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BACKGROUND: KEAP1 mutations have been associated with reduced survival in lung adenocarcinoma (LUAD) patients treated with immune checkpoint inhibitors (ICIs), particularly in the presence of STK11/KRAS alterations. We hypothesized that, beyond co-occurring genomic events, clonality prediction may help identify deleterious KEAP1 mutations and their counterparts with retained sensitivity to ICIs. PATIENTS AND METHODS: Beta-binomial modelling of sequencing read counts was used to infer KEAP1 clonal inactivation by combined somatic mutation and loss of heterozygosity (KEAP1 C-LOH) versus partial inactivation [KEAP1 clonal diploid-subclonal (KEAP1 CD-SC)] in the Memorial Sloan Kettering Cancer Center (MSK) MetTropism cohort (N = 2550). Clonality/LOH prediction was compared to a streamlined clinical classifier that relies on variant allele frequencies (VAFs) and tumor purity (TP) (VAF/TP ratio). The impact of this classification on survival outcomes was tested in two independent cohorts of LUAD patients treated with immunotherapy (MSK/Rome N = 237; DFCI N = 461). Immune-related features were studied by exploiting RNA-sequencing data (TCGA) and multiplexed immunofluorescence (DFCI mIF cohort). RESULTS: Clonality/LOH inference in the MSK MetTropism cohort overlapped with a clinical classification model defined by the VAF/TP ratio. In the ICI-treated MSK/Rome discovery cohort, predicted KEAP1 C-LOH mutations were associated with shorter progression-free survival (PFS) and overall survival (OS) compared to KEAP1 wild-type cases (PFS log-rank P = 0.001; OS log-rank P < 0.001). Similar results were obtained in the DFCI validation cohort (PFS log-rank P = 0.006; OS log-rank P = 0.014). In both cohorts, we did not observe any significant difference in survival outcomes when comparing KEAP1 CD-SC and wild-type tumors. Immune deconvolution and multiplexed immunofluorescence revealed that KEAP1 C-LOH and KEAP1 CD-SC differed for immune-related features. CONCLUSIONS: KEAP1 C-LOH mutations are associated with an immune-excluded phenotype and worse clinical outcomes among advanced LUAD patients treated with ICIs. By contrast, survival outcomes of patients whose tumors harbored KEAP1 CD-SC mutations were similar to those with KEAP1 wild-type LUADs.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/patología , Proteína 1 Asociada A ECH Tipo Kelch/genética , Factor 2 Relacionado con NF-E2/genética , Mutación , Pérdida de Heterocigocidad , InmunoterapiaRESUMEN
Human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase receptor that promotes tumor cell growth and is implicated in the pathogenesis of human breast cancer. The role of HER2 in canine mammary carcinomas (CMCs) is not clear. Therefore, this study aimed to examine the protein expression and cytogenetic changes of HER2 and their correlation with other clinical-pathological parameters in CMC. We retrospectively selected 112 CMCs. HER2, ER, and Ki67 were assessed by immunohistochemistry. HER2 antibody validation was investigated by immunoblot on mammary tumor cell lines. Fluorescence in situ hybridization (FISH) was performed with probes for HER2 and CRYBA1 (control gene present on CFA9). HER2 protein overexpression was detected in 15 carcinomas (13.5%). A total of 90 carcinomas were considered technically adequate by FISH, and 8 out of 90 CMC (10%) were HER2 amplified, 3 of which showed a cluster-type pattern. HER2 overexpression was correlated with an increased number of HER2 gene copies (p = 0.01; R = 0.24) and overall survival (p = 0.03), but no correlation with ER, Ki67, grade, metastases, and tumor-specific survival was found. Surprisingly, co-amplification or polysomy was identified in three tumors, characterized by an increased copy number of both HER2 and CRYBA1. A morphological translocation-fusion pattern was recognized in 20 carcinomas (22%), with a co-localized signal of HER2 and CRYBA1. HER2 is not associated with clinical-pathological parameters of increased malignancy in canine mammary tumors, but it is suitable for studying different amplification patterns.
