Cargando…

Attenuation of the Hypoxia Inducible Factor Pathway after Oncolytic Adenovirus Infection Coincides with Decreased Vessel Perfusion

The interplay between oncolytic virus infection and tumour hypoxia is particularly unexplored in vivo, although hypoxia is present in virtually all solid carcinomas. In this study, oncolytic adenovirus infection foci were found within pimonidazole-reactive, oxygen-poor areas in a colorectal xenograf...

Descripción completa

Detalles Bibliográficos
Autores principales: Yousaf, Iris, Kaeppler, Jakob, Frost, Sally, Seymour, Len W., Jacobus, Egon J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225929/
https://www.ncbi.nlm.nih.gov/pubmed/32244697
http://dx.doi.org/10.3390/cancers12040851
_version_ 1783534167885086720
author Yousaf, Iris
Kaeppler, Jakob
Frost, Sally
Seymour, Len W.
Jacobus, Egon J.
author_facet Yousaf, Iris
Kaeppler, Jakob
Frost, Sally
Seymour, Len W.
Jacobus, Egon J.
author_sort Yousaf, Iris
collection PubMed
description The interplay between oncolytic virus infection and tumour hypoxia is particularly unexplored in vivo, although hypoxia is present in virtually all solid carcinomas. In this study, oncolytic adenovirus infection foci were found within pimonidazole-reactive, oxygen-poor areas in a colorectal xenograft tumour, where the expression of VEGF, a target gene of the hypoxia-inducible factor (HIF), was attenuated. We hypothesised that adenovirus infection interferes with the HIF-signalling axis in the hypoxic tumour niche, possibly modifying the local vascular supply. In vitro, enadenotucirev (EnAd), adenovirus 11p and adenovirus 5 decreased the protein expression of HIF-1α only during the late phase of the viral life cycle by transcriptional down-regulation and not post-translational regulation. The decreasing HIF levels resulted in the down-regulation of angiogenic factors such as VEGF, coinciding with reduced endothelial tube formation but also increased T-cell activation in conditioned media transfer experiments. Using intravital microscopy, a decreased perfused vessel volume was observed in infected tumour nodules upon systemic delivery of EnAd, encoding the oxygen-independent fluorescent reporter UnaG to a tumour xenograft grown under an abdominal window chamber. We conclude that the attenuation of the HIF pathway upon adenoviral infection may contribute to anti-vascular and immunostimulatory effects in the periphery of established infection foci in vivo.
format Online
Article
Text
id pubmed-7225929
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-72259292020-05-18 Attenuation of the Hypoxia Inducible Factor Pathway after Oncolytic Adenovirus Infection Coincides with Decreased Vessel Perfusion Yousaf, Iris Kaeppler, Jakob Frost, Sally Seymour, Len W. Jacobus, Egon J. Cancers (Basel) Article The interplay between oncolytic virus infection and tumour hypoxia is particularly unexplored in vivo, although hypoxia is present in virtually all solid carcinomas. In this study, oncolytic adenovirus infection foci were found within pimonidazole-reactive, oxygen-poor areas in a colorectal xenograft tumour, where the expression of VEGF, a target gene of the hypoxia-inducible factor (HIF), was attenuated. We hypothesised that adenovirus infection interferes with the HIF-signalling axis in the hypoxic tumour niche, possibly modifying the local vascular supply. In vitro, enadenotucirev (EnAd), adenovirus 11p and adenovirus 5 decreased the protein expression of HIF-1α only during the late phase of the viral life cycle by transcriptional down-regulation and not post-translational regulation. The decreasing HIF levels resulted in the down-regulation of angiogenic factors such as VEGF, coinciding with reduced endothelial tube formation but also increased T-cell activation in conditioned media transfer experiments. Using intravital microscopy, a decreased perfused vessel volume was observed in infected tumour nodules upon systemic delivery of EnAd, encoding the oxygen-independent fluorescent reporter UnaG to a tumour xenograft grown under an abdominal window chamber. We conclude that the attenuation of the HIF pathway upon adenoviral infection may contribute to anti-vascular and immunostimulatory effects in the periphery of established infection foci in vivo. MDPI 2020-04-01 /pmc/articles/PMC7225929/ /pubmed/32244697 http://dx.doi.org/10.3390/cancers12040851 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Yousaf, Iris
Kaeppler, Jakob
Frost, Sally
Seymour, Len W.
Jacobus, Egon J.
Attenuation of the Hypoxia Inducible Factor Pathway after Oncolytic Adenovirus Infection Coincides with Decreased Vessel Perfusion
title Attenuation of the Hypoxia Inducible Factor Pathway after Oncolytic Adenovirus Infection Coincides with Decreased Vessel Perfusion
title_full Attenuation of the Hypoxia Inducible Factor Pathway after Oncolytic Adenovirus Infection Coincides with Decreased Vessel Perfusion
title_fullStr Attenuation of the Hypoxia Inducible Factor Pathway after Oncolytic Adenovirus Infection Coincides with Decreased Vessel Perfusion
title_full_unstemmed Attenuation of the Hypoxia Inducible Factor Pathway after Oncolytic Adenovirus Infection Coincides with Decreased Vessel Perfusion
title_short Attenuation of the Hypoxia Inducible Factor Pathway after Oncolytic Adenovirus Infection Coincides with Decreased Vessel Perfusion
title_sort attenuation of the hypoxia inducible factor pathway after oncolytic adenovirus infection coincides with decreased vessel perfusion
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225929/
https://www.ncbi.nlm.nih.gov/pubmed/32244697
http://dx.doi.org/10.3390/cancers12040851
work_keys_str_mv AT yousafiris attenuationofthehypoxiainduciblefactorpathwayafteroncolyticadenovirusinfectioncoincideswithdecreasedvesselperfusion
AT kaepplerjakob attenuationofthehypoxiainduciblefactorpathwayafteroncolyticadenovirusinfectioncoincideswithdecreasedvesselperfusion
AT frostsally attenuationofthehypoxiainduciblefactorpathwayafteroncolyticadenovirusinfectioncoincideswithdecreasedvesselperfusion
AT seymourlenw attenuationofthehypoxiainduciblefactorpathwayafteroncolyticadenovirusinfectioncoincideswithdecreasedvesselperfusion
AT jacobusegonj attenuationofthehypoxiainduciblefactorpathwayafteroncolyticadenovirusinfectioncoincideswithdecreasedvesselperfusion