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The role of tumor interaction with stromal components during carcinogenesis is crucial for the design of efficient cancer treatment approaches. It is widely admitted that tumor hypoxic stress is associated with tumor aggressiveness and thus impacts susceptibility and resistance to different types of treatments. Notable biological processes that hypoxia functions in include its regulation of tumor heterogeneity and plasticity. While hypoxia has been reported as a major player in tumor survival and dissemination regulation, the significance of hypoxia inducible factors in cancer stem cell development remains poorly understood. Several reports indicate that the emergence of cancer stem cells in addition to their phenotype and function within a hypoxic tumor microenvironment impacts cancer progression. In this respect, evidence showed that cancer stem cells are key elements of intratumoral heterogeneity and more importantly are responsible for tumor relapse and escape to treatments. This paper briefly reviews our current knowledge of the interaction between tumor hypoxic stress and its role in stemness acquisition and maintenance. Our review extensively covers the influence of hypoxia on the formation and maintenance of cancer stem cells and discusses the potential of targeting hypoxia-induced alterations in the expression and function of the so far known stem cell markers in cancer therapy approaches. We believe that a better and integrated understanding of the effect of hypoxia on stemness during carcinogenesis might lead to new strategies for exploiting hypoxia-associated pathways and their targeting in the clinical setting in order to overcome resistance mechanisms. More importantly, at the present time, efforts are oriented towards the design of innovative therapeutical approaches that specifically target cancer stem cells.
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Tumors use several strategies to evade the host immune response, including creation of an immune-suppressive and hostile tumor environment. Tissue hypoxia due to inadequate blood supply is reported to develop very early during tumor establishment. Hypoxic stress has a strong impact on tumor cell biology. In particular, tissue hypoxia contributes to therapeutic resistance, heterogeneity and progression. It also interferes with immune plasticity, promotes the differentiation and expansion of immune-suppressive stromal cells, and remodels the metabolic landscape to support immune privilege. Therefore, tissue hypoxia has been regarded as a central factor for tumor aggressiveness and metastasis. In this regard, manipulating host-tumor interactions in the context of the hypoxic tumor microenvironment may be important in preventing or reverting malignant conversion. We will discuss how tumor microenvironment-driven transient compositional tumor heterogeneity involves hypoxic stress. Tumor hypoxia is a therapeutic concern since it can reduce the effectiveness of conventional therapies as well as cancer immunotherapy. Thus, understanding how tumor and stromal cells respond to hypoxia will allow for the design of innovative cancer therapies that can overcome these barriers. A better understanding of hypoxia-dependent mechanisms involved in the regulation of immune tolerance could lead to new strategies to enhance antitumor immunity. Therefore, discovery and validation of therapeutic targets derived from the hypoxic tumor microenvironment is of major importance. In this context, critical hypoxia-associated pathways are attractive targets for immunotherapy of cancer. In this review, we summarize current knowledge regarding the molecular mechanisms induced by tumor cell hypoxia with a special emphasis on therapeutic resistance and immune suppression. We emphasize mechanisms of manipulating hypoxic stress and its associated pathways, which may support the development of more durable and successful cancer immunotherapy approaches in the future.
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Hipoxia de la Célula/inmunología , Inmunoterapia/métodos , Neoplasias/inmunología , Neoplasias/terapia , Animales , Humanos , Microambiente TumoralRESUMEN
In the 1990s, the application of immunotherapy approaches to target cancer cells resulted in significant clinical responses in patients with advanced malignancies who were refractory to conventional therapies. While early immunotherapeutics were focused on T cell-mediated cytotoxic activity, subsequent efforts were centered on targeted antibody-mediated anticancer therapy. The initial success with antibody therapy encouraged further studies and, consequently, there are now more than 25 FDA-approved antibodies directed against a range of targets. Although both T cell and antibody therapies continue to result in significant clinical responses with minimal toxicity, a significant subset of patients does not respond to immunotherapy and another subset develops resistance following an initial response. This review is focused on describing examples showing that cancer resistance to immunotherapies indeed occurs. In addition, it reviews the mechanisms being used to overcome the resistance to immunotherapies by targeting the tumor cell directly and/or the tumor microenvironment.
