RESUMEN
PURPOSE: Recent studies demonstrate the role of the tumor microenvironment in tumor progression. However, strategies used to overcome the malignant phenotypes of cancer cells modulated by the microenvironment have not been thoroughly explored. In this study, we evaluated the therapeutic efficacy of a newly developed mAb targeting microfibril-associated protein 5 (MFAP5), which is secreted predominately by cancer-associated fibroblast (CAF), in ovarian and pancreatic cancer models.Experimental Design: MAbs were developed using human MFAP5 recombinant protein as an antigen in mice, and antibodies from hybridoma clones were evaluated for their specificity to human and murine MFAP5. An Octet RED384 system was used to determine the kinetics of binding affinity and the specificity of the antibody clones, which were followed by epitope mapping and functional characterization by in vitro assays. The therapeutic efficacy of a lead anti-MFAP5 antibody clone 130A in tumor suppression was evaluated by ovarian tumor- and pancreatic tumor-bearing mouse models. RESULTS: Three hybridoma clones, which produced antibodies with high affinity and specificity to MFAP5, were selected for functional studies. Antibody clone 130A, which recognizes a common epitope shared between human and murine MFAP5 protein, was further selected for in vivo studies. Results showed that clone 130A downregulated MFAP5-induced collagen production in CAFs, suppressed intratumoral microvessel leakiness, and enhanced paclitaxel bioavailability in both ovarian and pancreatic cancer mouse models. CONCLUSIONS: These data suggest that MFAP5 blockade using an immunologic approach inhibits fibrosis, induces tumor vessel normalization, and enhances chemosensitivity in ovarian and pancreatic cancer, and can be used as a novel therapeutic agent.
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Proteínas Contráctiles/genética , Fibrosis/tratamiento farmacológico , Péptidos y Proteínas de Señalización Intercelular/genética , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Animales , Fibroblastos Asociados al Cáncer/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proteínas Contráctiles/antagonistas & inhibidores , Progresión de la Enfermedad , Femenino , Fibrosis/genética , Fibrosis/inmunología , Fibrosis/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inmunoterapia/métodos , Ratones , Neoplasias Ováricas/genética , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Transducción de Señal/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacosRESUMEN
BACKGROUND: Bulk tumor tissue samples are used for generating gene expression profiles in most research studies, making it difficult to decipher the stroma-cancer crosstalk networks. In the present study, we describe the use of microdissected transcriptome profiles for the identification of cancer-stroma crosstalk networks with prognostic value, which presents a unique opportunity for developing new treatment strategies for ovarian cancer. METHODS: Transcriptome profiles from microdissected ovarian cancer-associated fibroblasts (CAFs) and ovarian cancer cells from patients with high-grade serous ovarian cancer (n = 70) were used as input data for the computational systems biology program CCCExplorer to uncover crosstalk networks between various cell types within the tumor microenvironment. The crosstalk analysis results were subsequently used for discovery of new indications for old drugs in ovarian cancer by computational ranking of candidate agents. Survival analysis was performed on ovarian tumor-bearing Dicer/Pten double-knockout mice treated with calcitriol, a US Food and Drug Administration-approved agent that suppresses the Smad signaling cascade, or vehicle control (9-11 mice per group). All statistical tests were two-sided. RESULTS: Activation of TGF-ß-dependent and TGF-ß-independent Smad signaling was identified in a particular subtype of CAFs and was associated with poor patient survival (patients with higher levels of Smad-regulated gene expression by CAFs: median overall survival = 15 months, 95% confidence interval [CI] = 12.7 to 17.3 months; vs patients with lower levels of Smad-regulated gene expression: median overall survival = 26 months, 95% CI = 15.9 to 36.1 months, P = .02). In addition, the activated Smad signaling identified in CAFs was found to be targeted by repositioning calcitriol. Calcitriol suppressed Smad signaling in CAFs, inhibited tumor progression in mice, and prolonged the median survival duration of ovarian cancer-bearing mice from 36 to 48 weeks (P = .04). CONCLUSIONS: Our findings suggest the feasibility of using novel multicellular systems biology modeling to identify and repurpose known drugs targeting cancer-stroma crosstalk networks, potentially leading to faster and more effective cures for cancers.