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Introducción y objetivos Los octogenarios representan el segmento de población de más rápida expansión en Europa; la prevalencia de la insuficiencia cardiaca (IC) en este grupo supera el 10%. Se evaluaron los cambios en las características clínicas, el tratamiento y los resultados a un año durante dos décadas en pacientes ambulatorios con IC crónica de edad ≥ 80 años incluidos en un registro nacional de cardiología. Métodos Se incluyó a 2 520 octogenarios con mediciones de la fracción de eyección ecocardiográfica basal y seguimiento a 1 año disponibles, inscritos en 138 clínicas ambulatorias de IC (21% de los hospitales nacionales con unidades de cardiología), reclutados a lo largo de tres épocas (1999-2005, 2006-2011, 2012-2018). Resultados En el momento de la inclusión, a lo largo de los 3 periodos de estudio, aumentaron la edad, el índice de masa corporal, la fracción de eyección, la prevalencia de obesidad, diabetes, dislipemia, hipertensión preexistente y la historia de fibrilación auricular. La proporción de pacientes con fracción de eyección conservada aumentó del 19,4% al 32,7% (p de tendencia <0,0001). Los marcadores de enfermedad avanzada se hicieron menos prevalentes. La prescripción de bloqueadores beta y antagonistas de los receptores de mineralocorticoides aumentó con el tiempo. Durante el seguimiento a un año, 308 pacientes fallecieron (12,2%) y 360 (14,3%) fueron ingresados por causas cardiovasculares; en total, 591 (23,5%) alcanzaron el objetivo primario combinado de mortalidad por todas las causas u hospitalización cardiovascular. Mediante un análisis multivariable ajustado, la inclusión en 2006-2011 (HR=0,70; IC95%, 0,55-0,90; p=0,004) y 2012-2018 (HR=0,61; IC95%, 0,47-0,79; p=0,0002), conllevó un menor riesgo del resultado primario que la inclusión en el periodo 1999-2005. Conclusiones Entre los octogenarios, a lo largo de 2 décadas, la prevalencia de los factores de riesgo aumentó (AU)
Introduction and objectives Octogenarians represent the most rapidly expanding population segment in Europe. The prevalence of heart failure (HF) in this group exceeds 10%. We assessed changes in clinical characteristics, therapy, and 1-year outcomes over 2 decades in chronic HF outpatients aged ≥ 80 years enrolled in a nationwide cardiology registry. Methods We included 2520 octogenarians with baseline echocardiographic ejection fraction measurements and available 1-year follow-up, who were recruited at 138 HF outpatient clinics (21% of national hospitals with cardiology units), across 3 enrolment periods (1999-2005, 2006-2011, 2012-2018).Result At recruitment, over the 3 study periods, there was an increase in age, body mass index, ejection fraction, the prevalence of obesity, diabetes, dyslipidemia, pre-existing hypertension, and atrial fibrillation history. The proportion of patients with preserved ejection fraction rose from 19.4% to 32.7% (P for trend <.0001). Markers of advanced disease became less prevalent. Prescription of beta-blockers and mineralocorticoid receptor antagonists increased over time. During the 1-year follow-up, 308 patients died (12.2%) and 360 (14.3%) were admitted for cardiovascular causes; overall, 591 (23.5%) met the combined primary endpoint of all-cause mortality or cardiovascular hospitalization. On adjusted multivariable analysis, enrolment in 2006 to 2011 (HR, 0.70; 95%CI, 0.55-0.90; P=.004) and 2012 to 2018 (HR, 0.61; 95%CI, 0.47-0.79; P=.0002) carried a lower risk of the primary outcome than recruitment in 1999 to 2005. Conclusions Among octogenarians, over 2 decades, risk factor prevalence increased, management strategies improved, and survival remained stable, but the proportion hospitalized for cardiovascular causes declined. Despite increasing clinical complexity, in cardiology settings the burden of hospitalizations in the oldest old with chronic HF is declining (AU)
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Humanos , Masculino , Femenino , Anciano de 80 o más Años , Insuficiencia Cardíaca/terapia , Insuficiencia Cardíaca/mortalidad , Resultado del Tratamiento , Estudios de Seguimiento , Enfermedad Crónica , Ecocardiografía , PronósticoRESUMEN
Cellular adaptation to a hypoxic microenvironment is essential for tumour progression and is largely mediated by HIF-1α and hypoxia-regulated factors, including CXCR4, VEGF-A and GLUT-1. In human osteosarcoma, hypoxia is associated with resistance to chemotherapy as well as with metastasis and poor survival, whereas little is known about its role in canine osteosarcoma (cOSA). This study aimed primarily to evaluate the prognostic value of several known hypoxic markers in cOSA. Immunohistochemical analysis for HIF-1α, CXCR4, VEGF-A and GLUT-1 was performed on 56 appendicular OSA samples; correlations with clinicopathological features and outcome was investigated. The second aim was to investigate the in vitro regulation of markers under chemically induced hypoxia (CoCl2). Two primary canine osteosarcoma cell lines were selected, and Western blotting, immunofluorescence and qRT-PCR were used to study protein and gene expression. Dogs with high-grade OSA (35.7%) were more susceptible to the development of metastases (P = 0.047) and showed high HIF-1α protein expression (P = 0.007). Moreover, HIF-1α overexpression (56%) was correlated with a shorter disease-free interval (DFI; P = 0.01), indicating that it is a reliable negative prognostic marker. The in vitro experiments identified an accumulation of HIF-1α in cOSA cells after chemically induced hypoxia, leading to a significant increase in GLUT-1 transcript (P = 0.02). HIF-1α might be a promising prognostic marker, highlighting opportunities for the use of therapeutic strategies targeting the hypoxic microenvironment in cOSA. These results reinforce the role of the dog as a comparative animal model since similar hypoxic mechanisms are reported in human osteosarcoma.