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Anticuerpos Monoclonales/inmunología , Inmunoterapia , Neoplasias/terapia , Linfocitos T Citotóxicos/inmunología , Anticuerpos Monoclonales/uso terapéutico , Resistencia a Antineoplásicos/inmunología , Humanos , Neoplasias/inmunología , Linfocitos T/inmunología , Microambiente Tumoral/inmunologíaRESUMEN
The molecular basis for the resistance of tumor cells to cell-mediated cytotoxicity remains poorly understood and thus poses a major challenge for cancer immunotherapy. The present study was designed to determine whether the WNT1-inducible signaling pathway protein 2 (WISP2, also referred to as CCN5), a key regulator of tumor cell plasticity, interferes with tumor susceptibility to cytotoxic T-lymphocyte (CTL)-mediated lysis. We found that silencing WISP2 signaling in human breast adenocarcinoma MCF7 cells impairs CTL-mediated cell killing by a mechanism involving stem cell marker Kruppel-like factor-4 (KLF-4) induction and microRNA-7 (miR-7) downregulation. Inhibition of transforming growth factor beta (TGF-ß) signaling using the A83-01 inhibitor in MCF7-shWISP2 cells resulted in a significant reversal of the epithelial-to-mesenchymal-transitioned (EMT) phenotype, the expression of KLF-4 and a partial recovery of target susceptibility to CTLs. More importantly, we showed that silencing KLF-4 was accompanied by a reduction in MCF7-shWISP2 resistance to CTLs. Using human breast cancer tissues, we demonstrated the coexpression of KLF-4 with EMT markers and TGF-ß pathway signaling components. More importantly, we found that KLF-4 expression was accompanied by miR-7 inhibition, which is partly responsible for impairing CTL-mediated lysis. Thus, our data indicate that WISP2 has a role in regulating tumor cell susceptibility through EMT by inducing the TGF-ß signaling pathway, KLF-4 expression and miR-7 inhibition. These studies indicate for the first time that WISP2 acts as an activator of CTL-induced killing and suggests that the loss of its function promotes evasion of immunosurveillance and the ensuing progression of the tumor.
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Neoplasias de la Mama/inmunología , Proteínas CCN de Señalización Intercelular/inmunología , Regulación Neoplásica de la Expresión Génica/inmunología , Inmunidad Celular , Factores de Transcripción de Tipo Kruppel/inmunología , MicroARNs/inmunología , ARN Neoplásico/inmunología , Proteínas Represoras/inmunología , Linfocitos T/inmunología , Neoplasias de la Mama/patología , Proteínas CCN de Señalización Intercelular/genética , Línea Celular Tumoral , Femenino , Humanos , Factor 4 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel/genética , MicroARNs/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/inmunología , ARN Neoplásico/genética , Proteínas Represoras/genética , Linfocitos T/patología , Vía de Señalización WntRESUMEN
BACKGROUND: Angiogenesis is essential for tumour growth and metastasis. There are conflicting reports as to whether microvessel density (MVD) using the endothelial marker CD105 (cluster of differentiation molecule 105) in clear-cell renal cell carcinomas (ccRCC) is associated with prognosis. Recently, CD105 has been described as a RCC cancer stem cell marker. METHODS: A total of 102 ccRCC were analysed. Representative tumour sections were stained for CD105. Vascularity (endothelial CD105) was quantified by MVD. The immunohistochemistry analysis detected positive (if present) or negative (if absent) CD105 tumoral staining. This retrospective population-based study was evaluated using Kaplan-Meier method, t-test and Cox proportional hazard model. RESULTS: We found that the expression of endothelial CD105 (MVD) negatively correlated with nuclear grade (P<0.001), tumour stage (P<0.001) and Leibovitch score (P<0.001), whereas the expression of tumoral CD105 positively correlated with these three clinicopathological factors (P<0.001). In multivariate analysis, tumoral CD105 was found to be an independent predictor of poor overall survival (P=0.002). CONCLUSIONS: We have shown for the first time that tumoral CD105 is an independent predictive marker for death risk and unfavourable prognosis in patients with ccRCC after curative resection.
