Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is characterized by high resistance to anti-cancer therapies. This resistance is caused in part by hypo-vascularization and dysfunctional vessels which inefficiently deliver chemotherapy. Here, we define the mechanism of aerobic exercise-induced tumor vascular remodeling and improved chemotherapy delivery and efficacy. We found that aerobic exercise was able to improve tumor vascular function and increase the number of lymphatic vessels, and these effects were associated with increased gemcitabine delivery to and efficacy against PDAC in mice. Further, exercise increased sphingosine-1-phosphate (S1P) in plasma and the activation of sphingosine-1-phosphate receptor 1 (S1PR1) in tumor endothelial cells. S1PR1 endothelial cell-specific deletion blunted the exercise-induced improvements in tumor vascular function, gemcitabine efficacy and drug concentration. Preclinical findings were validated in a patient cohort in which we found that exercise during neoadjuvant chemotherapy remodeled PDAC vasculature and improved tumor vascular function. These findings provide direct evidence that exercise increases chemotherapy delivery and efficacy by improving vascular function, defining S1PR1 as a necessary mediator of exercise-induced vascular remodeling.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Small changes in wording for better addressing the section with clinical data. Added n of samples under each graph Corrected error in sample numerosity in Figure 1b, c and Supplementary Figure 6o, p.