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. A...

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Bibliographic Details
Published in:Cell reports (Cambridge) Vol. 36; no. 7; p. 109549
Main Authors: Ma, Shaolin, Mangala, Lingegowda S., Hu, Wen, Bayaktar, Emine, Yokoi, Akira, Hu, Wei, Pradeep, Sunila, Lee, Sanghoon, Piehowski, Paul D., Villar-Prados, Alejandro, Wu, Sherry Y., McGuire, Michael H., Lara, Olivia D., Rodriguez-Aguayo, Cristian, LaFargue, Christopher J., Jennings, Nicholas B., Rodland, Karin D., Liu, Tao, Kundra, Vikas, Ram, Prahlad T., Ramakrishnan, Sundaram, Lopez-Berestein, Gabriel, Coleman, Robert L., Sood, Anil K.
Format: Journal Article
Language:English
Published: United States Elsevier Inc 17.08.2021
Elsevier
Subjects:
Aged
angiogenesis
Animals
BASIC BIOLOGICAL SCIENCES
bevacizumab
Bevacizumab - pharmacology
Bevacizumab - therapeutic use
CD63
Cell Line, Tumor
Cell Proliferation
Disease Models, Animal
drug resistance
Extracellular vesicles
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
VEGF
bevacizumab
CD63
extracellular vesicles
drug resistance
VEGF
angiogenesis
ISSN:2211-1247, 2211-1247
Online Access:Get full text
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Description
Summary: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. [Display omitted] •Cancer cells package increasing amounts of VEGF in small EVs with anti-VEGF therapy•VEGF packaging into small EVs is mediated by the tetraspanin CD63•Anti-VEGF antibodies failed to recognize small EV-VEGF (eVEGF)•eVEGF triggers intracrine VEGF signaling and promotes angiogenesis Ma et.al report that cancer-cell-derived small EVs contain increasing amounts of VEGF (eVEGF) and contribute to resistance to anti-VEGF therapy (AVT). CD63 is a potential mediator that regulates packaging of VEGF into small EVs. eVEGF can trigger intracrine VEGF signaling in endothelial cells and promote angiogenesis despite AVT.
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content type line 23
AC05-76RL01830
USDOE Office of Science (SC)
PNNL-SA-154216
AUTHOR CONTRIBUTIONS
Conceptualization, A.K.S., and S.M.; methodology, S.M., L.S.M., Wen Hu, A.Y., E.B., S.L., A.V.-P., S.P., and A.K.S.; investigation, S.M., L.S.M., Wen Hu, A.Y., E.B., Wei Hu, M.H.M., O.D.L., C.J.L., N.B.J., C.R.-A., and S.Y.W.; data curation, S.M., Wen Hu, S.P., A.V.-P., S.L., P.D.P., T.L., K.D.R., and P.T.R.; writing – original draft, S.M.; writing – review & editing, all authors; resources: S.L., Wei Hu, V.K., S.R., G.L.-B., and R.L.C; supervision, A.K.S., and R.L.C; funding acquisition, A.K.S. and S.M. All authors read and approved the final manuscript.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2021.109549