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Antígenos CD/fisiología , Biomarcadores de Tumor/fisiología , Carcinoma de Células Renales/diagnóstico , Neoplasias Renales/diagnóstico , Receptores de Superficie Celular/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/cirugía , Endoglina , Femenino , Humanos , Neoplasias Renales/mortalidad , Neoplasias Renales/cirugía , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE: Eosinophilic gastroenteritis is a rare and heterogeneous disorder characterized by eosinophilic infiltration of one or more layers of the gastrointestinal tract. Although it can involve any part of the gastrointestinal tract, the stomach and the proximal small bowel are the most common sites of involvement. Clinical features depend on which layer and site are involved. We report eight cases of eosinophilic gastroenteritis. METHODS: We conducted a retrospective review of consecutive adult cases diagnosed with eosinophilic gastroenteritis from 1990 to 2010. The diagnosis was established by histologic examination of endoscopic biopsy or operative specimen or by the presence of eosinophilic ascites. RESULTS: Eight patients (three men, five women) were diagnosed with eosinophilic gastroenteritis during the study period. Three out of the eight patients had a history of allergy. All patients had gastrointestinal symptoms. The most common symptoms were abdominal pain, vomiting, weight loss and ascites. Seven patients (87.5%) had hypereosinophilia. Seven patients had involvement of the subserosa and one of the mucosa. Four patients were treated with oral prednisolone. The symptoms in all the patients subsided within one month. The remaining four patients improved spontaneously. Four of our patients were followed-up for at least 2 months (11 to 68 months). A single patient presented a relapse. CONCLUSION: Eosinophilic gastroenteritis should be suspected in patients having gastrointestinal discomfort along with peripheral eosinophilia. Definitive diagnosis requires histological demonstrations of eosinophilic infiltration of the gastrointestinal wall or high eosinophilic count in ascites fluid.
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Enteritis/epidemiología , Eosinofilia/epidemiología , Gastritis/epidemiología , Adolescente , Adulto , Enteritis/diagnóstico , Enteritis/terapia , Eosinofilia/diagnóstico , Eosinofilia/terapia , Femenino , Gastritis/diagnóstico , Gastritis/terapia , Humanos , Intestino Delgado/diagnóstico por imagen , Intestino Delgado/patología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Pruebas Serológicas , Estómago/diagnóstico por imagen , Estómago/patología , UltrasonografíaRESUMEN
Hepatitis C viral infection can be associated with other infectious diseases including viral and bacterial infections such as tuberculosis. Mycobacterium tuberculosis infection may be latent for many years and revealed during an immunodeficiency state. The responsibility of antiviral treatment in the reactivation of tuberculosis is controversial. We report two cases of tuberculous reactivation during bitherapy with pegylated interferon and ribavirin for chronic hepatitis C. A rapid viral response was obtained in both cases. Tuberculous reactivation occurred at 12 and 13 weeks of antiviral treatment, respectively. Tuberculosis involved urinary tract in one patient and lymph nodes in the other. Antituberculous treatment was given and antiviral treatment maintained. The outcome of tuberculosis was favourable and a sustained viral response was obtained for both patients.
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Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Polietilenglicoles/uso terapéutico , Recurrencia , Ribavirina/uso terapéutico , Antivirales/uso terapéutico , Femenino , Genotipo , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Hepacivirus/fisiología , Humanos , Interferón alfa-2 , Persona de Mediana Edad , Proteínas Recombinantes , Activación ViralRESUMEN
BACKGROUND: Peritoneal tuberculosis represents 0, 1 to 4% of all forms of tuberculosis. AIM: The aim of our study is to describe clinical, therapeutic characteristics and the outcome of peritoneal tuberculosis. METHODS: Retrospective study of all cases of peritoneal tuberculosis diagnosed in gastroenterology B department - Rabta Hospital during a 12 years period (1996 to 2007). RESULTS: Forty three cases of peritoneal tuberculosis were included: 15 male and 28 female with mean age of 38years (extremes: 16 to 85years). Five patients were cirrhotic. Clinical manifestations were dominated by ascitis (83%). Ascitic fluid were exsudative in 97% of cases and lymphocytic in all cases. The diagnostic was based on coelioscopy with peritoneal biopsy in 26 cases demonstrating caseating granulomatous lesions in 64% of cases. Extra peritoneal tuberculosis was noted in 60, 4% dominated by pleuro-pulmonary localisations. Patients were given antituberculous therapy for a mean duration of 9, 8 months and the outcome was favourable in 93%. CONCLUSION: Peritoneal tuberculosis is still a medical problem in Tunisia. It is more common in young female. Diagnosis is based on the results of peritoneal biopsies during celioscopy. The outcome is good in most cases after antituberculous treatment.
