Epithelial-to-Mesenchymal Transition in Pancreatic Adenocarcinoma

Epithelial to mesenchymal transition (EMT) is a physiologic process that allows morphological and genetic changes of carcinoma cells from an epithelial to a mesenchymal phenotype, which is the basis of the high metastatic potential of pancreatic cancer cells. EMT is triggered by various tumor microenvironmental factors, including cytokines, growth factors, and chemotherapeutic agents. This review summarizes the state-of-the-art knowledge on the molecular mechanisms that support pancreatic cancer EMT and the evidences that support its involvement in invasiveness/aggressiveness, and the drug resistance of pancreatic cancer cells

Chloroquine plays a cell-dependent role in the response to treatment of pancreatic adenocarcinoma

In this study, our aim is to assess the role played by autophagy and its inhibition in the different PDAC cellular compartments, and its involvement in chemo-resistance using primary human pancreatic cancer-derived cells (PCC) and Cancer Associated Fibroblasts (CAF). Autophagy flux, as measured by LC3-I and -II in the presence of Chloroquine, showed a variable level in PCC and CAFs. We found no correlation between autophagy level and degree of tumor differentiation. Association of Chloroquine with gemcitabine, 5FU, oxaliplatin, irinotecan and docetaxel revealed that its effect on survival is cell- and drug-dependent in vitro and in vivo. In addition, we demonstrated that autophagy in CAFs can play an important role in sensitizing PDAC to anticancer treatments since its inhibition increased the resistance of PCCs to gemcitabine. In conclusion, this work clearly shows a heterogeneity in the effect of Chloroquine and highlights a role of CAFs autophagy in sensitizing tumors to treatments. It also reveals that the role of autophagy is more complex than expected in PDAC as well as its sensitivity to treatments.Fil: Molejon, Maria Ines. Institut National de la Santé et de la Recherche Médicale; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Ciencias de la Tierra y Ambientales de La Pampa. Universidad Nacional de La Pampa. Facultad de Ciencias Exactas y Naturales. Instituto de Ciencias de la Tierra y Ambientales de La Pampa; ArgentinaFil: Swayden, Mirna. Institut National de la Santé et de la Recherche Médicale; FranciaFil: Fanale, Daniele. 3 Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy.; Argentina. University of Palermo. Department of Surgical, Oncological and Oral Sciences; ItaliaFil: Bintz, Jennifer. Institut National de la Santé et de la Recherche Médicale; FranciaFil: Gayet, Odile. Institut National de la Santé et de la Recherche Médicale; FranciaFil: Soubeyran, Philippe. Institut National de la Santé et de la Recherche Médicale; FranciaFil: Iovanna, Juan Lucio. Institut National de la Santé et de la Recherche Médicale; Franci

Autophagy in Pancreatic Cancer

Pancreatic adenocarcinoma (PDAC) is a devastating disease with an extremely poor life expectancy and no effective treatment. Autophagy is a process of degradation of cytoplasmic component capable of recycling cellular components or eliminate specific targets. The presence of autophagy in PDAC has been demonstrated. However, the implicated cellular pathways are not fully understood and, more importantly, the role of autophagy in PDAC is matter of intensive debate. This review summarizes recently published data in an attempt to clarify the importance of autophagy in this disease and try to reconcile apparently contradictory results

Induction of antioxidant mechanisms in lung during experimental pancreatitis in rats

297-305Lung complications are the most common cause of death in patients with acute pancreatitis. In this study, we investigated how induction of mild acute pancreatitis could modify the course of lung inflammation, eventually, induced by a severe acute pancreatitis in rats. A severe and a mild forms of an experimental acute pancreatitis were respectively established by intra-ductal administration of sodium taurocholate to final dose of 50 g/kg body wt. and intra-peritoneal injection of caerulein to supramaximal dose of 40 g/kg body wt. We observed reduced levels of thiobarbiturate acid reacting substances when severe pancreatitis was preceded by the induction of mild pancreatitis. Moreover, mRNAs expression of both HSP-70 and Mn-SOD was increased in the lung. By contrast, the level of glutathione was reduced, but no change in the infiltration of neutrophils was observed. Therefore, we conclude that during the course of pancreatitis and its related lung inflammation, the pulmonary cells response involved in the expression of different protective proteins, including HSP-70 and Mn-SOD, which possibly improves the defensive mechanisms against inflammation in lung cells