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Neoplasias Óseas/veterinaria , Hipoxia de la Célula/fisiología , Enfermedades de los Perros/fisiopatología , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/fisiología , Osteosarcoma/veterinaria , Animales , Biomarcadores de Tumor/análisis , Neoplasias Óseas/química , Neoplasias Óseas/fisiopatología , Línea Celular Tumoral , Enfermedades de los Perros/patología , Perros , Femenino , Regulación Neoplásica de la Expresión Génica , Transportador de Glucosa de Tipo 1/análisis , Subunidad alfa del Factor 1 Inducible por Hipoxia/análisis , Inmunohistoquímica/veterinaria , Masculino , Metástasis de la Neoplasia/fisiopatología , Osteosarcoma/química , Osteosarcoma/fisiopatología , Pronóstico , Receptores CXCR4/análisis , Factor A de Crecimiento Endotelial Vascular/análisisRESUMEN
BACKGROUND: Immune checkpoint inhibitors (ICIs) have demonstrated significant overall survival (OS) benefit in lung adenocarcinoma (LUAD). Nevertheless, a remarkable interpatient heterogeneity characterizes immunotherapy efficacy, regardless of programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB). KEAP1 mutations are associated with shorter survival in LUAD patients receiving chemotherapy. We hypothesized that the pattern of KEAP1 co-mutations and mutual exclusivity may identify LUAD patients unresponsive to immunotherapy. PATIENTS AND METHODS: KEAP1 mutational co-occurrences and somatic interactions were studied in the whole MSKCC LUAD dataset. The impact of coexisting alterations on survival outcomes in ICI-treated LUAD patients was verified in the randomized phase II/III POPLAR/OAK trials (blood-based sequencing, bNGS cohort, N = 253). Three tissue-based sequencing studies (Rome, MSKCC and DFCI) were used for independent validation (tNGS cohort, N = 289). Immunogenomic features were analyzed using The Cancer Genome Atlas (TCGA) LUAD study. RESULTS: On the basis of KEAP1 mutational co-occurrences, we identified four genes potentially associated with reduced efficacy of immunotherapy (KEAP1, PBRM1, SMARCA4 and STK11). Independent of the nature of co-occurring alterations, tumors with coexisting mutations (CoMut) had inferior survival as compared with single-mutant (SM) and wild-type (WT) tumors (bNGS cohort: CoMut versus SM log-rank P = 0.048, CoMut versus WT log-rank P < 0.001; tNGS cohort: CoMut versus SM log-rank P = 0.037, CoMut versus WT log-rank P = 0.006). The CoMut subset harbored higher TMB than the WT disease and the adverse significance of coexisting alterations was maintained in LUAD with high TMB. Significant immunogenomic differences were observed between the CoMut and WT groups in terms of core immune signatures, T-cell receptor repertoire, T helper cell signatures and immunomodulatory genes. CONCLUSIONS: This study indicates that coexisting alterations in a limited set of genes characterize a subset of LUAD unresponsive to immunotherapy and with high TMB. An immune-cold microenvironment may account for the clinical course of the disease.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/terapia , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Humanos , Inmunoterapia , Proteína 1 Asociada A ECH Tipo Kelch/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Mutación , Factor 2 Relacionado con NF-E2 , Ensayos Clínicos Controlados Aleatorios como Asunto , Microambiente TumoralRESUMEN
Breast cancer (BC) is a complex disease with primary or acquired incurability characteristics in a significant part of patients. Immunotherapeutical agents represent an emerging option for breast cancer treatment, including the human epidermal growth factor 2 positive (HER2+) subtype. The immune system holds the ability to spontaneously implement a defensive response against HER2+ BC cells through complex mechanisms which can be exploited to modulate this response for obtaining a clinical benefit. Initial immune system modulating strategies consisted mostly in vaccine therapies, which are still being investigated and improved. However, the entrance of trastuzumab into the scenery of HER2+ BC treatment was the real game changing event, which embodied a dominant immune-mediated mechanism. More recently, the advent of the immune checkpoint inhibitors has caused a new paradigm shift for immuno-oncology, with promising initial results also for HER2+ BC. Breast cancer has been traditionally considered poorly immunogenic, being characterized by relatively low tumor mutation burden (TMB). Nevertheless, recent evidence has revealed high tumor infiltrating lymphocytes (TILs) and programmed cell death-ligand 1 (PD-L1) expression in a considerable proportion of HER2+ BC patients. This may translate into a higher potential to elicit anti-cancer response and, therefore, wider possibilities for the use and implementation of immunotherapy in this subset of BC patients. We are herein presenting and critically discussing the most representative evidence concerning immunotherapy in HER2+ BC cancer, both singularly and in combination with therapeutic agents acting throughout HER2-block, immune checkpoint inhibition and anti-cancer vaccines. The reader will be also provided with hints concerning potential future projection of the most promising immutherapeutic agents and approaches for the disease of interest.
