Aspirin’s effect on kinetic parameters ofcells contributes to its role in reducingincidence of advanced colorectaladenomas, shown by a multiscalecomputational 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 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.