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Peritonitis Tuberculosa/diagnóstico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antituberculosos/uso terapéutico , Ascitis/microbiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Peritonitis Tuberculosa/tratamiento farmacológico , Peritonitis Tuberculosa/epidemiología , Estudios Retrospectivos , Adulto JovenRESUMEN
Accumulating evidence indicates that the innate and adaptive immune systems participate in the recognition and destruction of cancer cells by a process known as cancer immunosurveillance. Tumor antigen-specific cytotoxic T-lymphocytes (CTL) are the major effectors in the immune response against tumor cells. The identification of tumor-associated antigen (TAA) recognized primarily by CD 8(+) T-lymphocytes has led to the development of several vaccination strategies that induce or potentiate specific immune responses. However, large established tumors, which are associated with the acquisition of tumor resistance to specific lysis, are usually not fully controlled by the immune system. Recently, it has become clear that the immune system not only protects the host against tumor development but also sculpts the immunogenic phenotype of a developing tumor and can favor the emergence of resistant tumor cell variants. Moreover, it has become obvious that the evasion of immunosurveillance by tumor cells is under the control of the tumor microenvironment complexity and plasticity. In this review, we will focus on some new mechanisms associated with the acquisition of tumor resistance to specific lysis during tumor progression, involving genetic instability, structural changes in cytoskeleton, and hypoxic stress. We will also discuss the interaction between CTLs and tumor endothelial cells, a major component of tumor stroma.
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Muerte Celular/inmunología , Citoesqueleto/inmunología , Vigilancia Inmunológica , Neoplasias/inmunología , Linfocitos T Citotóxicos/inmunología , Animales , Antígenos de Neoplasias/inmunología , Comunicación Celular/inmunología , Tejido Conectivo/inmunología , Tejido Conectivo/patología , Citoesqueleto/patología , Células Endoteliales/inmunología , Células Endoteliales/patología , Humanos , Inmunidad Innata , Ratones , Neoplasias/patologíaRESUMEN
INTRODUCTION: Sarcoidosis is a granulomatous disorder of unknown cause, characterised by noncaseating granulomas affecting multiple organs. Gastrointestinal tract involvement in sarcoidosis is rare. The stomach, particularly the antrum is the most common extra-hepatic organ to be involved. We report four cases of gastro-intestinal sarcoidosis. METHODS: Retrospective study of a series of four cases. RESULTS: All patients had gastric sarcoidosis. It involved the duodenum, ileum and gall bladder in a patient with a history of an acute pancreatitis probably due to sarcoidosis. This patient presented with obstructive intestinal manifestations, weight loss and exsudative enteropathy. Two patients presented with mild abdominal pain and the last patient was admitted for upper gastrointestinal bleeding. The endoscopy was normal in one case and showed an antral congestion in another case. Gastric ulcers were found in the patient with a history of upper gastro-intestinal bleeding. A pseudo-linitic aspect was noticed in the patient with obstructive manifestations. The duodenum and the ileum were normal. This patient had an antrectomy and was treated with corticosteroids. Surgery evidenced a perforated duodenal ulcer, which was obstructed by the gall bladder. The patient with gastrointestinal bleeding received proton pump inhibitor and corticosteroids. These two patients improved gradually. The two other patients recovered spontaneously. CONCLUSION: The stomach is the most commonly affected organ in gastrointestinal sarcoidosis. Gastric sarcoidosis can mimic a malignant lesion owing to narrowing of the gastric lumen or can be revealed by upper gastrointestinal bleeding. Duodenum, small bowel and colon involvement is uncommon but may be underestimated in the absence of systematic biopsies.
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Enfermedades Gastrointestinales , Sarcoidosis , Adulto , Femenino , Enfermedades Gastrointestinales/diagnóstico , Enfermedades Gastrointestinales/terapia , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Sarcoidosis/diagnóstico , Sarcoidosis/terapiaRESUMEN
The association of Budd-Chiari syndrome and celiac disease is rare and has been reported in only 13 cases. We report a 23-year-old man with celiac disease, treated with gluten-free diet since the age of 16 years. He presented with epigastric pain that was secondary to a Budd-Chiari syndrome. No other cause than celiac disease could be identified.