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Neoplasias de la Mama/terapia , Predisposición Genética a la Enfermedad , Inmunoterapia , Receptor ErbB-2/genética , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/genética , Femenino , HumanosRESUMEN
Aberrant Hedgehog/GLI signaling has been implicated in a diverse spectrum of human cancers, but its role in lung adenocarcinoma (LAC) is still under debate. We show that the downstream effector of the Hedgehog pathway, GLI1, is expressed in 76% of LACs, but in roughly half of these tumors, the canonical pathway activator, Smoothened, is expressed at low levels, possibly owing to epigenetic silencing. In LAC cells including the cancer stem cell compartment, we show that GLI1 is activated noncanonically by MAPK/ERK signaling. Different mechanisms can trigger the MAPK/ERK/GLI1 cascade including KRAS mutation and stimulation of NRP2 by VEGF produced by the cancer cells themselves in an autocrine loop or by stromal cells as paracrine cross talk. Suppression of GLI1, by silencing or drug-mediated, inhibits LAC cells proliferation, attenuates their stemness and increases their susceptibility to apoptosis in vitro and in vivo. These findings provide insight into the growth of LACs and point to GLI1 as a downstream effector for oncogenic pathways. Thus, strategies involving direct inhibition of GLI1 may be useful in the treatment of LACs.
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Adenocarcinoma/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/metabolismo , Células Madre Neoplásicas/metabolismo , Proteína con Dedos de Zinc GLI1/metabolismo , Adenocarcinoma/patología , Animales , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Femenino , Humanos , Neoplasias Pulmonares/patología , Ratones , Ratones SCID , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Células Madre Neoplásicas/patología , Neuropilina-2/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Piridinas/farmacología , Pirimidinas/farmacología , Interferencia de ARN/fisiología , ARN Interferente Pequeño/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Proteína con Dedos de Zinc GLI1/antagonistas & inhibidores , Proteína con Dedos de Zinc GLI1/genéticaRESUMEN
Canine osteosarcoma is highly resistant to current chemotherapy; thus, clarifying the mechanisms of tumor cell resistance to treatments is an urgent need. We tested the geldanamycin derivative 17-AAG (17-allylamino-17-demethoxygeldanamycin) prototype of Hsp90 (heat shock protein 90) inhibitors in 2 canine osteosarcoma cell lines, D22 and D17, derived from primary and metastatic tumors, respectively. With the aim to understand the interplay between cell death, autophagy, and mitophagy, in light of the dual effect of autophagy in regulating cancer cell viability and death, D22 and D17 cells were treated with different concentrations of 17-AAG (0.5 µM, 1 µM) for 24 and 48 hours. 17-AAG-induced apoptosis, necrosis, autophagy, and mitophagy were assessed by transmission electron microscopy, flow cytometry, and immunofluorescence. A simultaneous increase in apoptosis, autophagy, and mitophagy was observed only in the D22 cell line, while D17 cells showed low levels of apoptotic cell death. These results reveal differential cell response to drug-induced stress depending on tumor cell type. Therefore, pharmacological treatments based on proapoptotic chemotherapy in association with autophagy regulators would benefit from a predictive in vitro screening of the target cell type.
