Araştırma Çıktıları

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Author: search.filters.author.Ren, LeiSubject: search.filters.subject.Pancreatic cancer

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    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 Ekin
    Background 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.
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    Neoadjuvant therapy in pancreatic cancer: what is the true oncological benefit?
    (SPRINGER, 2020-01-01) Ren, Lei; Mota Reyes, Carmen; Friess, Helmut; Demir, Ihsan Ekin
    Background Neoadjuvant therapies (neoTx) have revolutionized the treatment of borderline resectable (BR) and locally advanced (LA) pancreatic cancer (PCa) by significantly increasing the rate of R0 resections, which remains the only curative strategy for these patients. However, there is still room for improvement of neoTx in PCa. Purpose Here, we aimed to critically analyze the benefits of neoTx in LA and BR PCa and its potential use on patients with resectable PCa. We also explored the feasibility of arterial resection (AR) to increase surgical radicality and the incorporation of immunotherapy to optimize neoadjuvant approaches in PCa. Conclusion For early stage, i.e., resectable, PCa, there is not enough scientific evidence for routinely recommending neoTx. For LA and BR PCa, optimization of neoadjuvant therapy necessitates more sophisticated complex surgical resections, machine learning and radiomic approaches, integration of immunotherapy due to the high antigen load, standardized histopathological assessment, and improved multidisciplinary communication.