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The ADAM17-directed Inhibitory Antibody MEDI3622 Antagonizes Radiotherapy-induced VEGF Release and Sensitizes Non–Small Cell Lung Cancer for Radiotherapy

The cellular response to ionizing radiation (IR) depends on tumor cell and microenvironmental factors. Here, we investigated the role of IR-induced ADAM17 matrix metalloproteinase activity for the intercellular communication between tumor cells and the tumor vasculature in non–small cell lung cancer...

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Autores principales: Tschanz, Fabienne, Bender, Sabine, Telarovic, Irma, Waller, Verena, Speck, Roberto F., Pruschy, Martin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9973400/
https://www.ncbi.nlm.nih.gov/pubmed/36860547
http://dx.doi.org/10.1158/2767-9764.CRC-21-0067
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author Tschanz, Fabienne
Bender, Sabine
Telarovic, Irma
Waller, Verena
Speck, Roberto F.
Pruschy, Martin
author_facet Tschanz, Fabienne
Bender, Sabine
Telarovic, Irma
Waller, Verena
Speck, Roberto F.
Pruschy, Martin
author_sort Tschanz, Fabienne
collection PubMed
description The cellular response to ionizing radiation (IR) depends on tumor cell and microenvironmental factors. Here, we investigated the role of IR-induced ADAM17 matrix metalloproteinase activity for the intercellular communication between tumor cells and the tumor vasculature in non–small cell lung cancer (NSCLC) tumor models. Factors shed by ADAM17 from NSCLC tumor cells (A549, H358) and relevant for endothelial cell migration were investigated using transwell migration assays, ELISA, and flow cytometry. Tumor angiogenesis–related endpoints were analyzed with the chorio-allantoic membrane assay and in murine NSCLC tumor models. Efficacy-oriented experiments were performed in a murine orthotopic NSCLC tumor model using irradiation with an image-guided small-animal radiotherapy platform alone and in combination with the novel ADAM17-directed antibody MEDI3622. In vitro, VEGF was identified as the major factor responsible for IR-induced and ADAM17-dependent endothelial cell migration toward attracting tumor cells. IR strongly enhanced tumor cell–associated ADAM17 activity, released VEGF in an ADAM17-dependent manner, and thereby coordinated the communication between tumor and endothelial cells. In vivo, tumor growth and microvessel size and density were strongly decreased in response to the combined treatment modality of IR and MEDI3622 but not by either treatment modality alone and thus suggest that the supra-additive effect of the combined treatment modality is in part due to abrogation of the ADAM17-mediated IR-induced protective effect on the tumor vasculature. Furthermore, we demonstrate that the novel ADAM17-inhibitory antibody MEDI3622 potently improves the radiotherapy response of NSCLC. SIGNIFICANCE: The tumor response to radiotherapy is influenced by several factors of the tumor microenvironment. We demonstrate that inhibition of the sheddase ADAM17 by the novel antibody MEDI3622 reduces IR-induced VEGF release from tumor cells relevant for endothelial cell migration and vasculature protection, thereby enhancing radiotherapy treatment outcome of NSCLC.
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spelling pubmed-99734002023-02-28 The ADAM17-directed Inhibitory Antibody MEDI3622 Antagonizes Radiotherapy-induced VEGF Release and Sensitizes Non–Small Cell Lung Cancer for Radiotherapy Tschanz, Fabienne Bender, Sabine Telarovic, Irma Waller, Verena Speck, Roberto F. Pruschy, Martin Cancer Res Commun Research Article The cellular response to ionizing radiation (IR) depends on tumor cell and microenvironmental factors. Here, we investigated the role of IR-induced ADAM17 matrix metalloproteinase activity for the intercellular communication between tumor cells and the tumor vasculature in non–small cell lung cancer (NSCLC) tumor models. Factors shed by ADAM17 from NSCLC tumor cells (A549, H358) and relevant for endothelial cell migration were investigated using transwell migration assays, ELISA, and flow cytometry. Tumor angiogenesis–related endpoints were analyzed with the chorio-allantoic membrane assay and in murine NSCLC tumor models. Efficacy-oriented experiments were performed in a murine orthotopic NSCLC tumor model using irradiation with an image-guided small-animal radiotherapy platform alone and in combination with the novel ADAM17-directed antibody MEDI3622. In vitro, VEGF was identified as the major factor responsible for IR-induced and ADAM17-dependent endothelial cell migration toward attracting tumor cells. IR strongly enhanced tumor cell–associated ADAM17 activity, released VEGF in an ADAM17-dependent manner, and thereby coordinated the communication between tumor and endothelial cells. In vivo, tumor growth and microvessel size and density were strongly decreased in response to the combined treatment modality of IR and MEDI3622 but not by either treatment modality alone and thus suggest that the supra-additive effect of the combined treatment modality is in part due to abrogation of the ADAM17-mediated IR-induced protective effect on the tumor vasculature. Furthermore, we demonstrate that the novel ADAM17-inhibitory antibody MEDI3622 potently improves the radiotherapy response of NSCLC. SIGNIFICANCE: The tumor response to radiotherapy is influenced by several factors of the tumor microenvironment. We demonstrate that inhibition of the sheddase ADAM17 by the novel antibody MEDI3622 reduces IR-induced VEGF release from tumor cells relevant for endothelial cell migration and vasculature protection, thereby enhancing radiotherapy treatment outcome of NSCLC. American Association for Cancer Research 2021-12-22 /pmc/articles/PMC9973400/ /pubmed/36860547 http://dx.doi.org/10.1158/2767-9764.CRC-21-0067 Text en © 2021 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by/4.0/This open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license.
spellingShingle Research Article
Tschanz, Fabienne
Bender, Sabine
Telarovic, Irma
Waller, Verena
Speck, Roberto F.
Pruschy, Martin
The ADAM17-directed Inhibitory Antibody MEDI3622 Antagonizes Radiotherapy-induced VEGF Release and Sensitizes Non–Small Cell Lung Cancer for Radiotherapy
title The ADAM17-directed Inhibitory Antibody MEDI3622 Antagonizes Radiotherapy-induced VEGF Release and Sensitizes Non–Small Cell Lung Cancer for Radiotherapy
title_full The ADAM17-directed Inhibitory Antibody MEDI3622 Antagonizes Radiotherapy-induced VEGF Release and Sensitizes Non–Small Cell Lung Cancer for Radiotherapy
title_fullStr The ADAM17-directed Inhibitory Antibody MEDI3622 Antagonizes Radiotherapy-induced VEGF Release and Sensitizes Non–Small Cell Lung Cancer for Radiotherapy
title_full_unstemmed The ADAM17-directed Inhibitory Antibody MEDI3622 Antagonizes Radiotherapy-induced VEGF Release and Sensitizes Non–Small Cell Lung Cancer for Radiotherapy
title_short The ADAM17-directed Inhibitory Antibody MEDI3622 Antagonizes Radiotherapy-induced VEGF Release and Sensitizes Non–Small Cell Lung Cancer for Radiotherapy
title_sort adam17-directed inhibitory antibody medi3622 antagonizes radiotherapy-induced vegf release and sensitizes non–small cell lung cancer for radiotherapy
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9973400/
https://www.ncbi.nlm.nih.gov/pubmed/36860547
http://dx.doi.org/10.1158/2767-9764.CRC-21-0067
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