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Antineoplásicos/farmacología , Benzoquinonas/farmacología , Neoplasias Óseas/veterinaria , Enfermedades de los Perros/patología , Lactamas Macrocíclicas/farmacología , Osteosarcoma/veterinaria , Animales , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Benzoquinonas/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/patología , Línea Celular Tumoral , Enfermedades de los Perros/tratamiento farmacológico , Perros , Relación Dosis-Respuesta a Droga , Lactamas Macrocíclicas/uso terapéutico , Microscopía Electrónica de Transmisión/veterinaria , Mitofagia/efectos de los fármacos , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/patologíaRESUMEN
Although a significant subset of prostate tumors remain indolent during the entire life, the advanced forms are still one of the leading cause of cancer-related death. There are not reliable markers distinguishing indolent from aggressive forms. Here we highlighted a new molecular circuitry involving microRNA and coding genes promoting cancer progression and castration resistance. Our preclinical and clinical data demonstrated that c-Met activation increases miR-130b levels, inhibits androgen receptor expression, promotes cancer spreading and resistance to hormone ablation therapy. The relevance of these findings was confirmed on patients' samples and by in silico analysis on an independent patient cohort from Taylor's platform. Data suggest c-Met/miR-130b axis as a new prognostic marker for patients' risk assessment and as an indicator of therapy resistance. Our results propose new biomarkers for therapy decision-making in all phases of the pathology. Data may help identify high-risk patients to be treated with adjuvant therapy together with alternative cure for castration-resistant forms while facilitating the identification of possible patients candidates for anti-Met therapy. In addition, we demonstrated that it is possible to evaluate Met/miR-130b axis expression in exosomes isolated from peripheral blood of surgery candidates and advanced patients offering a new non-invasive tool for active surveillance and therapy monitoring.
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Biomarcadores de Tumor/genética , MicroARNs/genética , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata/genética , Proteínas Proto-Oncogénicas c-met/genética , Animales , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Progresión de la Enfermedad , Xenoinjertos , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , MicroARNs/metabolismo , Neoplasias de la Próstata/enzimología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/enzimología , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Proteínas Proto-Oncogénicas c-met/metabolismoRESUMEN
Canine malignant melanoma (CMM) is the most common canine oral tumour, and up to 70-75% of dogs in stage II-III die within 1 year after surgery. The purpose of this study was to evaluate the expression of platelet-derived growth factors receptors (PDGFR)-α and -ß in stage II and III CMMs and to correlate it with prognosis. PDGFRs expression was evaluated by immunohistochemistry on 48 cases of formalin-fixed CMM samples and correlated with clinical-pathological findings and outcome after surgery. PDGFRs co-expression was observed in 37.5% of cases. Positivity for PDGFR-α and -ß receptor was present in 54.2 and 47.9% of cases, respectively. Ki67 values >19.5% were ascertained in 66.7% of cases. Statistical analysis showed that PDGFRs co-expression and Ki67 values > 19.5% were both associated with worse prognosis. PDGFRs expression suggests a role in the pathogenesis and progression of CMM, and α and ß co-expression appears to be associated to worse prognosis.
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Enfermedades de los Perros/metabolismo , Melanoma/veterinaria , Neoplasias de la Boca/veterinaria , Receptores del Factor de Crecimiento Derivado de Plaquetas/metabolismo , Animales , Enfermedades de los Perros/diagnóstico , Enfermedades de los Perros/mortalidad , Perros , Femenino , Regulación Neoplásica de la Expresión Génica , Masculino , Melanoma/diagnóstico , Melanoma/metabolismo , Melanoma/mortalidad , Neoplasias de la Boca/diagnóstico , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/mortalidad , Pronóstico , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Análisis de SupervivenciaRESUMEN
Reported post-surgery 1-year survival rate for oral canine malignant melanoma (cMM) is around 30%; novel treatments are needed as the role of adjuvant chemotherapy is unclear. This prospective study regards adjuvant electrovaccination with human chondroitin sulfate proteoglycan-4 (hCSPG4)-encoded plasmid in 23 dogs with resected II/III-staged CSPG4-positive oral cMM compared with 19 dogs with resected only II/III-staged CSPG4-positive oral cMM. Vaccination resulted in 6-, 12-, 18- and 24-month survival rate of 95.6, 73.9, 47.8 and 30.4%, respectively [median survival time (MST) 684 days, range 78-1694, 8 of 23 dogs alive] and 6-, 12-, 18- and 24-month disease-free interval (DFI) rate of 82.6, 47.8, 26.1 and 17.4%, respectively (DFI 477 days, range 50-1694). Non-vaccinated dogs showed 6-, 12-, 18- and 24-month survival rate of 63.2, 26.3, 15.8 and 5.3%, respectively (MST 200 days, range 75-1507, 1 of 19 dogs alive) and 6-, 12-, 18- and 24-month DFI rate of 52.6, 26.3, 10.5 and 5.3%, respectively (DFI 180 days, range 38-1250). Overall survival and DFI of vaccinated dogs was longer in those <20 kg. In vaccinated and non-vaccinated dogs local recurrence rate was 34.8 and 42%, respectively while lung metastatic rate was 39 and 79%, respectively.
