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Permanent URI for this collectionhttps://hdl.handle.net/11443/932
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Item Indirect cholinergic activation slows down pancreatic cancer growth and tumor-associated inflammation(BMC, 2020-01-01) Pfitzinger, Paulo L.; Fangmann, Laura; Wang, Kun; Demir, Elke; Guerlevik, Engin; Fleischmann-Mundt, Bettina; Brooks, Jennifer; D'Haese, Jan G.; Teller, Steffen; Hecker, Andreas; Jesinghaus, Moritz; Jaeger, Carsten; Ren, Lei; Istvanffy, Rouzanna; Kuehnel, Florian; Friess, Helmut; Ceyhan, Guralp Onur; Demir, Ihsan EkinBackground Nerve-cancer interactions are increasingly recognized to be of paramount importance for the emergence and progression of pancreatic cancer (PCa). Here, we investigated the role of indirect cholinergic activation on PCa progression through inhibition of acetylcholinesterase (AChE) via clinically available AChE-inhibitors, i.e. physostigmine and pyridostigmine. Methods We applied immunohistochemistry, immunoblotting, MTT-viability, invasion, flow-cytometric-cell-cycle-assays, phospho-kinase arrays, multiplex ELISA and xenografted mice to assess the impact of AChE inhibition on PCa cell growth and invasiveness, and tumor-associated inflammation. Survival analyses were performed in a novel genetically-induced, surgically-resectable mouse model of PCa under adjuvant treatment with gemcitabine+/-physostigmine/pyridostigmine (n = 30 mice). Human PCa specimens (n = 39) were analyzed for the impact of cancer AChE expression on tumor stage and survival. Results We discovered a strong expression of AChE in cancer cells of human PCa specimens. Inhibition of this cancer-cell-intrinsic AChE via pyridostigmine and physostigmine, or administration of acetylcholine (ACh), diminished PCa cell viability and invasion in vitro and in vivo via suppression of pERK signaling, and reduced tumor-associated macrophage (TAM) infiltration and serum pro-inflammatory cytokine levels. In the novel genetically-induced, surgically-resectable PCa mouse model, adjuvant co-therapy with AChE blockers had no impact on survival. Accordingly, survival of resected PCa patients did not differ based on tumor AChE expression levels. Patients with higher-stage PCa also exhibited loss of the ACh-synthesizing enzyme, choline-acetyltransferase (ChAT), in their nerves. Conclusion For future clinical trials of PCa, direct cholinergic stimulation of the muscarinic signaling, rather than indirect activation via AChE blockade, may be a more effective strategy.Item Genetic landscape of pancreatic cancer: a narrative review(AME PUBL CO, 2022-01-01) Yakar, Didem Oncel; Bozkirli, Bahadir Osman; Ceyhan, Guralp OnurBackground and Objective: Pancreatic cancer is an aggressive disease with an impaired survival despite improvements in clinical management. Thus, understanding disease biology is of vital importance in order to overcome therapeutic challenges and achieve better prognosis. The purpose of this review is to outline the genetic landscape of pancreatic cancer along with its clinical implications. Methods: We reviewed existing literature using electronic databases to outline the genetic landscape in pancreatic cancer. Key Content and Findings: This review mainly contains information on the genetic background of pancreatic cancer, mainly KRAS, CDKN2A, TP53 and SMAD4, with emphasis on the importance of understanding disease biology. Conclusions: The genetic aspects of pancreatic cancer have been well described especially with the introduction of next generation sequencing techniques. Future studies focusing on translation of these alterations in clinical application might pave the way for personalized surveillance and therapy.