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Open AccessArticle

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

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Stephenson Cancer Center, University of Oklahoma Health Sciences Center, 975 NE, 10th, Oklahoma City, OK 73104, USA
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McGovern Medical School, Institute of Molecular Medicine, University of Texas Health Science Center at Houston, 1825 Hermann Pressler, Houston, TX 77030, USA
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School of Medicine, University of Oklahoma Health Sciences Center, 800 Stanton L. Young Blvd., Oklahoma City, OK 73104, USA
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Department of Pharmaceutical Sciences, Thomas Jefferson University, 1020 Locust St, Philadelphia, PA 19107, USA
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Department of Pathology, College of Medicine, University of Oklahoma Health Sciences Center, 940 SL Young Blvd, Oklahoma City, OK 73104, USA
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Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, 825 NE. 13th, Oklahoma City, OK 73104, USA
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AM Biotechnologies, LLC, 12521 Gulf Freeway, Houston, TX 77034, USA
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Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, 1015 Chestnut St., Philadelphia, PA 19107, USA
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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; https://doi.org/10.3390/cancers12030725
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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