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Proteoglicanos Tipo Condroitín Sulfato/inmunología , Enfermedades de los Perros/terapia , Melanoma/veterinaria , Neoplasias de la Boca/veterinaria , Adyuvantes Inmunológicos/uso terapéutico , Animales , Vacunas contra el Cáncer/uso terapéutico , Terapia Combinada , Enfermedades de los Perros/mortalidad , Perros , Femenino , Masculino , Melanoma/mortalidad , Melanoma/terapia , Neoplasias de la Boca/mortalidad , Neoplasias de la Boca/terapiaRESUMEN
Human papillomavirus (HPV) is widely known as a cause of cervical cancer (CC) and cervical intraepithelial neoplasia (CIN). HPVs related to cancer express two main oncogenes, i.e. E6 and E7, considered as tumorigenic genes; their integration into the host genome results in the abnormal regulation of cell cycle control. Due to their peculiarities, these oncogenes represent an excellent target for cancer immunotherapy. In this work the authors highlight the potential use of therapeutic vaccines as safe and effective pharmacological tools in cervical disease, focusing on vaccines that have reached the clinical trial phase. Many therapeutic HPV vaccines have been tested in clinical trials with promising results. Adoptive T-cell therapy showed clinical activity in a phase II trial involving advanced CC patients. A phase II randomized trial showed clinical activity of a nucleic acid-based vaccine in HPV16 or HPV18 positive CIN. Several trials involving peptide-protein-based vaccines and live-vector based vaccines demonstrated that these approaches are effective in CIN as well as in advanced CC patients. HPV therapeutic vaccines must be regarded as a therapeutic option in cervical disease. The synergic combination of HPV therapeutic vaccines with radiotherapy, chemotherapy, immunomodulators or immune checkpoint inhibitors opens a new and interesting scenario in this disease.
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Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/inmunología , Infecciones por Papillomavirus/complicaciones , Neoplasias del Cuello Uterino/terapia , Ensayos Clínicos como Asunto , Descubrimiento de Drogas/tendencias , Femenino , HumanosRESUMEN
Glioblastoma (GBM) is one of the deadliest human cancers. Because of the extremely unfavorable prognosis of GBM, it is important to develop more effective diagnostic and therapeutic strategies based on biologically and clinically relevant subclassification systems. Analyzing a collection of seventeen patient-derived glioblastoma stem-like cells (GSCs) by gene expression profiling, NMR spectroscopy and signal transduction pathway activation, we identified two GSC clusters, one characterized by a pro-neural-like phenotype and the other showing a mesenchymal-like phenotype. Evaluating the levels of proteins differentially expressed by the two GSC clusters in the TCGA GBM sample collection, we found that SRC activation is associated with a GBM subgroup showing better prognosis whereas activation of RPS6, an effector of mTOR pathway, identifies a subgroup with a worse prognosis. The two clusters are also differentiated by NMR spectroscopy profiles suggesting a potential prognostic stratification based on metabolic evaluation. Our data show that the metabolic/proteomic profile of GSCs is informative of the genomic/proteomic GBM landscape, which differs among tumor subtypes and is associated with clinical outcome.
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Regulación Neoplásica de la Expresión Génica , Glioblastoma/metabolismo , Glioblastoma/mortalidad , Proteínas de Neoplasias/biosíntesis , Células Madre Neoplásicas/metabolismo , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Resonancia Magnética Nuclear Biomolecular , Proteómica , Tasa de SupervivenciaRESUMEN
Although the development of bone metastasis is a major detrimental event in prostate cancer, the molecular mechanisms responsible for bone homing and destruction remain largely unknown. Here we show that loss of miR-15 and miR-16 in cooperation with increased miR-21 expression promote prostate cancer spreading and bone lesions. This combination of microRNA endows bone-metastatic potential to prostate cancer cells. Concomitant loss of miR-15/miR-16 and gain of miR-21 aberrantly activate TGF-ß and Hedgehog signaling, that mediate local invasion, distant bone marrow colonization and osteolysis by prostate cancer cells. These findings establish a new molecular circuitry for prostate cancer metastasis that was validated in patients' cohorts. Our data indicate a network of biomarkers and druggable pathways to improve patient treatment.
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Biomarcadores de Tumor/biosíntesis , Neoplasias Óseas/genética , MicroARNs/biosíntesis , Neoplasias de la Próstata/genética , Animales , Neoplasias Óseas/patología , Neoplasias Óseas/secundario , Línea Celular Tumoral , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , Proteínas Hedgehog/biosíntesis , Humanos , Masculino , MicroARNs/genética , Invasividad Neoplásica/genética , Neoplasias de la Próstata/patología , Transducción de Señal/genética , Factor de Crecimiento Transformador beta/biosíntesisRESUMEN
Recent investigations in thyroid carcinogenesis have led to the isolation and characterisation of a subpopulation of stem-like cells, responsible for tumour initiation, progression and metastasis. Nevertheless, the cellular origin of thyroid cancer stem cells (SCs) remains unknown and it is still necessary to define the process and the target population that sustain malignant transformation of tissue-resident SCs or the reprogramming of a more differentiated cell. Here, we will critically discuss new insights into thyroid SCs as a potential source of cancer formation in light of the available information on the oncogenic role of genetic modifications that occur during thyroid cancer development. Understanding the fine mechanisms that regulate tumour transformation may provide new ground for clinical intervention in terms of prevention, diagnosis and therapy.
