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

Shaolin Ma & Anil K. Sood et al.

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.
Authors
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
Funding
Cancer Center Support GrantTargeted therapeutics for ovarian cancer and its microenvironment - treatment and theoretical modelingCore 1: Pathology CoreData and Omics Sciences CoreHarnessing the power of exosomes for non-coding RNA deliveryNovel extra cellular RNA-based combinatorial RNA inhibition therapyRole of HSP70 in Pancreatic DiseasesData and Omics Sciences Core (DATAOmics)Biostatistics & Bioinformatics Shared ResourceTraining of Academic Surgical OncologistsAstraZeneca FundingGenentech FundingOvarian Cancer Research Fund Alliance FundingOvarian Cancer Research Alliance FundingAmerican Cancer Society FundingClovis Oncology FundingNational Cancer Institute Grant ACN15006-001Core 1: Pathology CoreCancer Center Support GrantHarnessing the power of exosomes for non-coding RNA deliveryTraining of Academic Surgical OncologistsWomen's Cancer Research Foundation Grant FP00009883Janssen Pharmaceuticals FundingNovel extra cellular RNA-based combinatorial RNA inhibition therapyPacific Northwest National Laboratory FundingU.S. Department of Energy Grant DE-AC05-76RL01830U.S. Department of Energy Grant NIHP30CA016672Merck FundingAbbVie FundingUniversity of Texas MD Anderson Cancer Center Funding

NCI NIH HHS

P30 CA016672

NCI NIH HHS

U01 CA213759

NCI NIH HHS

P50 CA217685

NCI NIH HHS

U54 CA096297

NCI NIH HHS

R35 CA209904

NCATS NIH HHS

UH3 TR000943

NCI NIH HHS

R01 CA124723

NCI NIH HHS

U54 CA096300

NCI NIH HHS

P30 CA240139

NCI NIH HHS

T32 CA009599

National Cancer Institute

P50CA217685

National Cancer Institute

R35CA209904

Women's Cancer Research Foundation

5T32CA009599

National Institutes of Health

UH3TR000943