Neutralization of the induced VEGF-A potentiates the therapeutic effect of an anti-VEGFR2 antibody on gastric cancer in vivo

Abstract The vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) axis is an essential regulator of angiogenesis and important therapeutic target in cancer. Ramucirumab is an anti-VEGFR2 monoclonal antibody used for the treatment of several cancers. Increased circulating VEGF-A levels aft...

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Main Authors:	Tetsuo Mashima, Takeru Wakatsuki, Naomi Kawata, Myung-Kyu Jang, Akiko Nagamori, Haruka Yoshida, Kenichi Nakamura, Toshiro Migita, Hiroyuki Seimiya, Kensei Yamaguchi
Format:	article
Language:	EN
Published:	Nature Portfolio 2021
Subjects:	Medicine R Science Q
Online Access:	https://doaj.org/article/422426adde034efd8700a487b51f4081
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spelling	oai:doaj.org-article:422426adde034efd8700a487b51f40812021-12-02T16:50:25ZNeutralization of the induced VEGF-A potentiates the therapeutic effect of an anti-VEGFR2 antibody on gastric cancer in vivo10.1038/s41598-021-94584-92045-2322https://doaj.org/article/422426adde034efd8700a487b51f40812021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-94584-9https://doaj.org/toc/2045-2322Abstract The vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) axis is an essential regulator of angiogenesis and important therapeutic target in cancer. Ramucirumab is an anti-VEGFR2 monoclonal antibody used for the treatment of several cancers. Increased circulating VEGF-A levels after ramucirumab administration are associated with a worse prognosis, suggesting that excess VEGF-A induced by ramucirumab negatively affects treatment efficacy and that neutralizing VEGF-A may improve treatment outcomes. Here, we evaluated the effect of combination treatment with an anti-VEGFR2 antibody and anti-VEGF-A antibody on gastric tumor progression and normal tissues using a preclinical BALB/c-nu/nu mouse xenograft model. After anti-VEGFR2 antibody treatment in mice, a significant increase in plasma VEGF-A levels was observed, mirroring the clinical response. The elevated VEGF-A was host-derived. Anti-VEGF-A antibody co-administration enhanced the anti-tumor effect of the anti-VEGFR2-antibody without exacerbating the toxicity. Mechanistically, the combination treatment induced intra-tumor molecular changes closely related to angiogenesis inhibition and abolished the gene expression changes specifically induced by anti-VEGFR2 antibody treatment alone. We particularly identified the dual treatment-selective downregulation of ZEB1 expression, which was critical for gastric cancer cell proliferation. These data indicate that the dual blockade of VEGF-A and VEGFR2 is a rational strategy to ensure the anti-tumor effect of angiogenesis-targeting therapy.Tetsuo MashimaTakeru WakatsukiNaomi KawataMyung-Kyu JangAkiko NagamoriHaruka YoshidaKenichi NakamuraToshiro MigitaHiroyuki SeimiyaKensei YamaguchiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Tetsuo Mashima Takeru Wakatsuki Naomi Kawata Myung-Kyu Jang Akiko Nagamori Haruka Yoshida Kenichi Nakamura Toshiro Migita Hiroyuki Seimiya Kensei Yamaguchi Neutralization of the induced VEGF-A potentiates the therapeutic effect of an anti-VEGFR2 antibody on gastric cancer in vivo
description	Abstract The vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) axis is an essential regulator of angiogenesis and important therapeutic target in cancer. Ramucirumab is an anti-VEGFR2 monoclonal antibody used for the treatment of several cancers. Increased circulating VEGF-A levels after ramucirumab administration are associated with a worse prognosis, suggesting that excess VEGF-A induced by ramucirumab negatively affects treatment efficacy and that neutralizing VEGF-A may improve treatment outcomes. Here, we evaluated the effect of combination treatment with an anti-VEGFR2 antibody and anti-VEGF-A antibody on gastric tumor progression and normal tissues using a preclinical BALB/c-nu/nu mouse xenograft model. After anti-VEGFR2 antibody treatment in mice, a significant increase in plasma VEGF-A levels was observed, mirroring the clinical response. The elevated VEGF-A was host-derived. Anti-VEGF-A antibody co-administration enhanced the anti-tumor effect of the anti-VEGFR2-antibody without exacerbating the toxicity. Mechanistically, the combination treatment induced intra-tumor molecular changes closely related to angiogenesis inhibition and abolished the gene expression changes specifically induced by anti-VEGFR2 antibody treatment alone. We particularly identified the dual treatment-selective downregulation of ZEB1 expression, which was critical for gastric cancer cell proliferation. These data indicate that the dual blockade of VEGF-A and VEGFR2 is a rational strategy to ensure the anti-tumor effect of angiogenesis-targeting therapy.
format	article
author	Tetsuo Mashima Takeru Wakatsuki Naomi Kawata Myung-Kyu Jang Akiko Nagamori Haruka Yoshida Kenichi Nakamura Toshiro Migita Hiroyuki Seimiya Kensei Yamaguchi
author_facet	Tetsuo Mashima Takeru Wakatsuki Naomi Kawata Myung-Kyu Jang Akiko Nagamori Haruka Yoshida Kenichi Nakamura Toshiro Migita Hiroyuki Seimiya Kensei Yamaguchi
author_sort	Tetsuo Mashima
title	Neutralization of the induced VEGF-A potentiates the therapeutic effect of an anti-VEGFR2 antibody on gastric cancer in vivo
title_short	Neutralization of the induced VEGF-A potentiates the therapeutic effect of an anti-VEGFR2 antibody on gastric cancer in vivo
title_full	Neutralization of the induced VEGF-A potentiates the therapeutic effect of an anti-VEGFR2 antibody on gastric cancer in vivo
title_fullStr	Neutralization of the induced VEGF-A potentiates the therapeutic effect of an anti-VEGFR2 antibody on gastric cancer in vivo
title_full_unstemmed	Neutralization of the induced VEGF-A potentiates the therapeutic effect of an anti-VEGFR2 antibody on gastric cancer in vivo
title_sort	neutralization of the induced vegf-a potentiates the therapeutic effect of an anti-vegfr2 antibody on gastric cancer in vivo
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/422426adde034efd8700a487b51f4081
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Neutralization of the induced VEGF-A potentiates the therapeutic effect of an anti-VEGFR2 antibody on gastric cancer in vivo

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