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Transformación Celular Neoplásica/patología , Células Madre Neoplásicas/patología , Glándula Tiroides/patología , Neoplasias de la Tiroides/patología , HumanosRESUMEN
Human Mena (hMENA), an actin regulatory protein of the ENA/VASP family, cooperates with ErbB receptor family signaling in breast cancer. It is overexpressed in high-risk preneoplastic lesions and in primary breast tumors where it correlates with HER2 overexpression and an activated status of AKT and MAPK. The concomitant overexpression of hMENA and HER2 in breast cancer patients is indicative of a worse prognosis. hMENA is expressed along with alternatively expressed isoforms, hMENA(11a) and hMENAΔv6 with opposite functions. A novel role for the epithelial-associated hMENA(11a) isoform in sustaining HER3 activation and pro-survival pathways in HER2-overexpressing breast cancer cells has been identified by reverse phase protein array and validated in vivo in a series of breast cancer tissues. As HER3 activation is crucial in mechanisms of cell resistance to PI3K inhibitors, we explored whether hMENA(11a) is involved in these resistance mechanisms. The specific hMENA(11a) depletion switched off the HER3-related pathway activated by PI3K inhibitors and impaired the nuclear accumulation of HER3 transcription factor FOXO3a induced by PI3K inhibitors, whereas PI3K inhibitors activated hMENA(11a) phosphorylation and affected its localization. At the functional level, we found that hMENA(11a) sustains cell proliferation and survival in response to PI3K inhibitor treatment, whereas hMENA(11a) silencing increases molecules involved in cancer cell apoptosis. As shown in three-dimensional cultures, hMENA(11a) contributes to resistance to PI3K inhibition because its depletion drastically reduced cell viability upon treatment with PI3K inhibitor BEZ235. Altogether, these results indicate that hMENA(11a) in HER2-overexpressing breast cancer cells sustains HER3/AKT axis activation and contributes to HER3-mediated resistance mechanisms to PI3K inhibitors. Thus, hMENA(11a) expression can be proposed as a marker of HER3 activation and resistance to PI3K inhibition therapies, to select patients who may benefit from these combined targeted treatments. hMENA(11a) activity could represent a new target for antiproliferative therapies in breast cancer.
Asunto(s)
Neoplasias de la Mama/genética , Resistencia a Antineoplásicos/genética , Proteínas de Microfilamentos/metabolismo , Receptor ErbB-3/genética , Antineoplásicos/farmacología , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Electroforesis en Gel Bidimensional , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Inmunohistoquímica , Proteínas de Microfilamentos/genética , Inhibidores de las Quinasa Fosfoinosítidos-3 , Isoformas de Proteínas , Inhibidores de Proteínas Quinasas/farmacología , ARN Interferente Pequeño , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor ErbB-2/genética , TransfecciónRESUMEN
Stemness was recently depicted as a dynamic condition in normal and tumor cells. We found that the embryonic protein Cripto-1 (CR1) was expressed by normal stem cells at the bottom of colonic crypts and by cancer stem cells (CSCs) in colorectal tumor tissues. CR1-positive populations isolated from patient-derived tumor spheroids exhibited increased clonogenic capacity and expression of stem-cell-related genes. CR1 expression in tumor spheroids was variable over time, being subject to a complex regulation of the intracellular, surface and secreted protein, which was related to changes of the clonogenic capacity at the population level. CR1 silencing induced CSC growth arrest in vitro with a concomitant decrease of Src/Akt signaling, while in vivo it inhibited the growth of CSC-derived tumor xenografts and reduced CSC numbers. Importantly, CR1 silencing in established xenografts through an inducible expression system decreased CSC growth in both primary and metastatic tumors, indicating an essential role of CR1 in the regulation the CSC compartment. These results point to CR1 as a novel and dynamically regulated effector of stem cell functions in colorectal cancer.
