Here we present evidence that allows us to consider a combined therapy regimen comprising an autophagy inhibitor and a MAPK or NF-kB pathway inhibitor as a possible treatment strategy for pancreatic cancer.
Pancreatic cancer is an aggressive disease. Its incidence has increased over the last two decades. It is currently the fourth cause of death among cancers in the western world. Unfortunately, systemic chemotherapy still relies on just a few drugs which until now have produced unsatisfactory results. Gemcitabine (2'-2'-difluorodeoxycytidine) is currently the standard chemotherapy treatment at all stages of pancreatic adenocarcinoma. Survival benefit and clinical impact however remain moderate due to a high degree of intrinsic and acquired resistance. Autophagy plays an important role in cell death decision but can also protect cells from various apoptotic stimuli. We investigated the function of autophagy in pancreatic carcinoma cells, which are frequently insensitive to standard chemotherapeutic agents. Here, we demonstrate that autophagy is one of the mechanisms responsible for the refractory response of pancreatic tumors to gemcitabine. We present evidence in vitro and in vivo that proves autophagy plays a protective role in pancreatic ductal carcinoma cells, preventing them from entering the apoptotic pathway after stimulus with gemcitabine, thus contributing to treatment resistance. A better understanding of the role in the process may help in the discovery of new strategies to overcome tumor drug resistance in this aggressive disease.
Sipunculans, a small phylum of coelomated marine worms closely related to polychaete annelids, lack a true circulatory system. We have previously shown that the sipunculan Themiste petricola can form a cellular clot, without congealing, of cell-free coelomic fluid. The clot is formed by the aggregation of large granular leukocytes (LGLs) and may serve not only haemostatic but immune functions, since dissimilar particles may become entrapped within it. We have now evaluated the capacity of a massive clot, induced in vitro by sea water contact, to stop coelomic fluid flow. We have further studied smaller clots induced on glass-slides either with or without the presence of bacteria placed for entrapment within the clot. The fate of clotting LGLs is cell death while forming a cohesive mass, although cytoplasmic and nuclear remnants are shed from the clot. These remnants and any bacteria that avoid clot entrapment or are detached from the clot are engulfed by non-clotting cells that include small granular leukocytes (SGLs) and large hyaline amebocytes (LHAs). Both cell types can be found other than in the clot but SGLs also occur around the clot edges heavily loaded with engulfed material. The cytoskeletal arrangement of SGLs evaluated with phalloidin-rhodamine correspond to motile cells and contrast with that of clotting LGLs that form a massive network of F-actin. Thus, the complementary roles between clotting LGLs and non-clotting SGLs and LHAs act a central immune strategy of Themiste petricola to deal with body wall injury and pathogen intrusion into the coelomic cavity.
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