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Antineoplásicos/farmacología , Biomarcadores de Tumor/metabolismo , Fibroblastos Asociados al Cáncer/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias Ováricas/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Microambiente Tumoral/efectos de los fármacos , Biomarcadores de Tumor/genética , Fibroblastos Asociados al Cáncer/efectos de los fármacos , Fibroblastos Asociados al Cáncer/patología , Proliferación Celular , Cistadenocarcinoma Seroso/tratamiento farmacológico , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patología , Femenino , Redes Reguladoras de Genes , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Pronóstico , Transducción de Señal , Tasa de Supervivencia , Factor de Crecimiento Transformador beta/genética , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Increased number of tumor-infiltrating CD8+ lymphocytes is associated with improved survival in patients with advanced stage high grade serous ovarian cancer (HGSOC) but the underlying molecular mechanism has not been thoroughly explored. Using transcriptome profiling of microdissected HGSOC tissue with high and low CD8+ lymphocyte count and subsequent validation studies, we demonstrated that significantly increased ISG15 (Interferon-stimulated gene 15) expression in HGSOC was associated with high CD8+ lymphocyte count and with the improvement in median overall survival in both univariate and multivariate analyses. Further functional studies showed that endogenous and exogenous ISG15 suppressed ovarian cancer progression through ISGylation of ERK in HGSOC, and activation of NK cells and CD8+ T lymphocytes. These data suggest that the development of treatment strategies based on up-regulating ISG15 in ovarian cancer cells or increased circulating ISG15 in ovarian cancer patients is warranted.
RESUMEN
The molecular mechanism by which cancer-associated fibroblasts (CAFs) confer chemoresistance in ovarian cancer is poorly understood. The purpose of the present study was to evaluate the roles of CAFs in modulating tumor vasculature, chemoresistance, and disease progression. Here, we found that CAFs upregulated the lipoma-preferred partner (LPP) gene in microvascular endothelial cells (MECs) and that LPP expression levels in intratumoral MECs correlated with survival and chemoresistance in patients with ovarian cancer. Mechanistically, LPP increased focal adhesion and stress fiber formation to promote endothelial cell motility and permeability. siRNA-mediated LPP silencing in ovarian tumor-bearing mice improved paclitaxel delivery to cancer cells by decreasing intratumoral microvessel leakiness. Further studies showed that CAFs regulate endothelial LPP via a calcium-dependent signaling pathway involving microfibrillar-associated protein 5 (MFAP5), focal adhesion kinase (FAK), ERK, and LPP. Thus, our findings suggest that targeting endothelial LPP enhances the efficacy of chemotherapy in ovarian cancer. Our data highlight the importance of CAF-endothelial cell crosstalk signaling in cancer chemoresistance and demonstrate the improved efficacy of using LPP-targeting siRNA in combination with cytotoxic drugs.
Asunto(s)
Fibroblastos Asociados al Cáncer/metabolismo , Proteínas del Citoesqueleto/metabolismo , Resistencia a Antineoplásicos , Proteínas con Dominio LIM/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Animales , Línea Celular Tumoral , Movimiento Celular , Progresión de la Enfermedad , Células Endoteliales/metabolismo , Femenino , Fibrosis , Adhesiones Focales , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Humanos , Ratones , Microcirculación , Neovascularización Patológica , Permeabilidad , ARN Interferente Pequeño/metabolismo , Transducción de Señal , Resultado del Tratamiento , Regulación hacia ArribaRESUMEN
Transcription factors are master switches for various biochemical pathways. However, transcription factors involved in the pathogenesis of ovarian cancer have yet to be explored thoroughly. Therefore, in the present study, we assessed the prognostic value of the transcription factor E74-like factor 3 (ELF3) identified via transcriptome profiling of the epithelial components of microdissected ovarian tumor samples isolated from long- and short-term survivors and determined its roles in ovarian cancer pathogenesis. Immunohistochemical analysis of ELF3 in tumor tissue sections suggested that ELF3 was exclusively expressed by epithelial ovarian cancer cells. Furthermore, using 112 high-grade ovarian cancer samples isolated from patients and The Cancer Genome Atlas (TCGA) data, we found that downregulation of ELF3 expression was markedly associated with reduced survival. Functional studies demonstrated that overexpression of ELF3 in ovarian cancer cells suppressed proliferation and anchorage-dependent growth of the cells and that ELF3 silencing increased cell proliferation. Furthermore, upregulation of ELF3 increased expression of epithelial markers, decreased expression of mesenchymal markers, and mediated translocation of epithelial-mesenchymal transition (EMT) signaling molecules in ovarian cancer cells. Finally, we validated the tumor-inhibitory roles of ELF3 using animal models. In conclusion, ELF3 is a favorable prognostic marker for ovarian cancer. As a negative regulator of EMT, ELF3-modulated reversal of EMT may be a new effective modality in the treatment of ovarian cancer.
