Tumor Vessel Normalization through Increased Shear Stress by Exercise Enhances Chemotherapeutic Efficacy

Chemotherapy is the standard of care for most cancers but has limited efficacy and associated adverse side effects. Targeted therapies are now utilized in combination with chemotherapy to improve outcome. Anti-angiogenic agents are targeted therapies that enhance chemotherapeutic efficacy by normalizing tumor vasculature to improve delivery of chemotherapy. Tumor vessels are disorganized and largely dysfunctional, with disrupted blood flow impeding drug delivery to cancer cells. Although pharmacologic anti-angiogenic therapy can remodel tumor vessels, there is a limited window of efficacy and these drugs are associated with severe side effects necessitating alternatives for vascular normalization. Shear stress, the force exerted on endothelial cells by blood flow, regulates vessel sprouting and permeability. Increasing vascular shear stress through aerobic exercise can alter blood vessels in normal tissues. We found that increasing shear stress in mice using a clinically relevant program of moderate aerobic exercise normalized tumor vasculature, increasing the number of functional vessels and ultimately drug delivery, in melanoma, pancreatic ductal adenocarcinoma, and Ewing sarcoma models. Importantly, combining exercise with chemotherapy caused a significantly greater decrease in tumor growth than chemotherapy alone in all tumor models. Further, we demonstrate that shear stress activates the transcription factor Nuclear Factor of Activated T cells (NFAT) to induce expression of Thrombospondin-1 (Tsp-1) in endothelial cells. Our data indicate that endothelial activation of calcineurin-NFAT-Tsp-1 signaling plays a critical role in exercise-induced, shear stress-mediated tumor vessel remodeling. Our work suggests that the vascular normalizing effects of aerobic exercise can be an effective chemotherapy adjuvant.