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

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

doi:10.1016/j.celrep.2021.109549

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

Cell Rep. 2021 Aug 17;36(7):109549. doi: 10.1016/j.celrep.2021.109549.

Authors

Shaolin Ma¹, Lingegowda S Mangala², Wen Hu³, Emine Bayaktar⁴, Akira Yokoi⁴, Wei Hu⁴, Sunila Pradeep⁵, Sanghoon Lee⁶, Paul D Piehowski⁷, Alejandro Villar-Prados⁸, Sherry Y Wu⁴, Michael H McGuire⁴, Olivia D Lara⁴, Cristian Rodriguez-Aguayo⁹, Christopher J LaFargue⁴, Nicholas B Jennings⁴, Karin D Rodland⁷, Tao Liu⁷, Vikas Kundra¹⁰, Prahlad T Ram⁶, Sundaram Ramakrishnan¹¹, Gabriel Lopez-Berestein⁹, Robert L Coleman⁴, Anil K Sood¹²

Affiliations

¹ 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.
² 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.
³ 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.
⁴ Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁵ 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.
⁶ Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁷ Pacific Northwest National Laboratory, Richland, WA 99352, USA.
⁸ 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.
⁹ 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.
¹⁰ Department of Abdominal Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹¹ Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
¹² 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.

Abstract

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.

Keywords: CD63; VEGF; angiogenesis; bevacizumab; drug resistance; extracellular vesicles.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Animals
Bevacizumab / pharmacology
Bevacizumab / therapeutic use
Cell Line, Tumor
Cell Proliferation
Disease Models, Animal
Extracellular Vesicles / metabolism*
Extracellular Vesicles / ultrastructure
Female
Humans
Mice
Mice, Nude
Middle Aged
Neovascularization, Pathologic / metabolism
Neovascularization, Pathologic / pathology
Ovarian Neoplasms / drug therapy
Protein Isoforms / metabolism
Signal Transduction
Tetraspanin 30 / metabolism*
Vascular Endothelial Growth Factor A / antagonists & inhibitors*
Vascular Endothelial Growth Factor A / metabolism
Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

Protein Isoforms
Tetraspanin 30
Vascular Endothelial Growth Factor A
Bevacizumab
Vascular Endothelial Growth Factor Receptor-2

Abstract

Publication types

MeSH terms

Substances

Grants and funding