CD63-mediated cloaking of VEGF in small extracellular vesicles contributes to anti-VEGF therapy resistance.

Aug 19, 2021

Contributor: Shaolin Ma,Lingegowda S Mangala,Wen Hu,Emine Bayaktar,Akira Yokoi,Wei Hu,Sunila Pradeep,Sanghoon Lee,Paul D Piehowski,Alejandro Villar-Prados,Sherry Y Wu,Michael H McGuire,Olivia D Lara,Cristian Rodriguez-Aguayo,Christopher J LaFargue,Nicholas B Jennings,Karin D Rodland,Tao Liu,Vikas Kundra,Prahlad T Ram,Sundaram Ramakrishnan,Gabriel Lopez-Berestein,Robert L Coleman,Anil K Sood

CD63-mediated cloaking of VEGF in small extracellular vesicles contributes to anti-VEGF therapy resistance.

Despite wide use of anti-vascular endothelial growth factor (VEGF) therapy for many solid cancers, most individuals become resistant to this therapy, leading to disease progression. Therefore, new biomarkers and strategies for blocking adaptive resistance of cancer to anti-VEGF therapy are needed. As described here, we demonstrate that cancer-derived small extracellular vesicles package increasing quantities of VEGF and other factors in response to anti-VEGF therapy. The packaging process of VEGF into small extracellular vesicles (EVs) is mediated by the tetraspanin CD63. Furthermore, small EV-VEGF (eVEGF) is not accessible to anti-VEGF antibodies and can trigger intracrine VEGF signaling in endothelial cells. eVEGF promotes angiogenesis and enhances tumor growth despite bevacizumab treatment. These data demonstrate a mechanism where VEGF is partitioned into small EVs and promotes tumor angiogenesis and progression. These findings have clinical implications for biomarkers and therapeutic strategies for ovarian cancer.
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

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About The Expert

Shaolin Ma

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Gynecological Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, China.

Lingegowda S Mangala

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Wen Hu

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, China.

Emine Bayaktar

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Akira Yokoi

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Wei Hu

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Sunila Pradeep

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.

Sanghoon Lee

Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Paul D Piehowski

Pacific Northwest National Laboratory, Richland, WA 99352, USA.

Alejandro Villar-Prados

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Medicine, Stanford University, Stanford, CA 94305, USA.

Sherry Y Wu

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Michael H McGuire

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Olivia D Lara

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Cristian Rodriguez-Aguayo

Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Christopher J LaFargue

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Nicholas B Jennings

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Karin D Rodland

Pacific Northwest National Laboratory, Richland, WA 99352, USA.

Tao Liu

Pacific Northwest National Laboratory, Richland, WA 99352, USA.

Vikas Kundra

Department of Abdominal Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Prahlad T Ram

Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Sundaram Ramakrishnan

Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.

Gabriel Lopez-Berestein

Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Robert L Coleman

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Anil K Sood

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: asood@mdanderson.org.

References

PubMed