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Síndrome de Budd-Chiari/etiología , Enfermedad Celíaca/complicaciones , Síndrome de Budd-Chiari/epidemiología , Síndrome de Budd-Chiari/cirugía , Enfermedad Celíaca/dietoterapia , Dieta Sin Gluten , Humanos , Masculino , Proteína C/metabolismo , Proteína S/metabolismo , Adulto JovenRESUMEN
OBJECTIVES: Helicobacter pylori is a worldwide infection, although little data are available in the Tunisian population. The aims of our study were to detect the prevalence of H. pylori in a blood-donor population (n=250) and in another population of hospital-consulting patients comprising 87 symptomatic patients and 59 controls, and to determine the factors that influence the prevalence. MATERIALS AND METHODS: Study subjects answered a standardized questionnaire, and IgG anti-H. pylori and anti-cag were detected by ELISA. In the second population, culture and cagA polymerase chain reaction were performed. RESULTS: The seroprevalence of H. pylori in blood donors was 64%, and 11% had anti-cag. All patients positive for anti-cag were also positive for anti-H. pylori antibodies. The seroprevalence of H. pylori was 99.3% in the hospital-consulting patients, of whom 55.5% were positive for anti-cag. The difference between the anti-cag and symptomatic patients (66.7%) and controls (39%) was significant. Symptomatic patients had a higher rate of anti-cag (66.7%) compared with the controls (39%) and blood donors (11%). CONCLUSION: H. pylori seroprevalence in blood donors is low (64%) compared with symptomatic patients (99.3%), and anti-cag was statistically associated with symptomatic patients and pathology. Also, some environmental factors were correlated with H. pylori seroprevalence.
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Donantes de Sangre , Infecciones por Helicobacter/inmunología , Helicobacter pylori/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antígenos Bacterianos/sangre , Proteínas Bacterianas/sangre , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Seroepidemiológicos , Túnez/epidemiología , Adulto JovenRESUMEN
The focus of this study was to investigate NK cell reconstitution early after hematopoietic stem cell transplantation (HSCT). We were particularly interested in acute myeloid leukemia (AML) since patients with this disease may display an altered NK cell function. The function and the phenotype of donor-derived NK cells obtained from 35 allografted patients 30 and 60 days after HSCT for AML or other-than-AML hematological malignancies has been assessed. NK functional status was investigated by measuring the degranulation capacity (externalization of CD107a) of NK cells against human K562. We also concomitantly determined the concentration of selected cytokines known to modulate NK function and/or receptor expression. At day 30, donor-derived AML and non-AML NK cells could efficiently degranulate when exposed to leukemic K562 targets. At day 60, we observed a reduced NK degranulation potential in AML patients only. Decreased NK activity in AML patients was concomitant to NKp46 and NKp30 down-regulation. AML NK cells were chronically exposed to low IL-2 levels following HSCT. TGF-beta(1) was undetectable in all patients. In AML, the functional activity of donor-derived NK cells is remarkable at day 30 but may strongly decrease two months after HSCT. Therefore, in this condition, early NK immune-modulation might improve HSCT outcome.
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Trasplante de Células Madre Hematopoyéticas , Células Asesinas Naturales/inmunología , Leucemia Mieloide Aguda/inmunología , Adolescente , Adulto , Anciano , Femenino , Humanos , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Fenotipo , Donantes de Tejidos , Resultado del Tratamiento , Adulto JovenRESUMEN
The invasion of tumor cells into brain tissue is a pathologic hallmark of malignant gliomas and contributes to treatment failures. Diffuse glioblastomas contain numerous microglial cells, which enhance the progression of gliomas; however, factors responsible for invasion-promoting role of microglia are unknown. Transforming growth factor-beta (TGF-beta) can enhance tumor growth, invasion, angiogenesis and immunosuppression. Antagonizing TGF-beta activity has been shown to inhibit tumor invasion in vitro and tumorigenicity, but a systemic inhibition or lack of TGF-beta signaling results in acute inflammation and disruption of immune system homeostasis. We developed plasmid-transcribed small hairpin RNAs (shRNAs) to downregulate the TGF-beta type II receptor (TbetaIIR) expression, which effectively inhibited cytokine-induced signaling pathways and transcriptional responses in transiently transfected human glioblastoma cells. Silencing of TbetaIIR abolished TGF-beta-induced glioblastoma invasiveness and migratory responses in vitro. Moreover, tumorigenicity of glioblastoma cells stably expressing TbetaIIR shRNAs in nude mice was reduced by 50%. Microglia strongly enhanced glioma invasiveness in the co-culture system, but this invasion-promoting activity was lost in glioma cells stably expressing shTbetaRII, indicating a crucial role of microglia-derived TGF-beta in tumor-host interactions. Our results demonstrate a successful targeting of TGF-beta-dependent invasiveness and tumorigenicity of glioblastoma cells by RNAi-mediated gene silencing.
