Abstract 5281: An exercise intervention for pancreas cancer patients increases tumor vascularity

Claudia Alvarez Florez, Nathan Parker, Matthew Katz, An Ngo-Huang, Carol Ferreira Cardoso, Huamin Wang, Maria Petzel, David Fogelman, Keri Schadler
2018 Cancer Research  
The efficacy of chemotherapy is reduced by dysfunctional tumor vasculature, which may limit chemotherapy delivery to tumors. preclinical studies have shown that moderate aerobic exercise improves tumor vascular function and increases chemotherapy efficacy in mouse models, but the effect of exercise on human tumor vasculature has not yet been determined. Here, we demonstrate that exercise remodels the tumor vasculature, accelerates the regression, and delays the regrowth of pancreatic ductal
more » ... ncreatic ductal adenocarcinoma in a patient-derived xenograft mouse model treated with gemcitabine. By evaluating pancreatic adenocarcinoma specimens from patients treated with preoperative chemotherapy or chemoradiation therapy, we also demonstrate for the first time that tumor vascular remodeling occurs in association with exercise in humans. future studies will evaluate whether exercise-induced vascular remodeling improves gemcitabine or other chemotherapy efficacy in patients, as this study evaluated only changes in tumor vascular structure. Physical activity as a component of care for cancer patients is well accepted as a method to treat fatigue, fitness loss, and the psychosocial side effects of cancer treatment 1-3 . In addition, pre-clinical evidence suggests that exercise is useful as an adjuvant to chemotherapy by improving chemotherapy delivery and anti-tumor efficacy. We and others have demonstrated that moderate aerobic exercise remodels tumor vasculature to improve blood delivery, and thus drug delivery, to prostate, breast, and pancreas tumors in mouse models 4-6 . Pancreas ductal adenocarcinoma have a dense stromal component that compresses vasculature, stunts blood vessel growth, and reduces blood vessel function, preventing the effective delivery of drugs to the tumor cells. Therefore, one possible method for improving outcomes for patients receiving standard chemotherapy is to improve the vasculature within the tumor. In one study, the combination of gemcitabine plus treadmill walking inhibited the growth of a pancreatic ductal adenocarcinoma cell line subcutaneously injected into mice significantly more than gemcitabine alone. This greater inhibition depended on vascular remodeling after exercise, which correlated with more chemotherapy delivery to tumors 6 . When vascular remodeling was prevented pharmacologically or genetically, the improved efficacy afforded by exercise was lost, indicating a direct relationship between improved vasculature and improved chemotherapy efficacy. Although the ability of moderate-intensity aerobic exercise to remodel tumor vasculature in animal models is well established, the exercise intensity or duration necessary to induce vascular remodeling in patients is unclear. It is also unclear whether human tumor vasculature will remodel in response to exercise, as predicted by animal models. To obtain the maximal benefit of exercise for patients, it is important to understand whether exercise
doi:10.1158/1538-7445.am2018-5281 fatcat:3rj5jqsoszhw3p2vxoy4m6hq7y