@article{524f9e5a15d440d28580ffd593ed7bc3,
title = "CD63-mediated cloaking of VEGF in small extracellular vesicles contributes to anti-VEGF therapy resistance",
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",
author = "Shaolin Ma and Mangala, {Lingegowda S.} and Wen Hu and Emine Bayaktar and Akira Yokoi and Wei Hu and Sunila Pradeep and Sanghoon Lee and Piehowski, {Paul D.} and Alejandro Villar-Prados and Wu, {Sherry Y.} and McGuire, {Michael H.} and Lara, {Olivia D.} and Cristian Rodriguez-Aguayo and LaFargue, {Christopher J.} and Jennings, {Nicholas B.} and Rodland, {Karin D.} and Tao Liu and Vikas Kundra and Ram, {Prahlad T.} and Sundaram Ramakrishnan and Gabriel Lopez-Berestein and Coleman, {Robert L.} and Sood, {Anil K.}",
note = "Funding Information: This publication is part of the NIH Extracellular RNA Communication Consortium paper package and was supported by the NIH Common Fund {\textquoteright}s exRNA Communication Program . This work was supported, in part, by NIH grants UH3TR000943 , P50CA217685 , R35CA209904 , and P30CA016672 ; Interagency Agreement ACN15006-001 between the National Cancer Institute and the Pacific Northwest National Laboratory (PNNL); the Ovarian Cancer Research Alliance ; the Blanton-Davis Ovarian Cancer Research Program ; the American Cancer Society Research Professor Award; and the Frank McGraw Memorial Chair in Cancer Research . S.M. is supported by a Foundation for Women{\textquoteright}s Cancer Research grant (Sponsor Award number FP00009883 ). S.L. is supported by a Sprint for Life Research Award and the MD Anderson Ovarian Cancer Moon Shot Program . O.D.L. was supported by an NIH institutional training grant ( 5T32CA009599 ). S.Y.W. was supported by the Cancer Prevention & Research Institute of Texas Research Training Program (grants RP101502 , RP140106 , and RP170067 ). A.V.P. was supported by the NIH Partnership for Excellence in Cancer Research ( U54CA096300 / U54CA096297 ). Short tandem repeat DNA fingerprinting was supported by the NIH/NCI under award number P30CA016672 and used the Cytogenetics and Cell Authentication Core. We thank Scientific Publications (Dr. Donald R. Norwood) Research Medical Library at The University of Texas MD Anderson Cancer Center for reviewing and editing this manuscript. PNNL is a multiprogram national laboratory operated by Battelle for the DOE under contract DE-AC05-76RL01830. We thank Kenneth Dunner Jr. with the High Resolution Electron Microscopy Facility (grant NIHP30CA016672 ) at The University of Texas MD Anderson Cancer Center for performing the TEM studies. We thank Dr. Long H. Dang at Health First for providing RKO-PAR and RKO-VEGF −/− cells. We acknowledge the Flow Cytometry and Cellular Imaging Core Facility (FCCICF) ( NCI grants P30CA16672 ) at The University of Texas MD Anderson Cancer Center for performing flow cytometry experiments. Funding Information: This publication is part of the NIH Extracellular RNA Communication Consortium paper package and was supported by the NIH Common Fund's exRNA Communication Program. This work was supported, in part, by NIH grants UH3TR000943, P50CA217685, R35CA209904, and P30CA016672; Interagency Agreement ACN15006-001 between the National Cancer Institute and the Pacific Northwest National Laboratory (PNNL); the Ovarian Cancer Research Alliance; the Blanton-Davis Ovarian Cancer Research Program; the American Cancer Society Research Professor Award; and the Frank McGraw Memorial Chair in Cancer Research. S.M. is supported by a Foundation for Women's Cancer Research grant (Sponsor Award number FP00009883). S.L. is supported by a Sprint for Life Research Award and the MD Anderson Ovarian Cancer Moon Shot Program. O.D.L. was supported by an NIH institutional training grant (5T32CA009599). S.Y.W. was supported by the Cancer Prevention & Research Institute of Texas Research Training Program (grants RP101502, RP140106, and RP170067). A.V.P. was supported by the NIH Partnership for Excellence in Cancer Research (U54CA096300/U54CA096297). Short tandem repeat DNA fingerprinting was supported by the NIH/NCI under award number P30CA016672 and used the Cytogenetics and Cell Authentication Core. We thank Scientific Publications (Dr. Donald R. Norwood) Research Medical Library at The University of Texas MD Anderson Cancer Center for reviewing and editing this manuscript. PNNL is a multiprogram national laboratory operated by Battelle for the DOE under contract DE-AC05-76RL01830. We thank Kenneth Dunner Jr. with the High Resolution Electron Microscopy Facility (grant NIHP30CA016672) at The University of Texas MD Anderson Cancer Center for performing the TEM studies. We thank Dr. Long H. Dang at Health First for providing RKO-PAR and RKO-VEGF?/? cells. We acknowledge the Flow Cytometry and Cellular Imaging Core Facility (FCCICF) (NCI grants P30CA16672) at The University of Texas MD Anderson Cancer Center for performing flow cytometry experiments. 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. R.L.C. has received grant funding from Genentech, Merck, Janssen Pharmaceutical, Clovis Oncology, AstraZeneca, and AbbVie and serves as an investigator on the scientific steering committees for Tesaro, Clovis Oncology, AstraZeneca, and AbbVie. A.K.S. a consultant for KIYATEC, Merck, and AstraZeneca, has received research funding from M-Trap, and is a BioPath Holdings shareholder. Funding Information: R.L.C. has received grant funding from Genentech, Merck, Janssen Pharmaceutical, Clovis Oncology, AstraZeneca, and AbbVie and serves as an investigator on the scientific steering committees for Tesaro, Clovis Oncology, AstraZeneca, and AbbVie. A.K.S. a consultant for KIYATEC, Merck, and AstraZeneca, has received research funding from M-Trap, and is a BioPath Holdings shareholder. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = aug,
day = "17",
doi = "10.1016/j.celrep.2021.109549",
language = "English (US)",
volume = "36",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "7",
}