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Proteínas de Unión al ADN/genética , Transición Epitelial-Mesenquimal/genética , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Neoplasias Ováricas/genética , Proteínas Proto-Oncogénicas c-ets/genética , Factores de Transcripción/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Western Blotting , Línea Celular Tumoral , Proliferación Celular/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Perfilación de la Expresión Génica/estadística & datos numéricos , Humanos , Estimación de Kaplan-Meier , Microscopía Confocal , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Pronóstico , Modelos de Riesgos Proporcionales , Proteínas Proto-Oncogénicas c-ets/metabolismo , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sobrevivientes , Factores de Transcripción/metabolismo , Trasplante HeterólogoRESUMEN
Advanced ovarian cancer usually spreads to the visceral adipose tissue of the omentum. However, the omental stromal cell-derived molecular determinants that modulate ovarian cancer growth have not been characterized. Here, using next-generation sequencing technology, we identify significantly higher levels of microRNA-21 (miR21) isomiRNAs in exosomes and tissue lysates isolated from cancer-associated adipocytes (CAAs) and fibroblasts (CAFs) than in those from ovarian cancer cells. Functional studies reveal that miR21 is transferred from CAAs or CAFs to the cancer cells, where it suppresses ovarian cancer apoptosis and confers chemoresistance by binding to its direct novel target, APAF1. These data suggest that the malignant phenotype of metastatic ovarian cancer cells can be altered by miR21 delivered by exosomes derived from neighbouring stromal cells in the omental tumour microenvironment, and that inhibiting the transfer of stromal-derived miR21 is an alternative modality in the treatment of metastatic and recurrent ovarian cancer.
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Factor Apoptótico 1 Activador de Proteasas/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Exosomas/metabolismo , MicroARNs/metabolismo , Neoplasias Ováricas/metabolismo , Paclitaxel/farmacología , Células del Estroma/metabolismo , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Adipocitos/patología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Exosomas/efectos de los fármacos , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Invasividad Neoplásica , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Paclitaxel/uso terapéutico , Células del Estroma/efectos de los fármacosRESUMEN
Ovarian cancer is a histologically, clinically, and molecularly diverse disease with a five-year survival rate of less than 30%. It has been estimated that approximately 21,980 new cases of epithelial ovarian cancer will be diagnosed and 14,270 deaths will occur in the United States in 2015, making it the most lethal gynecologic malignancy. Ovarian tumor tissue is composed of cancer cells and a collection of different stromal cells. There is increasing evidence that demonstrates that stromal involvement is important in ovarian cancer pathogenesis. Therefore, stroma-specific signaling pathways, stroma-derived factors, and genetic changes in the tumor stroma present unique opportunities for improving the diagnosis and treatment of ovarian cancer. Cancer-associated fibroblasts (CAFs) are one of the major components of the tumor stroma that have demonstrated supportive roles in tumor progression. In this review, we highlight various types of signaling crosstalk between ovarian cancer cells and stromal cells, particularly with CAFs. In addition to evaluating the importance of signaling crosstalk in ovarian cancer progression, we discuss approaches that can be used to target tumor-promoting signaling crosstalk and how these approaches can be translated into potential ovarian cancer treatment.