PAP1 signaling involves MAPK signal transduction

El pdf del artículo es la versión post-print.-- et al.Pancreatitis-associated protein 1 (PAP1) belongs to the Reg family of secretory proteins. Several important biological roles have been attributed to PAP1 but the signaling pathways activated by this protein remain only partially understood. Here, we describe the intracellular pathways triggered by PAP1 in a pancreatic acinar cell line. Taking advantage of the fact that PAP1 induces its own transcription, we performed ChIP assays to analyze the recruitment of transcriptional factors on its promoter. Our results show that PAP1 increased the transactivation activity of pap1 and the binding on its promoter of the nuclear factors C/EBPβ, P-CREB, P-ELK1, EGR1, STAT3, and ETS2, which are downstream targets of MAPK signaling. p44/42, p38, and JNK MAPKs activity increased after PAP1 treatment. In addition, pharmacological inhibition of these kinases markedly inhibited the induction of pap1 mRNA. Taken together, these results indicated that the mechanism of PAP1 action involves the activation of the MAPK superfamily.This work was supported by the FIS PI050599 and FIS PI081608 projects to E. Folch-Puy, Acción Integrada HF2006-0092 and CIBERehd to D. Closa and Spanish Ministry of Science and Technology BFU2007-63120 and CSD2006-49 to G. López-Rodas. CIBERehd is funded by the Instituto de Salud Carlos III. E. Folch-Puy is the recipient of a Ramón y Cajal contract from the Spanish Ministry of Education and Science. M. Ferrés-Masó is the recipient of a FIS-Instituto de Salud Carlos III contract PI050599.Peer reviewe

Pancreatic Cancer: Molecular, Biochemical, Chemopreventive, and Therapeutic Aspects

Pancreatic cancer (PC) is the fourth leading cause of cancer death, with a median survival of 6 months and a dismal 5-year survival rate of 35%, a figure which has remained relatively unchanged over the past 25 years. PC is one of the most difficult diseases to treat due to late initial diagnosis and to resistance to the usual treatments. The presence of occult or clinical metastases at the time of diagnosis, together with the lack of effective chemotherapies, contributes to the high mortality in patients with PC. Its lethal nature stems from its propensity to disseminate rapidly to the lymphatic system and distant organs. Yet, understanding and stopping metastasis may prove to be one of the great potential strategies of treating PC. There is a dire need for the design of new and targeted therapeutic strategies that can overcome the drug resistance and improve the clinical outcome for patients diagnosed with the illness. The knowledge of the molecular aspects of PC is very important, and it is likely to be helpful in the design of newer drugs and the molecular selection of existing agents for targeted therapy. The inhibition of signal pathways can be carried out not only by small molecules, able to bind to selected regions of the target protein, but also by using large molecules as antibodies. The pathway to successful new therapies has been inhibited because of the rapidity with which agents tend to move into randomized, controlled trials without the extensive early testing necessary to optimize treatment regimens. However, lessons have been learned and our collective research effort has generated a substantial platform of knowledge from which further work will spring. The bioavailability of compounds such as antisense oligonucleotides and siRNAs in humans remains a big hurdle, which will require further improvement of gene-delivery strategies. Finally, the long-term goal of the therapy individualization for patients is possible if factors that predict treatment response, such as biological markers, could be determined accurately. These approaches are likely to comprise a mixture of targeted agents in combination with conventional chemotherapy and radiotherapy. For a clinically significant effect to be achieved, treatment strategies should either be in the form of (1) a horizontal approach, in which several oncogenic pathways (as those described in this series of reviews) are inhibited; or (2) a vertical approach, whereby multiple levels of a major pathway are targeted. Combination therapies, together with improved diagnostic tools and predictive markers, are ultimately desired in order to improve the bleak outlook for patients diagnosed with PC

The reg4gene, amplified in the early stages of pancreatic cancer development, is a promising therapeutic target

