title: 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.
authors: Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Abramson Family Cancer Research Institute, Philadelphia, PA 19104, USA.
authors: Keri L
authors: KL
authors: Schadler
authors: Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Abramson Family Cancer Research Institute, Philadelphia, PA 19104, USA.
authors: Nicholas J
authors: NJ
authors: Thomas
authors: Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Peter A
authors: PA
authors: Galie
authors: Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Abramson Family Cancer Research Institute, Philadelphia, PA 19104, USA.
authors: Dong Ha
authors: DH
authors: Bhang
authors: Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Abramson Family Cancer Research Institute, Philadelphia, PA 19104, USA.
authors: Kerry C
authors: KC
authors: Roby
authors: Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Abramson Family Cancer Research Institute, Philadelphia, PA 19104, USA.
authors: Prince
authors: P
authors: Addai
authors: Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Abramson Family Cancer Research Institute, Philadelphia, PA 19104, USA.
authors: Jacob E
authors: JE
authors: Till
authors: Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Abramson Family Cancer Research Institute, Philadelphia, PA 19104, USA.
authors: Kathleen
authors: K
authors: Sturgeon
authors: Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Abramson Family Cancer Research Institute, Philadelphia, PA 19104, USA.
authors: Alexander
authors: A
authors: Zaslavsky
authors: Department of Bioengineering, Boston University, Boston, MA 02215, USA.
authors: Christopher S
authors: CS
authors: Chen
authors: Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Abramson Family Cancer Research Institute, Philadelphia, PA 19104, USA.
authors: Sandra
authors: S
authors: Ryeom
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019703:Calcineurin / Q000378:metabolism; D003131:Combined Modality Therapy; D004317:Doxorubicin / Q000627:therapeutic use*; D004730:Endothelium, Vascular / Q000502:physiology*; D015444:Exercise; D005081:Exercise Therapy; D006801:Humans; D040542:Mechanotransduction, Cellular; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000628:therapy*; D033081:Shear Strength; D015398:Signal Transduction; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism; D066253:Vascular Remodeling
chemical_list: D000970:Antineoplastic Agents; D050778:NFATC Transcription Factors; D019700:Thrombospondin 1; C585483:Thbs1 protein, mouse; D004317:Doxorubicin; D019703:Calcineurin
keywords: NFAT; exercise; thrombospondin-1; tumor vascular normalization