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Movimiento Celular/fisiología , Silenciador del Gen/fisiología , Glioma/patología , Microglía/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Receptores de Factores de Crecimiento Transformadores beta/genética , Factor de Crecimiento Transformador beta/metabolismo , Animales , Técnicas de Cocultivo , Colágeno/metabolismo , Combinación de Medicamentos , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Glioma/metabolismo , Humanos , Laminina/metabolismo , Masculino , Ratones , Ratones Desnudos , Invasividad Neoplásica , Proteínas Serina-Treonina Quinasas/metabolismo , Proteoglicanos/metabolismo , ARN Mensajero/metabolismo , Ratas , Receptor Tipo II de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Transfección , Células Tumorales CultivadasRESUMEN
BACKGROUND: Recombinant tumor necrosis factor-alpha (TNF-alpha) combined to melphalan is clinically administered through isolated limb perfusion (ILP) for regionally advanced soft tissue sarcomas of the limbs. In preclinical studies, wild-type p53 gene is involved in the regulation of cytotoxic action of TNF-alpha and loss of p53 function contributes to the resistance of tumour cells to TNF-alpha. The relationship between p53 status and response to TNF-alpha and melphalan in patients undergoing ILP is unknown. PATIENTS AND METHODS: We studied 110 cases of unresectable limbs sarcomas treated by ILP. Immunohistochemistry was carried out using DO7mAb, which reacts with an antigenic determinant from the N-terminal region of both the wild-type and mutant forms of the p53 protein, and PAb1620mAb, which reacts with the 1620 epitope characteristic of the wild-type native conformation of the p53 protein. The immunohistochemistry data were then correlated with various clinical parameters. RESULTS: P53DO7 was found expressed at high levels in 28 patients, whereas PAb1620 was negative in 20. The tumours with poor histological response to ILP with TNF-alpha and melphalan showed significantly higher levels of p53-mutated protein. CONCLUSIONS: Our results might be a clue to a role of p53 protein status in TNF-alpha and melphalan response in clinical use.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Biomarcadores de Tumor/análisis , Quimioterapia del Cáncer por Perfusión Regional , Sarcoma/química , Sarcoma/tratamiento farmacológico , Proteína p53 Supresora de Tumor/análisis , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/inmunología , Niño , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Imagen por Resonancia Magnética , Masculino , Melfalán/administración & dosificación , Persona de Mediana Edad , Mutación Missense , Sarcoma/patología , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/administración & dosificación , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/inmunologíaRESUMEN
BACKGROUND: Prion protein (PrPc) has been previously reported to be associated with resistance to proapoptotic stimuli. We evaluated whether the expression of PrPc was associated with the resistance to adjuvant chemotherapy in patients with estrogen receptor (ER) -negative breast cancer. PATIENTS AND METHODS: The expression of PrPc by primary tumors was assessed by immunohistochemistry in a series of 756 patients included in two randomized trials that compared anthracycline-based chemotherapy to no chemotherapy. The PrPc expression was correlated with ER expression and the benefit of adjuvant chemotherapy was assessed according to PrPc expression in patients with ER-negative tumors. RESULTS: Immunostaining analysis showed that PrPc was mainly expressed by myoepithelial cells in normal breast tissue. Tissue microarray analysis from 756 breast tumors showed that PrPc was associated with ER-negative breast cancer subsets (P < 0.001). Adjuvant chemotherapy was not associated with a significant risk reduction for death in patients with ER-negative/PrPc-positive disease [adjusted hazard ratio (HR) for death = 0.98, 95% confidence interval (CI) 0.45-2.1, P = 0.95], while it decreased the risk for death (HR = 0.39, 95% CI 0.2-0.74, P = 0.004) in patients with ER-negative/PrPc-negative tumors. CONCLUSION: These data indicate that ER-negative/PrPc-negative phenotype is associated with a high sensitivity to adjuvant chemotherapy.
