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Open AccessArticle

Functional Blockade of E-Selectin in Tumor-Associated Vessels Enhances Anti-Tumor Effect of Doxorubicin in Breast Cancer

Stephenson Cancer Center, University of Oklahoma Health Sciences Center, 975 NE, 10th, Oklahoma City, OK 73104, USA
McGovern Medical School, Institute of Molecular Medicine, University of Texas Health Science Center at Houston, 1825 Hermann Pressler, Houston, TX 77030, USA
School of Medicine, University of Oklahoma Health Sciences Center, 800 Stanton L. Young Blvd., Oklahoma City, OK 73104, USA
Department of Pharmaceutical Sciences, Thomas Jefferson University, 1020 Locust St, Philadelphia, PA 19107, USA
Department of Pathology, College of Medicine, University of Oklahoma Health Sciences Center, 940 SL Young Blvd, Oklahoma City, OK 73104, USA
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, 825 NE. 13th, Oklahoma City, OK 73104, USA
AM Biotechnologies, LLC, 12521 Gulf Freeway, Houston, TX 77034, USA
Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, 1015 Chestnut St., Philadelphia, PA 19107, USA
Department of Pathology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226, USA
Author to whom correspondence should be addressed.
Cancers 2020, 12(3), 725;
Received: 30 January 2020 / Revised: 11 March 2020 / Accepted: 11 March 2020 / Published: 19 March 2020
Chemotherapy is a mainstay of treatment for solid tumors. However, little is known about how therapy-induced immune cell infiltration may affect therapy response. We found substantial CD45+ immune cell density adjacent to E-selectin expressing inflamed vessels in doxorubicin (DOX)-treated residual human breast tumors. While CD45 level was significantly elevated in DOX-treated wildtype mice, it remained unchanged in DOX-treated tumors from E-selectin null mice. Similarly, intravenous administration of anti-E-selectin aptamer (ESTA) resulted in a significant reduction in CD45+ immune cell density in DOX-treated residual tumors, which coincided with a delay in tumor growth and lung metastasis in MMTV-pyMT mice. Additionally, both tumor infiltrating T-lymphocytes and tumor associated-macrophages were skewed towards TH2 in DOX-treated residual breast tumors; however, ESTA suppressed these changes. This study suggests that DOX treatment instigates de novo intratumoral infiltration of immune cells through E-selectin, and functional blockade of E-selectin may reduce residual tumor burden as well as metastasis through suppression of TH2 shift. View Full-Text
Keywords: E-selectin; aptamer; doxorubicin; tumor-associated-macrophages E-selectin; aptamer; doxorubicin; tumor-associated-macrophages
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Morita, Y.; Leslie, M.; Kameyama, H.; Lokesh, G.L.R.; Ichimura, N.; Davis, R.; Hills, N.; Hasan, N.; Zhang, R.; Kondo, Y.; Gorenstein, D.G.; Volk, D.E.; Chervoneva, I.; Rui, H.; Tanaka, T. Functional Blockade of E-Selectin in Tumor-Associated Vessels Enhances Anti-Tumor Effect of Doxorubicin in Breast Cancer. Cancers 2020, 12, 725.

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