ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) offers an optimal model for discovering "druggable" molecular pathways that participate in inflammation-associated cancer development. Chronic pancreatitis, a common prolonged inflammatory disease, behaves as a well-known premalignant condition that contributes to PDAC development. Although the mechanisms underlying the pancreatitis-to-cancer transition remain to be fully elucidated, emerging evidence supports the hypothesis that the actions of proinflammatory mediators on cells harboring Kras mutations promote neoplastic transformation. Recent elegant studies demonstrated that the IL17 pathway mediates this phenomenon and can be targeted with antibodies, but the downstream mechanisms by which IL17 functions during this transition are currently unclear. In this study, we demonstrate that IL17 induces the expression of REG3ß, a well-known mediator of pancreatitis, during acinar-to-ductal metaplasia and in early pancreatic intraepithelial neoplasia (PanIN) lesions. Furthermore, we found that REG3ß promotes cell growth and decreases sensitivity to cell death through activation of the gp130-JAK2-STAT3-dependent pathway. Genetic inactivation of REG3ß in the context of oncogenic Kras-driven PDAC resulted in reduced PanIN formation, an effect that could be rescued by administration of exogenous REG3ß. Taken together, our findings provide mechanistic insight into the pathways underlying inflammation-associated pancreatic cancer, revealing a dual and contextual pathophysiologic role for REG3ß during pancreatitis and PDAC initiation.
Subject(s)
Carcinoma, Pancreatic Ductal/pathology , Cell Transformation, Neoplastic/metabolism , Pancreatic Neoplasms/pathology , Precancerous Conditions/metabolism , Signal Transduction , Animals , Antigens, Neoplasm , Biomarkers, Tumor , Cell Line, Tumor , Disease Progression , Humans , Immunoblotting , Inflammation/metabolism , Inflammation/pathology , Interleukin-17/metabolism , Janus Kinase 2/metabolism , Lectins, C-Type , Mice , Mice, Knockout , Pancreatitis, Chronic/complications , Pancreatitis, Chronic/metabolism , Pancreatitis-Associated Proteins , Proteins/metabolism , Reverse Transcriptase Polymerase Chain Reaction , STAT3 Transcription Factor/metabolism , Signal Transduction/physiologyABSTRACT
It has been commonly found that in patients presenting Pancreatic Ductal Adenocarcinoma (PDAC), after a period of satisfactory response to standard treatments, the tumor becomes non-responsive and patient death quickly follows. This phenomenon is mainly due to the rapid and uncontrolled development of the residual tumor. The origin and biological characteristics of residual tumor cells in PDAC still remain unclear. In this work, using PDACs from patients, preserved as xenografts in nude mice, we demonstrated that a residual PDAC tumor originated from a small number of CD44+ cells present in the tumor. During PDAC relapse, proliferating CD44+ cells decrease expression of ZEB1, while overexpressing the MUC1 protein, and gain morphological and biological characteristics of differentiation. Also, we report that CD44+ cells, in primary and residual PDAC tumors, are part of a heterogeneous population, which includes variable numbers of CD133+ and EpCAM+ cells. We confirmed the propagation of CD44+ cells in samples from cases of human relapse, following standard PDAC treatment. Finally, using systemic administration of anti-CD44 antibodies in vivo, we demonstrated that CD44 is an efficient therapeutic target for treating tumor relapse, but not primary PDAC tumors. We conclude that CD44+ cells generate the relapsing tumor and, as such, are themselves promising therapeutic targets for treating patients with recurrent PDAC.
