The DOI matches its Crossref record; 11 of the 11 references it cites were found in a registry or an index.
Cholinergic Signaling via Muscarinic Receptors Directly and Indirectly Suppresses Pancreatic Tumorigenesis and Cancer Stemness
Open accessAbstract
In many solid tumors, parasympathetic input is provided by the vagus nerve, which has been shown to modulate tumor growth. However, whether cholinergic signaling directly regulates progression of pancreatic ductal adenocarcinoma (PDAC) has not been defined. Here, we found that subdiaphragmatic vagotomy in LSL-Kras+/G12D;Pdx1-Cre (KC) mice accelerated PDAC development, whereas treatment with the systemic muscarinic agonist bethanechol restored the normal KC phenotype, thereby suppressing the accelerated tumorigenesis caused by vagotomy. In LSL-Kras+/G12D;LSL-Trp53+/R172H;Pdx1-Cre mice with established PDAC, bethanechol significantly extended survival. These effects were mediated in part through CHRM1, which inhibited downstream MAPK/EGFR and PI3K/AKT pathways in PDAC cells. Enhanced cholinergic signaling led to a suppression of the cancer stem cell (CSC) compartment, CD11b+ myeloid cells, TNFα levels, and metastatic growth in the liver. Therefore, these data suggest that cholinergic signaling directly and indirectly suppresses growth of PDAC cells, and therapies that stimulate muscarinic receptors may be useful in the treatment of PDAC. Significance: Subdiaphragmatic vagotomy or Chrm1 knockout accelerates pancreatic tumorigenesis, in part via expansion of the CSC compartment. Systemic administration of a muscarinic agonist suppresses tumorigenesis through MAPK and PI3K/AKT signaling, in early stages of tumor growth and in more advanced, metastatic disease. Therefore, CHRM1 may represent a potentially attractive therapeutic target. Cancer Discov; 8(11); 1458–73. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1333
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Autonomic nerve development contributes to prostate cancer progression
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Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function
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Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis
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Therapeutic developments in pancreatic cancer: current and future perspectives
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Self-citationMicroenvironmental Determinants of Pancreatic Cancer
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Self-citationNeurons release serine to support mRNA translation in pancreatic cancer
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Metadata
- Authors
- Renz, B. W., Tanaka, T., Sunagawa, M., Takahashi, R., Jiang, Z., Macchini, M., Dantes, Z., Valenti, G., White, R. A., Middelhoff, M. A., Ilmer, M., Oberstein, P. E., Angele, M. K., Deng, H., Hayakawa, Y., Westphalen, C. B., Werner, J., Remotti, H., Reichert, M., Tailor, Y. H., Nagar, K., Friedman, R. A., Iuga, A. C., Olive, K. P., & Wang, T. C.
- Venue
- Cancer Discovery
- Published
- 2018-11-01
- Volume
- 8
- Issue
- 11
- Pages
- 1458-1473
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- OpenAlex
- W2891570794
- Cited by
- 360
- References
- 11
- FWCI
- 14.05
- Type
- journal article
- Language
- en
- Open access
- green
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- Renz, B. W., Tanaka, T., Sunagawa, M., Takahashi, R., Jiang, Z., Macchini, M., Dantes, Z., Valenti, G., White, R. A., Middelhoff, M. A., Ilmer, M., Oberstein, P. E., Angele, M. K., Deng, H., Hayakawa, Y., Westphalen, C. B., Werner, J., Remotti, H., Reichert, M., . . . Wang, T. C. (2018). Cholinergic Signaling via Muscarinic Receptors Directly and Indirectly Suppresses Pancreatic Tumorigenesis and Cancer Stemness. Cancer Discovery. https://doi.org/10.1158/2159-8290.cd-18-0046
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