This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al.[Background]: The aim of our work was to identify the genes specifically altered in pancreatic adenocarcinoma and especially those that are altered early in cancer development.[Methodology/Principal Findings]: Gene copy number was systematically assessed with an ultra-high resolution CGH oligonucleotide microarray in DNA from samples of pancreatic cancer. Several new cancer-associated variations were observed. In this work we focused on one of them, involving the reg4 gene. Gene copy number gain of the reg4 gene was confirmed by qPCR in 14 cancer samples. It was also found with increased copy number in most PanIN3 samples. The relationship betweena gain in reg4 gene copy number and cancer development was investigated on the human pancreatic cancer cell line Mia-PaCa2 xenografted under the skin of nude mice. When cells were transfected with a vector allowing reg4 expression, they generated tumors almost twice larger in size. In addition, these tumors were more resistant to gemcitabine treatment than control tumors. Interestingly, weekly intraperitoneal administration of a monoclonal antibody to reg4 halved the size of tumors generated by Mia-PaCa2 cells, suggesting that the antibody interfered with a paracrine/autocrine mechanism involving reg4 and stimulating cancer progression. The addition of gemcitabine resulted in further reduction, tumors becoming 5 times smaller than control. Exposure to reg4 antibody resulted in a significant decrease in intra-tumor levels of pAkt, Bcl-xL, Bcl-2, survivin and cyclin D1.[Conclusions/Significance]: It was concluded that adjuvant therapies targeting reg4 could improve the standard treatment of pancreatic cancer with gemcitabine.This work was supported by grants from INSERM, Ligue Contre le Cancer and INCA to JLI and by the FIS PI081608 project, Acción Integrada HF2006-0092 and CIBERehd. CIBERehd is funded by the Instituto de Salud Carlos III to EF-P and DC. EF-P is the recipient of a Ramón y Cajal contract from the Spanish Ministry of Education and Science and MF-M is the recipient of a FIS-Instituto de Salud Carlos III contract PI050599.Peer reviewe

Current Knowledge on Pancreatic Cancer

Pancreatic cancer is the fourth leading cause of cancer death with a median survival of 6 months and a dismal 5-year survival rate of 3–5%. The development and progression of pancreatic cancer are caused by the activation of oncogenes, the inactivation of tumor suppressor genes, and the deregulation of many signaling pathways. Therefore, the strategies targeting these molecules as well as their downstream signaling could be promising for the prevention and treatment of pancreatic cancer. However, although targeted therapies for pancreatic cancer have yielded encouraging results in vitro and in animal models, these findings have not been translated into improved outcomes in clinical trials. This failure is due to an incomplete understanding of the biology of pancreatic cancer and to the selection of poorly efficient or imperfectly targeted agents. In this review, we will critically present the current knowledge regarding the molecular, biochemical, clinical, and therapeutic aspects of pancreatic cancer

Limitation and challenges in using pancreatic cancer-derived organoids as a preclinical tool

Pancreatic ductal adenocarcinoma (PDAC) is a dismaldisease with a fast evolution and unpredictable treatmentresponse. Nowadays, FOLFIRINOX and gemcitabine are the preferred treatments with a response rateof 33% and 11%, respectively. This poor patient responsehas been associated with an inefficient/non-personalizedtreatment allocation. Consequently, developing a rapidand efficient preclinical tool to test tumor drug sensitivityfor each patient is hugely needed. Biopsy patient-derivedorganoid (PDO) appears to be a promising tool for devel-oping individualized treatments for patients with PDAC.Several PDO-based platforms are in development world-wide as a guide to optimize therapy by directing tailored treatments.Fil: Fraunhoffer Navarro, Nicolas Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina. Aix-Marseille University; FranciaFil: Abuelafia, Analía Meilerman. Aix-Marseille University; FranciaFil: Dusetti, Nelson. Aix-Marseille University; FranciaFil: Iovanna, Juan Lucio. Aix-Marseille University; Franci

Pancreatic Cancer Heterogeneity Can Be Explained Beyond the Genome

Pancreatic ductal adenocarcinoma (PDAC) remains a major health problem because it induces almost systematic mortality. Carcinogenesis begins with genetic aberrations which trigger epigenetic modifications. While genetic mutations initiate tumorigenesis, they are unable to explain the vast heterogeneity observed among PDAC patients. Instead, epigenetic changes drive transcriptomic alterations that can regulate the malignant phenotype. The contribution of factors from the environment and tumor microenvironment defines different epigenetic landscapes that outline two clinical subtypes: basal, with the worst prognosis, and classical. The epigenetic nature of PDAC, as a reversible phenomenon, encouraged several studies to test epidrugs. However, these drugs lack specificity and although there are epigenetic patterns shared by all PDAC tumors, there are others that are specific to each subtype. Molecular characterization of the epigenetic mechanisms underlying PDAC heterogeneity could be an invaluable tool to predict personalized therapies, stratify patients and search for novel therapies with more specific phenotype-based targets. Novel therapeutic strategies using current anticancer compounds or existing drugs used in other pathologies, alone or in combination, could be used to kill tumor cells or convert aggressive tumors into a more benign phenotype