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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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
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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. [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.
AbstractList	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. 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. 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. 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. 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.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. Despite wide use of anti-vascular endothelial growth factor (VEGF) therapy for many solid 30 cancers, most of them become resistant to this therapy and develop into progressive disease. 31 Therefore, new biomarkers and strategies for blocking adaptive resistance of cancer to anti-VEGF therapy are needed. As described herein, we found that cancer-derived small extracellular vesicles (EVs) package increasing quantities of VEGF and other factors in response to anti-VEGF therapy. Notably, small EV-VEGF (eVEGF) is not recognized by bevacizumab and can be transferred to endothelial cells and trigger intracrine signaling and promote angiogenesis. Also, serum eVEGF was present at higher levels in ovarian cancer mouse models with adaptive resistance to bevacizumab than in models sensitive to it. Ovarian cancer cell-derived eVEGF increased tumor growth despite treatment with bevacizumab. Notably, the eVEGF level was elevated in patient serum after bevacizumab-containing therapy. Proteomic data of small EVs from mouse models suggested that several novel biomarkers are promising for drug response prediction. Collectively, these data demonstrated a new mechanism whereby eVEGF evades recognition by therapeutic antibodies and promotes tumor angiogenesis and progression. These findings have clinical implications for biomarkers and new therapeutic strategies for ovarian cancer.
ArticleNumber	109549
Author	Wu, Sherry Y. McGuire, Michael H. Jennings, Nicholas B. Rodriguez-Aguayo, Cristian Ma, Shaolin Mangala, Lingegowda S. LaFargue, Christopher J. Lopez-Berestein, Gabriel Kundra, Vikas Sood, Anil K. Piehowski, Paul D. Coleman, Robert L. Rodland, Karin D. Villar-Prados, Alejandro Yokoi, Akira Bayaktar, Emine Pradeep, Sunila Ram, Prahlad T. Hu, Wei Hu, Wen Liu, Tao Ramakrishnan, Sundaram Lara, Olivia D. Lee, Sanghoon
AuthorAffiliation	3 Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 12 Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 13 Lead contact 4 Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, China 9 Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 2 Department of Gynecological Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, China 10 Department of Abdominal Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 8 Department of Medicine, Stanford University, Stanford, CA 94305, 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 5 Department of Obstetrics and Gynecology, Med
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Author_xml	– sequence: 1 givenname: Shaolin surname: Ma fullname: Ma, Shaolin organization: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA – sequence: 2 givenname: Lingegowda S. surname: Mangala fullname: Mangala, Lingegowda S. organization: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA – sequence: 3 givenname: Wen surname: Hu fullname: Hu, Wen organization: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA – sequence: 4 givenname: Emine surname: Bayaktar fullname: Bayaktar, Emine organization: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA – sequence: 5 givenname: Akira surname: Yokoi fullname: Yokoi, Akira organization: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA – sequence: 6 givenname: Wei surname: Hu fullname: Hu, Wei organization: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA – sequence: 7 givenname: Sunila surname: Pradeep fullname: Pradeep, Sunila organization: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA – sequence: 8 givenname: Sanghoon surname: Lee fullname: Lee, Sanghoon organization: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA – sequence: 9 givenname: Paul D. surname: Piehowski fullname: Piehowski, Paul D. organization: Pacific Northwest National Laboratory, Richland, WA 99352, USA – sequence: 10 givenname: Alejandro surname: Villar-Prados fullname: Villar-Prados, Alejandro 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organization: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Keywords	bevacizumab CD63 extracellular vesicles drug resistance VEGF angiogenesis
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Notes	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 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.
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Snippet	Despite wide use of anti-vascular endothelial growth factor (VEGF) therapy for many solid cancers, most individuals become resistant to this therapy, leading... Despite wide use of anti-vascular endothelial growth factor (VEGF) therapy for many solid 30 cancers, most of them become resistant to this therapy and develop...
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SubjectTerms	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
Title	CD63-mediated cloaking of VEGF in small extracellular vesicles contributes to anti-VEGF therapy resistance
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