Tumor vessel normalization after aerobic exercise enhances chemotherapeutic efficacy

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.

Vascular modulation through exercise improves chemotherapy efficacy in Ewing sarcoma

“…Similar to our own findings, exercise has been found to increase drug delivery to the tumor . In the present study, we found that exercise does not, however, increase chemotherapy delivery to non‐tumor‐bearing organs, including the heart, lungs, liver, and skeletal muscle.…”

“…The tumor vascular response to exercise appears to be partially dependent on tumor type. Others have demonstrated that exercise changes microvessel density, vessel length, or vessel patency; these were unchanged in our model . We did, however, have a similar observation in an increase in pericyte coverage .…”

“…Shear stress has been proposed to mediate exercise‐induced improvements in tumor vascular function . S1PR1 and S1PR2 regulate endothelium in vascular disease and cancer and are shear stress responsive .…”

“…Inefficient tumor vessels create heterogeneous, disturbed blood flow that results in uneven chemotherapy delivery to the tumor, consequently reducing chemotherapy efficacy. Using mouse models of cancers primarily found in the adult population (melanoma, pancreatic, breast, and prostate cancer), we and others have demonstrated that exercise can remodel tumor vasculature and improve chemotherapy efficacy by increasing drug delivery as well as oxygenation. In prostate tumors, for example, increased blood flow to the tumor after exercise decreased intratumoral hypoxia, converting a hypoxic, aggressive tumor phenotype with poorly structured tumor vasculature to a more oxygenated, slower‐growing tumor phenotype with organized, mature vasculature …”

Diet and exercise interventions for pediatric cancer patients during therapy: tipping the scales for better outcomes

“…Five days per week of high intensity treadmill running alone had no effect on tumor growth in mice bearing orthotopic glioblastoma tumors, but increased survival and decreased tumor growth when combined with temozolomide (TMZ) compared to TMZ alone (69). Similarly, treadmill running at a more moderate intensity increased the efficacy of gemcitabine against pancreatic ductal adenocarcinoma and of doxorubicin against melanoma in mice (70). Voluntary wheel running also significantly increased the efficacy of chemotherapy in multiple models.…”