Cholinergic Signaling via Muscarinic Receptors Directly and Indirectly Suppresses Pancreatic Tumorigenesis and Cancer Stemness
| Autor: | Yagnesh Tailor, Marina Macchini, Timothy C. Wang, Bernhard W. Renz, Zahra Dantes, Moritz Middelhoff, J. Werner, Paul E. Oberstein, Alina Iuga, Richard A. Friedman, Huan Deng, C. Benedikt Westphalen, Kenneth P. Olive, Matthias Ilmer, Yoku Hayakawa, Giovanni Valenti, Ryota Takahashi, Ruth A. White, Helen Remotti, Zhengyu Jiang, Maximilian Reichert, Masaki Sunagawa, Martin K. Angele, Karan Nagar, Takayuki Tanaka |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway endocrine system diseases Cholinergic Agents Bethanechol Mice SCID Muscarinic agonist Article 03 medical and health sciences Mice Mice Inbred NOD Muscarinic acetylcholine receptor medicine Animals Humans Protein kinase B PI3K/AKT/mTOR pathway Mice Knockout Chemistry Receptor Muscarinic M1 digestive system diseases Mice Inbred C57BL Pancreatic Neoplasms 030104 developmental biology Cell Transformation Neoplastic Genes ras Oncology Cancer research Neoplastic Stem Cells Cholinergic Tumor necrosis factor alpha medicine.drug Carcinoma Pancreatic Ductal Signal Transduction |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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