Subject(s)
Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/metabolism , Hyaluronan Receptors/metabolism , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/metabolism , Animals , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/pathology , Cell Differentiation/drug effects , Cell Growth Processes/drug effects , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Humans , Mice , Mice, Nude , Molecular Targeted Therapy , Neoplasm Recurrence, Local , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Recurrence , Xenograft Model Antitumor Assays , Gemcitabine , Pancreatic NeoplasmsABSTRACT
Introducción: 'Globesity' es el término que la Organización Mundial de la Salud (OMS) emplea para denominar el progresivo aumento de la obesidad experimentado desde los últimos 40 años en los países desarrollados y cuyo contagio a los países en vías de desarrollo ha sido inevitable. Esta situación ha llevado a los gobiernos y organizaciones internacionales de todo el mundo a plantear estrategias destinadas a frenar dicha epidemia. Objetivo: Recopilar los conocimientos más actuales que se tienen de la relación entre los macronutrientes (en especial de la grasa y los sistemas de liberación de lípidos) y la secreción de péptidos gastrointestinales relacionados con la saciedad y saciación. Metodología: Se realizó una búsqueda bibliográfica basada en la combinación de términos MeSH en Medline (vía PubMed) y en LILACs mediante DeCS, así como una selección de otros artículos relacionados con la temática de la revisión. Resultados y discusión: Actualmente, numerosos laboratorios públicos y privados se encuentran investigando diversos ingredientes bioactivos relacionados con la regulación del apetito. Destacan los relacionados con la grasa ingerida y la forma en que esta puede ser tratada físicamente, sobre todo emulsiones y estructuras parecidas y su influencia sobre la saciedad y/o disminución de la sensación de hambre. Conclusiones: Estos ingredientes alimentarios se plantean como el futuro de los alimentos funcionales enfocados a la prevención de la ganancia de peso y ayuda a otras estrategias contra la obesidad (alimentarias, conductuales, etc...) (AU)
Introduction: 'Globesity' is the term that the World Health Organization (WHO) employs to define the growth of obesity in the world from the last 40 years which started in the developed countries and has been inevitably propagated to the developing ones. Governments and international organizations are aware of the problem and they are trying to implement measures to fight it. Aim: To analyze the current evidence in terms of studies about the relationship between macronutrients (especially fat and lipid release systems) and the secretion of gastrointestinal peptides that are involved with satiety and satiation. Methods: The search was conducted in Medline (via Pubmed) using different combinations of MeSH terms and in the database LILACs using 'DeCS'. A selection of another articles relevant to the review topic was also examined. Results and discussion: At present, there are several laboratories and industries developing novel bioactive ingredients aimed at the regulation of food intake, with emphasis on those related with fat intake and the different ways in which fat can be technologically processed in order to create structures able to enhance satiety and/or diminish hunger. Conclusion: These ingredients will be the future of functional foods focused on the prevention of weight gain and the support of other strategies against obesity (dietary, behavioral, etc ) (AU)
Subject(s)
Humans , Nutrients , Dietary Fats/administration & dosage , Dietary Fats , Body Weight/genetics , Obesity/complications , Peptides/administration & dosage , Dietary Fats , Dietary Fats/pharmacology , Body Weight/physiology , Obesity/prevention & control , PeptidesABSTRACT
Activating mutations in the KRAS oncogene are prevalent in pancreatic ductal adenocarcinoma (PDAC). We previously demonstrated that pancreatic intraepithelial neoplasia (PanIN) formation, which precedes malignant transformation, associates with the expression of immediate early response 3 (Ier3) as part of a prooncogenic transcriptional pathway. Here, we evaluated the role of IER3 in PanIN formation and PDAC development. In human pancreatic cancer cells, IER3 expression efficiently sustained ERK1/2 phosphorylation by inhibiting phosphatase PP2A activity. Moreover, IER3 enhanced KrasG12D-dependent oncogenesis in the pancreas, as both PanIN and PDAC development were delayed in IER3-deficient KrasG12D mice. IER3 expression was discrete in healthy acinar cells, becoming highly prominent in peritumoral acini, and particularly high in acinar ductal metaplasia (ADM) and PanIN lesions, where IER3 colocalized with phosphorylated ERK1/2. However, IER3 was absent in undifferentiated PDAC, which suggests that the IER3-dependent pathway is an early event in pancreatic tumorigenesis. IER3 expression was induced by both mild and severe pancreatitis, which promoted PanIN formation and progression to PDAC in KrasG12D mice. In IER3-deficient mice, pancreatitis abolished KrasG12D-induced proliferation, which suggests that pancreatitis enhances the oncogenic effect of KRAS through induction of IER3 expression. Together, our data indicate that IER3 supports KRASG12D-associated oncogenesis in the pancreas by sustaining ERK1/2 phosphorylation via phosphatase PP2A inhibition.
