TY - JOUR
T1 - Vascular modulation through exercise improves chemotherapy efficacy in Ewing sarcoma
AU - Morrell, Miriam B.G.
AU - Alvarez-Florez, Claudia
AU - Zhang, Aiqian
AU - Kleinerman, Eugenie S.
AU - Savage, Hannah
AU - Marmonti, Enrica
AU - Park, Minjeong
AU - Shaw, Angela
AU - Schadler, Keri L.
N1 - Funding Information:
informationThis publication was supported in part by MD Anderson's Histopathology Core Lab, award number 2P30CA016672-38 from the NIH National Cancer Institute.The authors gratefully acknowledge the Department of Scientific Publications, especially Mr Joseph Munch, for their editorial support and the Center for Energy Balance in Cancer Prevention and Survivorship at the MD Anderson Cancer Center. This publication was supported in part by MD Anderson's Histopathology Core Lab, award number 2P30CA016672-38 from the NIH National Cancer Institute, and by the Cancer Prevention and Research Institute of Texas award RP190256. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. The data that support the findings of this study are available from the corresponding author upon reasonable request.
Funding Information:
The authors gratefully acknowledge the Department of Scientific Publications, especially Mr Joseph Munch, for their editorial support and the Center for Energy Balance in Cancer Prevention and Survivorship at the MD Anderson Cancer Center. This publication was supported in part by MD Anderson’s Histopathology Core Lab, award number 2P30CA016672-38 from the NIH National Cancer Institute, and by the Cancer Prevention and Research Institute of Texas award RP190256. Its contents are solely the responsibility of the authors and
Publisher Copyright:
© 2019 The Authors. Pediatric Blood & Cancer Published by Wiley Periodicals, Inc.
PY - 2019/9
Y1 - 2019/9
N2 - Recent studies in mouse models of cancer have shown that exercise improves tumor vascular function, thereby improving chemotherapy delivery and efficacy. However, the mechanisms underlying this improvement remain unclear and the effect of exercise on Ewing sarcoma (ES), a pediatric bone and soft tissue cancer, is unknown. The effect of exercise on tumor vascular hyperpermeability, which inversely correlates with drug delivery to the tumor, has also not been evaluated. We hypothesized that exercise improves chemotherapy efficacy by enhancing its delivery through improving tumor vascular permeability. We treated ES-bearing mice with doxorubicin with or without moderate treadmill exercise. Exercise did not significantly alter ES tumor vessel morphology. However, compared to control mice, tumors of exercised mice had significantly reduced hyperpermeability, significantly decreased hypoxia, and higher doxorubicin penetration. Compared to doxorubicin alone, doxorubicin plus exercise inhibited tumor growth more efficiently. We evaluated endothelial cell sphingosine-1-phosphate receptors 1 and 2 (S1PR1 and S1PR2) as potential mediators of the improved vascular permeability and increased function afforded by exercise. Relative to tumors from control mice, vessels in tumors from exercised mice had increased S1PR1 and decreased S1PR2 expression. Our results support a model in which exercise remodels ES vasculature to reduce vessel hyperpermeability, potentially via modulation of S1PR1 and S1PR2, thereby improving doxorubicin delivery and inhibiting tumor growth more than doxorubicin alone does. Our data suggest moderate aerobic exercise should be tested in clinical trials as a potentially useful adjuvant to standard chemotherapy for patients with ES.
AB - Recent studies in mouse models of cancer have shown that exercise improves tumor vascular function, thereby improving chemotherapy delivery and efficacy. However, the mechanisms underlying this improvement remain unclear and the effect of exercise on Ewing sarcoma (ES), a pediatric bone and soft tissue cancer, is unknown. The effect of exercise on tumor vascular hyperpermeability, which inversely correlates with drug delivery to the tumor, has also not been evaluated. We hypothesized that exercise improves chemotherapy efficacy by enhancing its delivery through improving tumor vascular permeability. We treated ES-bearing mice with doxorubicin with or without moderate treadmill exercise. Exercise did not significantly alter ES tumor vessel morphology. However, compared to control mice, tumors of exercised mice had significantly reduced hyperpermeability, significantly decreased hypoxia, and higher doxorubicin penetration. Compared to doxorubicin alone, doxorubicin plus exercise inhibited tumor growth more efficiently. We evaluated endothelial cell sphingosine-1-phosphate receptors 1 and 2 (S1PR1 and S1PR2) as potential mediators of the improved vascular permeability and increased function afforded by exercise. Relative to tumors from control mice, vessels in tumors from exercised mice had increased S1PR1 and decreased S1PR2 expression. Our results support a model in which exercise remodels ES vasculature to reduce vessel hyperpermeability, potentially via modulation of S1PR1 and S1PR2, thereby improving doxorubicin delivery and inhibiting tumor growth more than doxorubicin alone does. Our data suggest moderate aerobic exercise should be tested in clinical trials as a potentially useful adjuvant to standard chemotherapy for patients with ES.
KW - Ewing sarcoma
KW - S1PR
KW - alternative medicine
KW - angiogenesis
KW - chemotherapy delivery
KW - exercise
KW - oncology
KW - pediatric oncology
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U2 - 10.1002/pbc.27835
DO - 10.1002/pbc.27835
M3 - Article
C2 - 31136074
AN - SCOPUS:85069522525
SN - 1545-5009
VL - 66
JO - Pediatric Blood and Cancer
JF - Pediatric Blood and Cancer
IS - 9
M1 - e27835
ER -