Senolytic elimination of Cox2-expressing senescent cells inhibits the growth of premalignant pancreatic lesions
| Autor: | Areej Khatib, Lior Roitman, Sharona Elgavish, Narmen Azazmeh, Anna Hochner-Ger, Eli Pikarsky, Gideon Zamir, Rachel Kalifa, Benjamin Assouline, Jonathan Demma, Yonatan Khalatnik, Yehuda Schlesinger, Yuval Dor, Karen Meir, Hadar Benyamini, Valery Krizhanovsky, Oren Parnas, Ittai Ben-Porath, Shaul Horwitz, Ashraf Imam, Karine Atlan, Yossi Ovadya, Dror Kolodkin-Gal, Eitan Winter |
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| Rok vydání: | 2021 |
| Předmět: |
pancreatic tumours
0301 basic medicine Pancreatic ductal adenocarcinoma endocrine system diseases cell cycle control Pancreatic Intraepithelial Neoplasia Cellular senescence Adenocarcinoma Biology Disease course Proinflammatory cytokine Mice 03 medical and health sciences Paracrine signalling 0302 clinical medicine Senotherapeutics cell biology Animals Senolytic Pancreas Cellular Senescence Gastroenterology 3. Good health Pancreatic Neoplasms Disease Models Animal 030104 developmental biology Tumour development Cyclooxygenase 2 030220 oncology & carcinogenesis Cancer research Precancerous Conditions |
| Zdroj: | Gut |
| ISSN: | 0017-5749 |
| DOI: | 10.1136/gutjnl-2020-321112 |
| Popis: | ObjectiveCellular senescence limits tumourigenesis by blocking the proliferation of premalignant cells. Additionally, however, senescent cells can exert paracrine effects influencing tumour growth. Senescent cells are present in premalignant pancreatic intraepithelial neoplasia (PanIN) lesions, yet their effects on the disease are poorly characterised. It is currently unknown whether senolytic drugs, aimed at eliminating senescent cells from lesions, could be beneficial in blocking tumour development.DesignTo uncover the functions of senescent cells and their potential contribution to early pancreatic tumourigenesis, we isolated and characterised senescent cells from PanINs formed in a Kras-driven mouse model, and tested the consequences of their targeted elimination through senolytic treatment.ResultsWe found that senescent PanIN cells exert a tumour-promoting effect through expression of a proinflammatory signature that includes high Cox2 levels. Senolytic treatment with the Bcl2-family inhibitor ABT-737 eliminated Cox2-expressing senescent cells, and an intermittent short-duration treatment course dramatically reduced PanIN development and progression to pancreatic ductal adenocarcinoma.ConclusionsThese findings reveal that senescent PanIN cells support tumour growth and progression, and provide a first indication that elimination of senescent cells may be effective as preventive therapy for the progression of precancerous lesions. |
| Databáze: | OpenAIRE |
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