Asunto(s)
Neoplasias Colorrectales/metabolismo , Proteínas Ligadas a GPI/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteínas de Neoplasias/metabolismo , Células Madre Neoplásicas/metabolismo , Animales , Neoplasias Colorrectales/fisiopatología , Femenino , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/fisiología , Regulación Neoplásica de la Expresión Génica , Genes src , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/fisiología , Ratones , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/fisiología , Células Madre Neoplásicas/fisiología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Esferoides Celulares , Células Tumorales CultivadasRESUMEN
Tyrosine kinase inhibitors (TKIs) have shown strong activity against non-small-cell lung cancer (NSCLC) patients harboring activating epidermal growth factor receptor (EGFR) mutations. However, a fraction of EGFR wild-type (WT) patients may have an improvement in terms of response rate and progression-free survival when treated with erlotinib, suggesting that factors other than EGFR mutation may lead to TKI sensitivity. However, at present, no sufficiently robust clinical or biological parameters have been defined to identify WT-EGFR patients with greater chances of response. Therapeutics validation has necessarily to focus on lung cancer stem cells (LCSCs) as they are more difficult to eradicate and represent the tumor-maintaining cell population. Here, we investigated erlotinib response of lung CSCs with WT-EGFR and identified EGFR phosphorylation at tyrosine1068 (EGFRtyr1068) as a powerful biomarker associated with erlotinib sensitivity both in vitro and in preclinical CSC-generated xenografts. In contrast to the preferential cytotoxicity of chemotherapy against the more differentiated cells, in EGFRtyr1068 cells, erlotinib was even more active against the LCSCs compared with their differentiated counterpart, acquiring potential value as CSC-directed therapeutics in the context of WT-EGFR lung cancer. Although tumor growth was inhibited to a similar extent during erlotinib or chemotherapy administration to responsive tumors, erlotinib proved superior to chemotherapy in terms of higher tolerability and reduced tumor aggressiveness after treatment suspension, substantiating the possibility of preferential LCSC targeting, both in adenocarcinoma (ADC) and squamous cell carcinoma (SCC) tumors. We conclude that EGFRtyr1068 may represent a potential candidate biomarker predicting erlotinib response at CSC-level in EGFR-WT lung cancer patients. Finally, besides its invariable association with erlotinib sensitivity in EGFR-WT lung CSCs, EGFRtyr1068 was associated with EGFR-sensitizing mutations in cell lines and patient tumors, with relevant diagnostic, clinical and therapeutic implications.
Asunto(s)
Antineoplásicos/farmacología , Receptores ErbB/genética , Clorhidrato de Erlotinib/farmacología , Regulación Neoplásica de la Expresión Génica , Células Madre Neoplásicas/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Anciano , Animales , Apoptosis/efectos de los fármacos , Biomarcadores Farmacológicos/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Receptores ErbB/metabolismo , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones SCID , Persona de Mediana Edad , Estadificación de Neoplasias , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Transducción de Señal , Tirosina/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoAsunto(s)
Cardiomiopatía Dilatada/terapia , Epinefrina/administración & dosificación , Edema Pulmonar/terapia , Choque Cardiogénico/terapia , Adulto , Cardiomiopatía Dilatada/diagnóstico por imagen , Cardiomiopatía Dilatada/fisiopatología , Cardiotónicos/administración & dosificación , Cesárea , Terapia Combinada , Progresión de la Enfermedad , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Edad Gestacional , Humanos , Contrapulsador Intraaórtico/métodos , Periodo Periparto , Edema Pulmonar/diagnóstico por imagen , Edema Pulmonar/fisiopatología , Radiografía Torácica , Medición de Riesgo , Choque Cardiogénico/diagnóstico , Factores de Tiempo , Resultado del Tratamiento , Remodelación Ventricular/fisiologíaRESUMEN
Metastatic growth in breast cancer (BC) has been proposed as an exclusive property of cancer stem cells (CSCs). However, formal proof of their identity as cells of origin of recurrences at distant sites and the molecular events that may contribute to tumor cell dissemination and metastasis development are yet to be elucidated. In this study, we analyzed a set of patient-derived breast cancer stem cell (BCSC) lines. We found that in vitro BCSCs exhibit a higher chemoresistance and migratory potential when compared with differentiated, nontumorigenic, breast cancer cells (dBCCs). By developing an in vivo metastatic model simulating the disease of patients with early BC, we observed that BCSCs is the only cell population endowed with metastatic potential. Gene-expression profile studies comparing metastagenic and non-metastagenic cells identified TAZ, a transducer of the Hippo pathway and biomechanical cues, as a central mediator of BCSCs metastatic ability involved in their chemoresistance and tumorigenic potential. Overexpression of TAZ in low-expressing dBCCs induced cell transformation and conferred tumorigenicity and migratory activity. Conversely, loss of TAZ in BCSCs severely impaired metastatic colonization and chemoresistance. In clinical data from 99 BC patients, high expression levels of TAZ were associated with shorter disease-free survival in multivariate analysis, thus indicating that TAZ may represent a novel independent negative prognostic factor. Overall, this study designates TAZ as a novel biomarker and a possible therapeutic target for BC.