Clinical evidence indicates that moderate to vigorous exercise is a powerful means to reduce metastatic cancer incidence. However, the mechanisms of this beneficial influence are not fully understood. Our present application is specially focused on the mechanisms of tumor cell extravasation into the brain. Such an emphasis on brain metastases is consistent with our interest in the blood-brain barrier physiology and pathology. In addition, brain metastases are one of the leadings causes of cancer-related morbidity and mortality. The central hypothesis of the present application is that exercise protects against the development of blood- borne brain metastases by increasing antioxidant capacity and modulating redox- regulated responses in the capillary endothelium. To study this hypothesis, we will employ an animal model of wheel running mice that mimics the voluntary pattern of human exercise. We will specifically focus on the exercise-mediated protection against vascular mechanisms of tumor cell extravasation via disruption of tight junction proteins of the endothelium. Tight junctions are the critical components of the brain capillaries which regulate the integrity of the blood-brain barrier. Mechanistically, the main emphasis will be placed on the involvement of the Ras and Rho signaling in alterations of phosphorylation and expression of tight junction proteins. The proposed research combines elements of exercise physiology, clinical approaches (namely, tumor dissemination and growth), cancer progression, and molecular and vascular biology. In addition, we will employ advanced systems biology approaches. Novelty and significance of the present proposal are related to our focus on the blood-brain barrier in brain metastasis, as tumor extravasation occurs at the level of the cerebrovasculature endothelium and the evaluation of the protective effects of physical activity on tumor dissemination and growth. We believe that the data obtained from this proposal will provide evidence that even moderate exercise can significantly protect against the development of blood-brain metastases. Furthermore, a better understanding of the pathophysiological regulation of BBB molecular and functional properties is critical in assessing brain metastasis etiology and in identifying future drug targets to develop more effective therapeutic approaches.

Public Health Relevance

We propose that exercise can attenuate the formation of brain tumor metastases at the level of the blood-brain barrier (BBB) via antioxidant related mechanisms. Specifically, we will explore the link between exercise and the protection against disruption of tight junction proteins, alterations of caveolae-associated redox signaling, and transcapillary dissemination of tumor cells. We believe that the data obtained from this proposal will provide evidence that exercise can significantly protect against the development of blood-brain metastases.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Chemo/Dietary Prevention Study Section (CDP)
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Emenaker, Nancy J
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University of Miami School of Medicine
Schools of Medicine
Coral Gables
United States
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Wrobel, Jagoda K; Toborek, Michal (2016) Blood-brain barrier remodeling during brain metastasis formation. Mol Med :
Wolff, Gretchen; Davidson, Sarah J; Wrobel, Jagoda K et al. (2015) Exercise maintains blood-brain barrier integrity during early stages of brain metastasis formation. Biochem Biophys Res Commun 463:811-7
Eum, Sung Yong; Jaraki, Dima; András, Ibolya E et al. (2015) Lipid rafts regulate PCB153-induced disruption of occludin and brain endothelial barrier function through protein phosphatase 2A and matrix metalloproteinase-2. Toxicol Appl Pharmacol 287:258-66
Wrobel, Jagoda K; Choi, Jeong June; Xiao, Rijin et al. (2015) Selenoglycoproteins attenuate adhesion of tumor cells to the brain microvascular endothelium via a process involving NF-κB activation. J Nutr Biochem 26:120-9
András, Ibolya E; Toborek, Michal (2014) HIV-1 stimulates nuclear entry of amyloid beta via dynamin dependent EEA1 and TGF-β/Smad signaling. Exp Cell Res 323:66-76
Wolff, Gretchen; Balke, Jordan E; Andras, Ibolya E et al. (2014) Exercise modulates redox-sensitive small GTPase activity in the brain microvasculature in a model of brain metastasis formation. PLoS One 9:e97033
Huang, Wen; Chen, Lei; Zhang, Bei et al. (2014) PPAR agonist-mediated protection against HIV Tat-induced cerebrovascular toxicity is enhanced in MMP-9-deficient mice. J Cereb Blood Flow Metab 34:646-53
Eum, Sung Yong; Jaraki, Dima; Bertrand, Luc et al. (2014) Disruption of epithelial barrier by quorum-sensing N-3-(oxododecanoyl)-homoserine lactone is mediated by matrix metalloproteinases. Am J Physiol Gastrointest Liver Physiol 306:G992-G1001
Równicka-Zubik, Joanna; Sułkowski, Leszek; Toborek, Michal (2014) Interactions of PCBs with human serum albumin: in vitro spectroscopic study. Spectrochim Acta A Mol Biomol Spectrosc 124:632-7
Wolff, Gretchen; Toborek, Michal (2013) Targeting the therapeutic effects of exercise on redox-sensitive mechanisms in the vascular endothelium during tumor progression. IUBMB Life 65:565-71

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