neuronal loss.