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Células Madre Neoplásicas/patología , Neoplasias Ováricas/tratamiento farmacológico , Células del Estroma/citología , Ensayos Clínicos como Asunto , Progresión de la Enfermedad , Femenino , Humanos , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Comunicación Paracrina/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Células del Estroma/efectos de los fármacos , Células del Estroma/metabolismo , Microambiente Tumoral/efectos de los fármacosRESUMEN
Ovarian cancer is the most lethal gynecological malignancy. It is usually diagnosed at a late stage, with a 5-yr survival rate of <30%. The majority of ovarian cancer cases are diagnosed after tumors have widely spread within the peritoneal cavity, limiting the effectiveness of debulking surgery and chemotherapy. Owing to a substantially lower survival rate at late stages of disease than at earlier stages, the major cause of ovarian cancer deaths is believed to be therapy-resistant metastasis. Although metastasis plays a crucial role in promoting ovarian tumor progression and decreasing patient survival rates, the underlying mechanisms of ovarian cancer spread have yet to be thoroughly explored. For many years, researchers have believed that ovarian cancer metastasizes via a passive mechanism by which ovarian cancer cells are shed from the primary tumor and carried by the physiological movement of peritoneal fluid to the peritoneum and omentum. However, the recent discovery of hematogenous metastasis of ovarian cancer to the omentum via circulating tumor cells instigated rethinking of the mode of ovarian cancer metastasis and the importance of the "seed-and-soil" hypothesis for ovarian cancer metastasis. In this review we discuss the possible mechanisms by which ovarian cancer cells metastasize from the primary tumor to the omentum, the cross-talk signaling events between ovarian cancer cells and various stromal cells that play crucial roles in ovarian cancer metastasis, and the possible clinical implications of these findings in the management of this deadly, highly metastatic disease.
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Metástasis de la Neoplasia/patología , Neoplasias Glandulares y Epiteliales/patología , Células Neoplásicas Circulantes/patología , Epiplón/patología , Neoplasias Ováricas/patología , Carcinoma Epitelial de Ovario , Progresión de la Enfermedad , Femenino , Humanos , Neoplasias Glandulares y Epiteliales/mortalidad , Neoplasias Glandulares y Epiteliales/terapia , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/terapia , Neoplasias Peritoneales/patología , Pronóstico , Transducción de Señal , Células del Estroma/patología , Tasa de SupervivenciaAsunto(s)
Proteínas Contráctiles/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Glicoproteínas/metabolismo , Neoplasias Ováricas/metabolismo , Transducción de Señal , Troponina C/metabolismo , Femenino , HumanosRESUMEN
Ovarian cancer is the most lethal gynaecologic malignancy in the United States, and advanced serous ovarian adenocarcinoma is responsible for most ovarian cancer deaths. However, the stroma-derived molecular determinants that modulate patient survival are yet to be characterized. Here we identify a stromal gene signature for advanced high-grade serous ovarian cancer using microdissected stromal ovarian tumour samples and find that stromal microfibrillar-associated protein 5 (MFAP5) is a prognostic marker for poor survival. Further functional studies reveal that FAK/CREB/TNNC1 signalling pathways mediate the effect of MFAP5 on ovarian cancer cell motility and invasion potential. Targeting stromal MFAP5 using MFAP5-specific siRNA encapsulated in chitosan nanoparticles significantly decreases ovarian tumour growth and metastasis in vivo, suggesting that it may be a new modality of ovarian cancer treatment.
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Proteínas Contráctiles/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Glicoproteínas/metabolismo , Neoplasias Ováricas/metabolismo , Transducción de Señal , Troponina C/metabolismo , Actinas/metabolismo , Adenocarcinoma/metabolismo , Calcio/metabolismo , Línea Celular Tumoral , Movimiento Celular , Femenino , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Humanos , Inmunohistoquímica , Péptidos y Proteínas de Señalización Intercelular , Metástasis de la Neoplasia , Pronóstico , ARN Interferente Pequeño/metabolismo , Células del Estroma/citología , Resultado del TratamientoRESUMEN
TGF-ß has limited effects on ovarian cancer cells, but its contributions to ovarian tumor growth might be mediated through elements of the tumor microenvironment. In the present study, we tested the hypothesis that TGF modulates ovarian cancer progression by modulating the contribution of cancer-associated fibroblasts (CAF) that are present in the microenvironment. Transcriptome profiling of microdissected stromal and epithelial components of high-grade serous ovarian tumors and TGF-ß-treated normal ovarian fibroblasts identified versican (VCAN) as a key upregulated target gene in CAFs. Functional evaluations in coculture experiments showed that TGF-ß enhanced the aggressiveness of ovarian cancer cells by upregulating VCAN in CAFs. VCAN expression was regulated in CAFs through TGF-ß receptor type II and SMAD signaling. Upregulated VCAN promoted the motility and invasion of ovarian cancer cells by activating the NF-κB signaling pathway and by upregulating expression of CD44, matrix metalloproteinase-9, and the hyaluronan-mediated motility receptor. Our work identified a TGF-ß-inducible gene signature specific to CAFs in advanced high-grade serous ovarian tumors, and showed how TGF-ß stimulates ovarian cancer cell motility and invasion by upregulating the CAF-specific gene VCAN. These findings suggest insights to develop or refine strategies for TGF-ß-targeted therapy of ovarian cancer.
