Indirect cholinergic activation slows down pancreatic cancer growth and tumor-associated inflammation Article Swipe
Paulo L. Pfitzinger
,
Laura Fangmann
,
Kun Wang
,
Elke Demir
,
Engin Gürlevik
,
Bettina Fleischmann-Mundt
,
Jennifer D. Brooks
,
Jan D‘Haese
,
Steffen Teller
,
Andreas Hecker
,
Moritz Jesinghaus
,
Carsten Jäger
,
Lei Ren
,
Rouzanna Istvánffy
,
Florian Kühnel
,
Helmut Friess
,
Güralp O. Ceyhan
,
İhsan Ekin Demir
·
YOU?
·
· 2020
· Open Access
·
· DOI: https://doi.org/10.21203/rs.3.rs-60829/v2
YOU?
·
· 2020
· Open Access
·
· DOI: https://doi.org/10.21203/rs.3.rs-60829/v2
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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Metadata
- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.21203/rs.3.rs-60829/v2
- https://www.researchsquare.com/article/rs-60829/latest.pdf
- OA Status
- green
- References
- 28
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4232891608
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4232891608Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.21203/rs.3.rs-60829/v2Digital Object Identifier
- Title
-
Indirect cholinergic activation slows down pancreatic cancer growth and tumor-associated inflammationWork title
- Type
-
preprintOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2020Year of publication
- Publication date
-
2020-12-21Full publication date if available
- Authors
-
Paulo L. Pfitzinger, Laura Fangmann, Kun Wang, Elke Demir, Engin Gürlevik, Bettina Fleischmann-Mundt, Jennifer D. Brooks, Jan D‘Haese, Steffen Teller, Andreas Hecker, Moritz Jesinghaus, Carsten Jäger, Lei Ren, Rouzanna Istvánffy, Florian Kühnel, Helmut Friess, Güralp O. Ceyhan, İhsan Ekin DemirList of authors in order
- Landing page
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https://doi.org/10.21203/rs.3.rs-60829/v2Publisher landing page
- PDF URL
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https://www.researchsquare.com/article/rs-60829/latest.pdfDirect link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
greenOpen access status per OpenAlex
- OA URL
-
https://www.researchsquare.com/article/rs-60829/latest.pdfDirect OA link when available
- Concepts
-
Inflammation, Cholinergic, Pancreatic cancer, Cancer, Cancer research, Medicine, Internal medicineTop concepts (fields/topics) attached by OpenAlex
- Cited by
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0Total citation count in OpenAlex
- References (count)
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28Number of works referenced by this work
- Related works (count)
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10Other works algorithmically related by OpenAlex
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| citation_normalized_percentile.value | 0.28562428 |
| citation_normalized_percentile.is_in_top_1_percent | False |
| citation_normalized_percentile.is_in_top_10_percent | False |