Abstract
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.
Highlights
Tumor vasculature is unorganized and leaky; as many as 50% of tumor vessels are non-functional [1]
One of the many effects of aerobic exercise is a systemic increase in blood flow that increases the mechanical force on endothelial cells at a rate proportional to exercise intensity [13]
Improved chemotherapy delivery through tumor vascular normalization has proven effective in multiple mouse models of cancer and in patients, but vascular normalization using anti-angiogenic agents has not gained wide clinical use due a small window of efficacy and significant adverse side effects [4, 16]
Summary
Tumor vasculature is unorganized and leaky; as many as 50% of tumor vessels are non-functional [1]. Drug delivery to tumors is inefficient, reducing chemotherapeutic efficacy. The concept of vascular normalization, originally proposed by Jain and colleagues in 2001, posits that restoring the balance of angiogenic regulators by decreasing pro-angiogenic factors remodels tumor vasculature to become more organized and functional, similar to normal vasculature [2]. Anti-angiogenic drugs normalize tumor vasculature to increase chemotherapy delivery to the tumor, and have been used in combination with chemotherapy to enhance chemotherapeutic efficacy in multiple cancer types [3]. The utility of vascular normalization has been demonstrated in glioblastoma patients who were treated with the anti-angiogenic agent cediranib in combination with chemoradiation. Resistance to anti-angiogenic therapy and significant adverse side effects necessitate better approaches to normalize tumor vasculature [5]
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