Aspirin’s effect on kinetic parameters of cells contributes to its role in reducing incidence of advanced colorectal adenomas, shown by a multiscale computational study
Aspirin intake has been shown to lead to significant protection against colorectal cancer, for example with an up to twofold reduction in colorectal adenoma incidence rates at higher doses. The mechanisms contributing to protection are not yet fully understood. While aspirin is an anti-inflammatory...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-04-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/71953 |
| _version_ | 1811203610994802688 |
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| author | Yifan Wang C Richard Boland Ajay Goel Dominik Wodarz Natalia L Komarova |
| author_facet | Yifan Wang C Richard Boland Ajay Goel Dominik Wodarz Natalia L Komarova |
| author_sort | Yifan Wang |
| collection | DOAJ |
| description | Aspirin intake has been shown to lead to significant protection against colorectal cancer, for example with an up to twofold reduction in colorectal adenoma incidence rates at higher doses. The mechanisms contributing to protection are not yet fully understood. While aspirin is an anti-inflammatory drug and can thus influence the tumor microenvironment, in vitro and in vivo experiments have recently shown that aspirin can also have a direct effect on cellular kinetics and fitness. It reduces the rate of tumor cell division and increases the rate of cell death. The question arises whether such changes in cellular fitness are sufficient to significantly contribute to the epidemiologically observed protection. To investigate this, we constructed a class of mathematical models of in vivo evolution of advanced adenomas, parameterized it with available estimates, and calculated population level incidence. Fitting the predictions to age incidence data revealed that only a model that included colonic crypt competition can account for the observed age-incidence curve. This model was then used to predict modified incidence patterns if cellular kinetics were altered as a result of aspirin treatment. We found that changes in cellular fitness that were within the experimentally observed ranges could reduce advanced adenoma incidence by a sufficient amount to account for age incidence data in aspirin-treated patient cohorts. While the mechanisms that contribute to the protective effect of aspirin are likely complex and multi-factorial, our study demonstrates that direct aspirin-induced changes of tumor cell fitness can significantly contribute to epidemiologically observed reduced incidence patterns. |
| first_indexed | 2024-04-12T02:59:21Z |
| format | Article |
| id | doaj.art-3a475a3033f544a39a1ab648e5ff87bf |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:59:21Z |
| publishDate | 2022-04-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-3a475a3033f544a39a1ab648e5ff87bf2022-12-22T03:50:43ZengeLife Sciences Publications LtdeLife2050-084X2022-04-011110.7554/eLife.71953Aspirin’s effect on kinetic parameters of cells contributes to its role in reducing incidence of advanced colorectal adenomas, shown by a multiscale computational studyYifan Wang0https://orcid.org/0000-0003-3292-4972C Richard Boland1https://orcid.org/0000-0002-8120-5088Ajay Goel2https://orcid.org/0000-0003-1396-6341Dominik Wodarz3https://orcid.org/0000-0002-8017-3707Natalia L Komarova4https://orcid.org/0000-0003-4876-0343Department of Mathematics, University of California Irvine, Irvine, United StatesDepartment of Medicine, University of California San Diego School of Medicine, San Diego, United StatesDepartment of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, United StatesDepartment of Mathematics, University of California Irvine, Irvine, United States; Department of Population Health and Disease Prevention, University of California Irvine, Irvine, United StatesDepartment of Mathematics, University of California Irvine, Irvine, United StatesAspirin intake has been shown to lead to significant protection against colorectal cancer, for example with an up to twofold reduction in colorectal adenoma incidence rates at higher doses. The mechanisms contributing to protection are not yet fully understood. While aspirin is an anti-inflammatory drug and can thus influence the tumor microenvironment, in vitro and in vivo experiments have recently shown that aspirin can also have a direct effect on cellular kinetics and fitness. It reduces the rate of tumor cell division and increases the rate of cell death. The question arises whether such changes in cellular fitness are sufficient to significantly contribute to the epidemiologically observed protection. To investigate this, we constructed a class of mathematical models of in vivo evolution of advanced adenomas, parameterized it with available estimates, and calculated population level incidence. Fitting the predictions to age incidence data revealed that only a model that included colonic crypt competition can account for the observed age-incidence curve. This model was then used to predict modified incidence patterns if cellular kinetics were altered as a result of aspirin treatment. We found that changes in cellular fitness that were within the experimentally observed ranges could reduce advanced adenoma incidence by a sufficient amount to account for age incidence data in aspirin-treated patient cohorts. While the mechanisms that contribute to the protective effect of aspirin are likely complex and multi-factorial, our study demonstrates that direct aspirin-induced changes of tumor cell fitness can significantly contribute to epidemiologically observed reduced incidence patterns.https://elifesciences.org/articles/71953mathematical modelingaspirinadvanced adenomacolon cancer |
| spellingShingle | Yifan Wang C Richard Boland Ajay Goel Dominik Wodarz Natalia L Komarova Aspirin’s effect on kinetic parameters of cells contributes to its role in reducing incidence of advanced colorectal adenomas, shown by a multiscale computational study eLife mathematical modeling aspirin advanced adenoma colon cancer |
| title | Aspirin’s effect on kinetic parameters of cells contributes to its role in reducing incidence of advanced colorectal adenomas, shown by a multiscale computational study |
| title_full | Aspirin’s effect on kinetic parameters of cells contributes to its role in reducing incidence of advanced colorectal adenomas, shown by a multiscale computational study |
| title_fullStr | Aspirin’s effect on kinetic parameters of cells contributes to its role in reducing incidence of advanced colorectal adenomas, shown by a multiscale computational study |
| title_full_unstemmed | Aspirin’s effect on kinetic parameters of cells contributes to its role in reducing incidence of advanced colorectal adenomas, shown by a multiscale computational study |
| title_short | Aspirin’s effect on kinetic parameters of cells contributes to its role in reducing incidence of advanced colorectal adenomas, shown by a multiscale computational study |
| title_sort | aspirin s effect on kinetic parameters of cells contributes to its role in reducing incidence of advanced colorectal adenomas shown by a multiscale computational study |
| topic | mathematical modeling aspirin advanced adenoma colon cancer |
| url | https://elifesciences.org/articles/71953 |
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