Tumor vessel normalization after aerobic exercise enhances chemotherapeutic efficacy
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Keri L. Schadler1, Nicholas J. Thomas1, Peter A. Galie2, Dong Ha Bhang1, Kerry C. Roby1, Prince Addai1, Jacob E. Till1, Kathleen Sturgeon1, Alexander Zaslavsky1, Christopher S. Chen3, Sandra Ryeom1
1Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Abramson Family Cancer Research Institute, Philadelphia, PA 19104, USA
2Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104, USA
3Department of Bioengineering, Boston University, Boston, MA 02215, USA
Sandra Ryeom, email: [email protected]
Keywords: tumor vascular normalization, NFAT, thrombospondin-1, exercise
Received: May 11, 2016 Accepted: August 25, 2016 Published: August 31, 2016
Targeted therapies aimed at tumor vasculature are utilized in combination with chemotherapy to improve drug delivery and efficacy after tumor vascular normalization. Tumor vessels are highly disorganized with disrupted blood flow impeding drug delivery to cancer cells. Although pharmacologic anti-angiogenic therapy can remodel and normalize tumor vessels, there is a limited window of efficacy and these drugs are associated with severe side effects necessitating alternatives for vascular normalization. Recently, moderate aerobic exercise has been shown to induce vascular normalization in mouse models. Here, we provide a mechanistic explanation for the tumor vascular normalization induced by exercise. Shear stress, the mechanical stimuli exerted on endothelial cells by blood flow, modulates vascular integrity. Increasing vascular shear stress through aerobic exercise can alter and remodel blood vessels in normal tissues. Our data in mouse models indicate that activation of calcineurin-NFAT-TSP1 signaling in endothelial cells plays a critical role in exercise-induced shear stress mediated tumor vessel remodeling. We show that moderate aerobic exercise with chemotherapy caused a significantly greater decrease in tumor growth than chemotherapy alone through improved chemotherapy delivery after tumor vascular normalization. Our work suggests that the vascular normalizing effects of aerobic exercise can be an effective chemotherapy adjuvant.
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