Subject(s)
Carcinoma in Situ/genetics , Carcinoma, Pancreatic Ductal/genetics , Extracellular Signal-Regulated MAP Kinases/metabolism , Immediate-Early Proteins/physiology , Pancreatic Neoplasms/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Animals , Carcinogenesis/genetics , Carcinogenesis/metabolism , Carcinoma in Situ/metabolism , Carcinoma, Pancreatic Ductal/metabolism , Cell Line, Tumor , Humans , MAP Kinase Signaling System , Male , Mice, Nude , Mice, Transgenic , Mutation, Missense , Neoplasm Transplantation , Pancreas/metabolism , Pancreas/pathology , Pancreatic Neoplasms/metabolism , Phosphorylation , Protein Phosphatase 2/metabolism , Protein Processing, Post-TranslationalABSTRACT
INTRODUCTION: "Globesity" is the term that the World Health Organization (WHO) employs to define the growth of obesity in the world from the last 40 years which started in the developed countries and has been inevitably propagated to the developing ones. Governments and international organizations are aware of the problem and they are trying to implement measures to fight it. AIM: To analyze the current evidence in terms of studies about the relationship between macronutrients (especially fat and lipid release systems) and the secretion of gastrointestinal peptides that are involved with satiety and satiation. METHODS: The search was conducted in Medline (via Pubmed) using different combinations of MeSH terms and in the database LILACs using "DeCS". A selection of another articles relevant to the review topic was also examined. RESULTS AND DISCUSSION: At present, there are several laboratories and industries developing novel bioactive ingredients aimed at the regulation of food intake, with emphasis on those related with fat intake and the different ways in which fat can be technologically processed in order to create structures able to enhance satiety and/ or diminish hunger. CONCLUSION: These ingredients will be the future of functional foods focused on the prevention of weight gain and the support of other strategies against obesity (dietary, behavioral, etc ).
Introducción: "Globesity" es el término que la Organización Mundial de la Salud (OMS) emplea para denominar el progresivo aumento de la obesidad experimentado desde los últimos 40 años en los países desarrollados y cuyo contagio a los países en vías de desarrollo ha sido inevitable. Esta situación ha llevado a los gobiernos y organizaciones internacionales de todo el mundo a plantear estrategias destinadas a frenar dicha epidemia. Objetivo: Recopilar los conocimientos más actuales que se tienen de la relación entre los macronutrientes (en especial de la grasa y los sistemas de liberación de lípidos) y la secreción de péptidos gastrointestinales relacionados con la saciedad y saciación. Metodología: Se realizó una búsqueda bibliográfica basada en la combinación de términos MeSH en Medline (vía PubMed) y en LILACs mediante DeCS, así como una selección de otros artículos relacionados con la temática de la revisión. Resultados y discusión: Actualmente, numerosos laboratorios públicos y privados se encuentran investigando diversos ingredientes bioactivos relacionados con la regulación del apetito. Destacan los relacionados con la grasa ingerida y la forma en que esta puede ser tratada físicamente, sobre todo emulsiones y estructuras parecidas y su influencia sobre la saciedad y/o disminución de la sensación de hambre. Conclusiones: Estos ingredientes alimentarios se plantean como el futuro de los alimentos funcionales enfocados a la prevención de la ganancia de peso y ayuda a otras estrategias contra la obesidad (alimentarias, conductuales, etc...).
