RESUMEN
Both clinical and experimental evidence have firmly established that chronic pancreatitis, in particular in the context of Kras oncogenic mutations, predisposes to pancreatic ductal adenocarcinoma (PDAC). However, the repertoire of molecular mediators of pancreatitis involved in Kras-mediated initiation of pancreatic carcinogenesis remains to be fully defined. In this study we demonstrate a novel role for vacuole membrane protein 1 (VMP1), a pancreatitis-associated protein critical for inducible autophagy, in the regulation of Kras-induced PDAC initiation. Using a newly developed genetically engineered model, we demonstrate that VMP1 increases the ability of Kras to give rise to preneoplastic lesions, pancreatic intraepithelial neoplasias (PanINs). This promoting effect of VMP1 on PanIN formation is due, at least in part, by an increase in cell proliferation combined with a decrease in apoptosis. Using chloroquine, an inhibitor of autophagy, we show that this drug antagonizes the effect of VMP1 on PanIN formation. Thus, we conclude that VMP1-mediated autophagy cooperate with Kras to promote PDAC initiation. These findings are of significant medical relevance, molecules targeting autophagy are currently being tested along chemotherapeutic agents to treat PDAC and other tumors in human trials.
Asunto(s)
Carcinoma Ductal/genética , Regulación Neoplásica de la Expresión Génica , Proteínas de la Membrana/genética , Neoplasias Pancreáticas/genética , Pancreatitis/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Animales , Autofagia/efectos de los fármacos , Carcinoma Ductal/etiología , Carcinoma Ductal/metabolismo , Carcinoma Ductal/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cloroquina/farmacología , Genes Reporteros , Células HEK293 , Humanos , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Proteínas de la Membrana/metabolismo , Ratones , Ratones Transgénicos , Páncreas/metabolismo , Páncreas/patología , Neoplasias Pancreáticas/etiología , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Pancreatitis/complicaciones , Pancreatitis/metabolismo , Pancreatitis/patología , Proteínas Asociadas a Pancreatitis , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Transducción de SeñalRESUMEN
Tuberculosis is the most frequent cause of fever from unknown etiology. On the other hand, mediastinal tuberculous adenopathy (TBM), without associated pulmonary affection is a rare form of presentation among adults, generally evolving with sustained fever until a thoracic radiology is performed showing mediastinal enlargement. We present a case which started as fever from unknown etiology (FUE), given that, according to the thoracic radiology performed one month after the onset of fever, no mediastinal affection was observed.