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Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Proteínas PrPC/metabolismo , Receptores de Estrógenos/análisis , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/sangre , Neoplasias de la Mama/cirugía , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Mastectomía/métodos , Persona de Mediana Edad , Proteínas PrPC/genética , Probabilidad , Pronóstico , Modelos de Riesgos Proporcionales , Ensayos Clínicos Controlados Aleatorios como Asunto , Medición de Riesgo , Estadísticas no Paramétricas , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Tumor necrosis factor (TNF) is a pro-inflammatory cytokine exerting pleiotropic effects on endothelial cells. Depending on the vascular context it can induce endothelial cell activation and survival or death. The microenvironmental cues determining whether endothelial cells will survive or die, however, have remained elusive. Here we report that integrin ligation acts permissive for TNF-induced protein kinase B (PKB/Akt) but not nuclear factor (NF)-kappaB activation. Concomitant activation of PKB/Akt and NF-kappaB is essential for the survival of endothelial cells exposed to TNF. Active PKB/Akt strengthens integrin-dependent endothelial cell adhesion, whereas disruption of actin stress fibers abolishes the protective effect of PKB/Akt. Integrin-mediated adhesion also represses TNF-induced JNK activation, but JNK activity is not required for cell death. The alphaVbeta3/alphaVbeta5 integrin inhibitor EMD121974 sensitizes endothelial cells to TNF-dependent cytotoxicity and active PKB/Akt attenuates this effect. Interferon gamma synergistically enhanced TNF-induced endothelial cell death in all conditions tested. Taken together, these observations reveal a novel permissive role for integrins in TNF-induced PKB/Akt activation and prevention of TNF-induced death distinct of NF-kappaB, and implicate the actin cytoskeleton in PKB/Akt-mediated cell survival. The sensitizing effect of EMD121974 on TNF cytotoxicity may open new perspectives to the therapeutic use of TNF as anticancer agent.
Asunto(s)
Apoptosis/fisiología , Adhesión Celular , Endotelio Vascular/citología , Integrina alfaVbeta3/metabolismo , Integrinas/metabolismo , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores de Vitronectina/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Actinas/metabolismo , Western Blotting , Células Cultivadas , Citoesqueleto/metabolismo , Ensayo de Cambio de Movilidad Electroforética , Endotelio Vascular/metabolismo , Citometría de Flujo , Humanos , Etiquetado Corte-Fin in Situ , Integrina alfaVbeta3/antagonistas & inhibidores , Integrinas/antagonistas & inhibidores , MAP Quinasa Quinasa 4/metabolismo , FN-kappa B/genética , Fosforilación , Receptores de Vitronectina/antagonistas & inhibidores , Transducción de Señal , Esferoides CelularesRESUMEN
In order to define genetic determinants of primary and metastatic melanoma cell susceptibility to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), we have applied oligonucleotide microarrays to TRAIL-sensitive primary T1 cells and TRAIL-resistant metastatic G1 cells treated or not with TRAIL. T1 and G1 cells are isogenic melanoma cell subclones. We examined 22 000 spots, 4.2% of which displayed differential expression in G1 and T1 cells. Cell susceptibility to TRAIL-mediated apoptosis was found to be correlated with gene expression signatures in this model. Some of the differentially expressed genes were identified as involved in ATP-binding and signaling pathways, based on previously published data. Further analysis provided evidences that c-kit was overexpressed in G1 cells while it was absent in T1 cells. The c-kit inhibitor, imatinib, did not restore TRAIL sensitivity, excluding a role for c-kit in TRAIL resistance in G1 cells. Surprisingly, imatinib inhibited cell proliferation and TRAIL-mediated apoptosis in melanoma cells. We investigated the possible involvement of several molecules, including c-ABL, platelet-derived growth factor receptor (PDGFR), cellular FADD-like interleukin-1 alpha-converting enzyme-like inhibitory protein (c-FLIP)(L/S), Fas-associated DD kinase, p53, p21(WAF1), proteins of B-cell leukemia/lymphoma 2 (Bcl-2) family and cytochrome c. Imatinib did not modulate the expression or activation of its own targets, such as c-ABL, PDGFRalpha and PDGFRbeta, but it did affect the expression of c-FLIP(L), BCL2-associated X protein (Bax) and Bcl-2. Moreover, c-FLIP(L) knockdown sensitized T1 cells to TRAIL-mediated apoptosis, with a sensitivity similar to that of cells previously