Search

Chemotherapy efficacy is reliant upon access to tumor cells. One method of increasing chemotherapy response is to enhance delivery of chemotherapy to the tumor by vascular normalization. Tumor vasculature is largely dysfunctional, leading to poor delivery of chemotherapy. Vascular normalization, the remodeling of tumor vessels to increase functionality, has been shown to improve drug delivery and response in patients with glioblastoma, ovarian and colorectal cancers. Current normalization strategies using anti-angiogenic agents have a narrow dose and time therapeutic window. Therefore, it is imperative to identify other methods of inducing tumor vessel normalization to enhance the delivery and efficacy of chemotherapy. Vascular development, and endothelial cell (EC) signaling, is controlled by shear stress. Shear stress is the mechanical force exerted on ECs by blood flow through the vessel lumen. The role of shear stress in tumor vessel development is poorly understood. Tumors have heterogeneous, low levels of vascular shear stress. Heterogeneous, low shear stress causes hyper-permeable vessels that inefficiently deliver blood throughout the tumor. Aerobic exercise is a well-studied method for increasing vascular shear stress. We demonstrated in mouse models of Ewing sarcoma and melanoma that increasing shear stress via moderate exercise caused improved tumor vascular function including reduced hyper-permeability. This correlated with significantly increased chemotherapy delivery and efficacy; doxorubicin was significantly more effective against both tumor models when combined with exercise. The molecular mechanisms of tumor vascular remodeling in response to exercise, particularly the decrease in vessel permeability leading to better drug delivery, are unclear. Vascular permeability is regulated in part via Sphingosine-1-Phosphate Receptors 1 and 2 (S1PR1, S1PR2) on ECs, which have contrasting effects on angiogenesis. S1PR1 signaling increases adherens junctions, decreasing vascular permeability. In contrast, S1PR2 signaling increases vessel permeability. We found that S1PR1 was increased while S1PR2 was decreased on tumor endothelium of exercised mice. We have now identified the novel regulator of tumor endothelial permeability, ERK5, as a key mediator of improved tumor vascular function in response to exercise. Pharmacologic activation of S1PR1 by SEW2871 or activation of ERK5 signaling by p90RSK decreased tumor vascular hyper-permeability and increased doxorubicin efficacy, mimicking the exercise effect. Ongoing work using inducible S1PR1 or ERK5 knockout mice will determine whether this pathway is essential for exercise-induced tumor vascular remodeling and improved chemotherapeutic efficacy. Citation Format: Hannah Savage, Enrica Marmonti, Claudia Bedoya, Miriam Garcia, Keri Schadler. Exercise as a novel method of tumor vascular remodeling [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5012.