PMID- 32244697
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240210
IS  - 2072-6694 (Print)
IS  - 2072-6694 (Electronic)
IS  - 2072-6694 (Linking)
VI  - 12
IP  - 4
DP  - 2020 Apr 1
TI  - Attenuation of the Hypoxia Inducible Factor Pathway after Oncolytic Adenovirus 
      Infection Coincides with Decreased Vessel Perfusion.
LID - 10.3390/cancers12040851 [doi]
LID - 851
AB  - 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-1alpha 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.
FAU - Yousaf, Iris
AU  - Yousaf I
AD  - Anticancer Viruses and Cancer Vaccines Research Group, Department of Oncology, 
      University of Oxford, Oxford OX3 7DQ, UK.
FAU - Kaeppler, Jakob
AU  - Kaeppler J
AUID- ORCID: 0000-0001-5973-0049
AD  - Mechanisms of Metastasis Research Group, Department of Oncology, University of 
      Oxford, Oxford OX3 7DQ, UK.
FAU - Frost, Sally
AU  - Frost S
AUID- ORCID: 0000-0002-0218-9949
AD  - Anticancer Viruses and Cancer Vaccines Research Group, Department of Oncology, 
      University of Oxford, Oxford OX3 7DQ, UK.
FAU - Seymour, Len W
AU  - Seymour LW
AUID- ORCID: 0000-0003-3825-0841
AD  - Anticancer Viruses and Cancer Vaccines Research Group, Department of Oncology, 
      University of Oxford, Oxford OX3 7DQ, UK.
FAU - Jacobus, Egon J
AU  - Jacobus EJ
AUID- ORCID: 0000-0002-4436-360X
AD  - Anticancer Viruses and Cancer Vaccines Research Group, Department of Oncology, 
      University of Oxford, Oxford OX3 7DQ, UK.
LA  - eng
GR  - 29106/CRUK_/Cancer Research UK/United Kingdom
GR  - C552/A17720/CRUK_/Cancer Research UK/United Kingdom
GR  - C552/A29106/CRUK_/Cancer Research UK/United Kingdom
PT  - Journal Article
DEP - 20200401
PL  - Switzerland
TA  - Cancers (Basel)
JT  - Cancers
JID - 101526829
PMC - PMC7225929
OTO - NOTNLM
OT  - HIF
OT  - UnaG
OT  - adenovirus
OT  - angiogenesis
OT  - enadenotucirev
OT  - hypoxia
OT  - intravital imaging
OT  - oncolytic
OT  - tumor microenvironment
OT  - two-photon microscopy
COIS- L.W.S. owns equity or share options in PsiOxus Therapeutics, which is leading the 
      clinical development of EnAd and its derivatives. The other authors declare no 
      conflict of interest.
EDAT- 2020/04/05 06:00
MHDA- 2020/04/05 06:01
PMCR- 2020/04/01
CRDT- 2020/04/05 06:00
PHST- 2020/02/26 00:00 [received]
PHST- 2020/03/25 00:00 [revised]
PHST- 2020/03/30 00:00 [accepted]
PHST- 2020/04/05 06:00 [entrez]
PHST- 2020/04/05 06:00 [pubmed]
PHST- 2020/04/05 06:01 [medline]
PHST- 2020/04/01 00:00 [pmc-release]
AID - cancers12040851 [pii]
AID - cancers-12-00851 [pii]
AID - 10.3390/cancers12040851 [doi]
PST - epublish
SO  - Cancers (Basel). 2020 Apr 1;12(4):851. doi: 10.3390/cancers12040851.