treated with imatinib. More notably, we found that the resistance to TRAIL in G1 cells was correlated with constitutive c-FLIP(L) recruitment to the DISC and the inhibition of caspase 8, 3 and 9 processing. Moreover, c-FLIP(L) knockdown partly restored TRAIL sensitivity in G1 cells, indicating that the expression level of c-FLIP(L) and its interaction with TRAIL receptor2 play a crucial role in determining TRAIL resistance in metastatic melanoma cells. Our results also show that imatinib enhances TRAIL-induced cell death independently of BH3-interacting domain death agonist translocation, in a process involving the Bax:Bcl-X(L) ratio, Bax:Bcl-X(L)/Bcl-2 translocation, cytochrome c release and caspase activation. Our data indicate that imatinib sensitizes T1 cells by directly downregulating c-FLIP(L), with the use of an alternative pathway for antitumor activity, because PDGFRalpha is not activated in T1 cells and these cells do not express c-kit, c-ABL or PDGFRbeta. Caspase cascade activation and mitochondria also play a key role in the imatinib-mediated sensitization of melanoma cells to the proapoptotic action of TRAIL.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Caspasas/metabolismo , Melanoma/patología , Piperazinas/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Pirimidinas/farmacología , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Benzamidas , Técnicas de Cultivo de Célula , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Activación Enzimática , Perfilación de la Expresión Génica , Humanos , Mesilato de Imatinib , Melanoma/genética , Melanoma/metabolismo , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas Proto-Oncogénicas c-kit/metabolismo , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Proteínas Recombinantes/farmacologíaRESUMEN
Natural Killer (NK) cells are critical in host defense against malignant transformation and are potent antileukemic cytotoxic effectors. In the present study, we investigated the peripheral NK function in patients with myelodysplastic syndromes (MDS). We demonstrated that the peripheral NK cell population was quantitatively normal in MDS patients. Furthermore, NK cells displayed an expression of the activating natural cytotoxicity receptors (NCR) NKp46 and NKp30 as well as NKG2D similar to that observed in donors, but exert a highly decreased constitutive cytolytic activity compared to resting normal NK cells. Although activation with IL-2 resulted in the upregulation of NKp46 expression by MDS-NK cells, their cytolytic function remained deeply altered as compared to activated donor NK cells. In addition, MDS NK cells did not proliferate in vitro, and displayed an increased rate of apoptosis in response to IL-2 stimulation although the spontaneous apoptosis was not significantly increased. Interestingly, a proportion of peripheral MDS-NK cells were derived from the MDS clone as the cytogenetic anomaly found in bone marrow karyotype was also detected in 20-50% of circulating NK cells. In conclusion, NK cells' cytolytic function and proliferative capacities in response to activation by cytokines are profoundly altered in MDS.
Asunto(s)
Citotoxicidad Inmunológica , Células Asesinas Naturales/inmunología , Síndromes Mielodisplásicos/inmunología , Apoptosis , Humanos , Inmunofenotipificación , Hibridación Fluorescente in Situ , CariotipificaciónRESUMEN
Interferon alpha (IFN-alpha) is an approved treatment in metastatic renal cell carcinoma (RCC). The underlying mechanisms are far from being clear, but are presumed to be a combination of stimulation of cell-mediated cytotoxicity, direct antiproliferative activity and antiangiogenic effects. Recently, the role of p53 in the cellular response to IFN-alpha has been proposed in other tumor models (hepatoblastoma). We therefore studied the expression of p53 during IFN-alpha treatment using two freshly established RCC cell lines RCC5 and RCC7. While IFN-alpha treatment significantly enhanced the expression of p53 in RCC7, no changes were observed in RCC5. Cell viability under IFN-alpha remained unchanged in both cell lines. Following gamma-irradiation, a p53-activating stimulus, an enhanced cell death was observed in IFN-alpha-treated RCC7 but not in RCC5. We further demonstrate that there were no changes in Bcl-2- and Bax-expression, two target genes regulated by p53. However, intracellular staining revealed that cell death induced by IFN-alpha and gamma-irradiation was preceded by a shift of Bax to the mitochondria in RCC7. Our results suggest a role of p53 and its downstream target Bax, in the control of RCC sensitivity to IFN-alpha.