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Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Factor de Crecimiento Transformador beta/genética , Microambiente Tumoral/genética , Versicanos/genética , Línea Celular Tumoral , Movimiento Celular/genética , Progresión de la Enfermedad , Células Epiteliales/metabolismo , Células Epiteliales/patología , Proteínas de la Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/metabolismo , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Humanos , Receptores de Hialuranos/genética , Receptores de Hialuranos/metabolismo , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , FN-kappa B/genética , FN-kappa B/metabolismo , Invasividad Neoplásica , Neoplasias Ováricas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Receptor Tipo II de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/genética , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Transducción de Señal , Proteínas Smad/genética , Proteínas Smad/metabolismo , Células del Estroma/metabolismo , Células del Estroma/patología , Transcriptoma , Factor de Crecimiento Transformador beta/metabolismo , Regulación hacia Arriba , Versicanos/metabolismoRESUMEN
OBJECTIVES: To assess the outcome of acute ischaemic stroke patients who received intra-arterial therapy in our unit. DESIGN: Case series. SETTING: A tertiary hospital in Hong Kong. PATIENTS: Patients with ischaemic stroke due to large artery occlusion treated within 6 hours from symptom onset between January 2007 and May 2011. INTERVENTION: Acute intra-arterial revascularisation therapy. MAIN OUTCOME MEASURES: Primary outcome was functional independence (modified Rankin Scale score of ≤ 2) at 3 months. Secondary outcome was rate of recanalisation. Safety outcomes were symptomatic intracranial haemorrhage and 3-month mortality. RESULTS: Twenty-one patients with a mean age of 67 years fulfilled the inclusion criteria. Their mean National Institutes of Health Stroke Scale score was 18. The mean onset-to-puncture time was 212 minutes. Nine received intra-arterial tissue plasminogen activator alone, 11 had an adjunctive mechanical thrombectomy, and one received balloon angioplasty without tissue plasminogen activator. At the end of the procedure, thrombolysis grade 2a or better was attained in 18 (86%) of the patients, and 8 (38%) achieved functional independence at 3 months. Rates of symptomatic intracranial haemorrhage and 3-month mortality were 10% and 24%, respectively. CONCLUSION: In this setting, intra-arterial revascularisation therapy appeared safe and efficacious for this selected group of ischaemic stroke patients with large artery occlusions. Experience gained from this pilot study may help improve clinical outcomes of such patients.
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Procedimientos Endovasculares/métodos , Accidente Cerebrovascular/mortalidad , Accidente Cerebrovascular/terapia , Terapia Trombolítica/métodos , Activador de Tejido Plasminógeno/uso terapéutico , Anciano , Anciano de 80 o más Años , Angioplastia de Balón/métodos , Isquemia Encefálica/complicaciones , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/terapia , Estudios de Cohortes , Terapia Combinada , Tratamiento de Urgencia , Femenino , Estudios de Seguimiento , Hong Kong , Mortalidad Hospitalaria , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Medición de Riesgo , Índice de Severidad de la Enfermedad , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/etiología , Tasa de Supervivencia , Centros de Atención Terciaria , Trombectomía/métodos , Tomografía Computarizada por Rayos X/métodos , Resultado del TratamientoRESUMEN
PURPOSE: To evaluate the prognostic value of fibroblast growth factor receptor 4 (FGFR4) protein expression in patients with advanced-stage, high-grade serous ovarian cancer, delineate the functional role of FGFR4 in ovarian cancer progression, and evaluate the feasibility of targeting FGFR4 in serous ovarian cancer treatment. EXPERIMENTAL DESIGN: Immunolocalization of FGFR4 was conducted on 183 ovarian tumor samples. The collected FGFR4 expression data were correlated with overall survival using Kaplan-Meier and Cox regression analyses. The effects of FGFR4 silencing on ovarian cancer cell growth, survival, invasiveness, apoptosis, and FGF1-mediated signaling pathway activation were evaluated by transfecting cells with FGFR4-specific siRNAs. An orthotopic mouse model was used to evaluate the effect of injection of FGFR4-specific siRNAs and FGFR4 trap protein encapsulated in nanoliposomes on ovarian tumor growth in vivo. RESULTS: Overexpression