Abstract
BackgroundWhile self-reported exercise is associated with a reduction in the risk of recurrence in colorectal cancer, the molecular mechanisms underpinning this relationship are unknown. Furthermore, the effect of exercise on intratumoral metabolic processes has not been investigated in detail in human cancers. In our current study, we generated six colorectal patient patient-derived xenografts (CRC PDXs) models and treated each PDX to voluntary wheel running (exercise) for 6–8 weeks or no exposure to the wheel (control). A comprehensive metabolomics analysis was then performed on the PDXs to identify exercise induced changes in the tumor that were associated with slower growth.ResultsTumor growth inhibition was observed in the voluntary wheel running group compared to the control group in three of the six models. A metabolomics analysis first revealed that central carbon metabolism was affected in each model irrespective of treatment. Interestingly, comparison of responsive and resistant models showed that levels of metabolites in nucleotide metabolism, known to be coupled to mitochondrial metabolism, were predictive of response. Furthermore, phosphocreatine levels which are linked to mitochondrial energy demands were associated with inhibition of tumor growth.ConclusionAltogether, this study provides evidence that changes to tumor cell mitochondrial metabolism may underlie in part the benefits of exercise.
Highlights
While self-reported exercise is associated with a reduction in the risk of recurrence in colorectal cancer, the molecular mechanisms underpinning this relationship are unknown
Using our established Patient-derived xenografts (PDX) approach coupled with metabolomics analysis of tumor samples, our current study provides the first characterization of the effect of exercise on PDX tumor growth as well as a global analysis of the metabolic alterations induced by exercise in both exercise-responsive and exercise-non-responsive tumors
Similar to our previous work, pathological features between matched PDX and patient tumor were observed (Additional file 1: Figure S1A). We subsequently used these six colorectal cancer (CRC) PDX models to study the effect of exercise on tumorigenesis
Summary
While self-reported exercise is associated with a reduction in the risk of recurrence in colorectal cancer, the molecular mechanisms underpinning this relationship are unknown. It is well appreciated that tumor cells alter their metabolism to support the demands of growth, survival, and proliferation [8, 9], whether exercise could affect cancer through alterations in metabolism remains unexplored in human cancer. As is it well appreciated that tumor cells alter their metabolism to support the demands of growth, survival, and proliferation [8, 9], numerous studies have documented selective requirements of mitochondria for tumor growth [10, 11]. Given that exercise alters systemic metabolism which should lead to concomitant changes in mitochondrial metabolism in all cells including cancer cells, a speculative hypothesis states that exercise may directly affect tumor cell proliferation by altering mitochondrial metabolism, but evidence to support such a theory is still lacking
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