of FGFR4 protein was significantly associated with decreased overall survival durations. FGFR4 silencing significantly decreased the proliferation, survival, and invasiveness and increased apoptosis of ovarian cancer cells. Also, downregulation of FGFR4 significantly abrogated the mitogen-activated protein kinase (MAPK), nuclear factor-κB (NF-κB), and WNT signaling pathways, which are activated by FGF1. Targeting FGFR4 with the FGFR4-specific siRNAs and FGFR4 trap protein significantly decreased ovarian tumor growth in vivo. CONCLUSIONS: FGFR4 is a prognostic marker for advanced-stage, high-grade serous ovarian carcinoma. Silencing FGFR4 and inhibiting ligand-receptor binding significantly decrease ovarian tumor growth both in vitro and in vivo, suggesting that targeting ovarian cancer cells with high levels of FGFR4 protein expression is a new therapeutic modality for this disease and will improve survival of it.
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Cistadenocarcinoma Seroso/genética , Neoplasias Ováricas/genética , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos , Animales , Apoptosis , Proliferación Celular , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patología , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Invasividad Neoplásica , Estadificación de Neoplasias , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Pronóstico , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/metabolismo , Transducción de SeñalRESUMEN
Currently, when stroke patients are offered thrombolytic therapy, their ischaemic stroke subtypes are usually unknown. Given the risk of haemorrhage that accompanies thrombolytic therapy, unselective (or undiscriminating) use of recombinant tissue plasminogen activator in patients without large-artery thromboemboli is potentially hazardous. Advances in computed tomography techniques have enabled the stroke pathophysiology to be quickly delineated by multimodal computed tomography without compromise in time for recombinant tissue plasminogen activator administration. Through description of the investigation of a typical stroke patient, we report how this technique is feasible in a regional hospital and may guide judicious use of recombinant tissue plasminogen activator.
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Isquemia Encefálica/diagnóstico por imagen , Accidente Cerebrovascular/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Anciano de 80 o más Años , Angiografía de Substracción Digital , Isquemia Encefálica/tratamiento farmacológico , Femenino , Humanos , Recuperación de la Función , Accidente Cerebrovascular/tratamiento farmacológico , Terapia Trombolítica , Activador de Tejido Plasminógeno/uso terapéuticoRESUMEN
BACKGROUND AND PURPOSE: Cerebral vasoreactivity and collateral circulation are important protective mechanisms against cerebral ischemia. Previous studies suggest that the efficiency of these mechanisms can be reflected by extracranial arterial blood flow volume. Brain damage leading to neurological impairments can influence patients' functional recovery after stroke. This study attempted to explore the potential value of post stroke extracranial arterial blood flow volume in the prediction of stroke patients' functional outcome. METHODS: We prospectively studied 362 consecutive patients who were hospitalized for recent acute strokes. All patients underwent extracranial arterial blood flow volume measurement of the carotid and vertebral arteries by color velocity imaging quantification within 3 days after admission. Their functional recovery was assessed 6 months after stroke. The effect of post stroke extracranial arterial blood flow volume on patients' functional outcome was tested by multivariate ordinal regression after controlling for other independent variables. Significance was at p<0.05. RESULTS: Post stroke extracranial arterial blood flow volume together with age, pre-stroke modified Rankin scale, the National Institutes of Health Stroke Scale and diabetes mellitus had significant effects on the patients' 6-month functional outcome as measured by the modified Rankin scale after controlling for other independent variables (p<0.05). CONCLUSIONS: Post stroke extracranial arterial blood flow volume is an independent outcome predictor. The graded predictive power of this parameter is potentially more superior than other outcome predictors by allowing classification of stroke outcome according to the degree of severity. A large prospective study is thus warranted to investigate its clinical value in the management of stroke patients.