Acute and chronic hypoxia differentially predispose lungs for metastases

Moritz Reiterer, Renato Colaço, Pardis Emrouznejad, Anders Jensen, Helene Rundqvist, Randall S Johnson, Cristina Branco

Research output: Contribution to journalArticle

2 Citations (Scopus)
72 Downloads (Pure)

Abstract

Oscillations in oxygen levels affect malignant cell growth, survival, and metastasis, but also somatic cell behaviour. In this work, we studied the effect of the differential expression of the two primary hypoxia inducible transcription factor isoforms, HIF-1α and HIF-2α, and pulmonary hypoxia to investigate how the hypoxia response of the vascular endothelium remodels the lung pre-metastatic niche. Molecular responses to acute versus chronic tissue hypoxia have been proposed to involve dynamic HIF stabilization, but the downstream consequences and the extent to which differential lengths of exposure to hypoxia can affect HIF-isoform activation and secondary organ pre-disposition for metastasis is unknown. We used primary pulmonary endothelial cells and mouse models with pulmonary endothelium-specific deletion of HIF-1α or HIF-2α, to characterise their roles in vascular integrity, inflammation and metastatic take after acute and chronic hypoxia. We found that acute hypoxic response results in increased lung metastatic tumours, caused by HIF-1α-dependent endothelial cell death and increased microvascular permeability, in turn facilitating extravasation. This is potentiated by the recruitment and retention of specific myeloid cells that further support a pro-metastatic environment. We also found that chronic hypoxia delays tumour growth to levels similar to those seen in normoxia, and in a HIF-2α-specific fashion, correlating with increased endothelial cell viability and vascular integrity. Deletion of endothelial HIF-2α rendered the lung environment more vulnerable to tumour cell seeding and growth. These results demonstrate that the nature of the hypoxic challenge strongly influences the nature of the endothelial cell response, and affects critical parameters of the pulmonary microenvironment, significantly impacting metastatic burden. Additionally, this work establishes endothelial cells as important players in lung remodelling and metastatic progression.

Original languageEnglish
Article number10246
Number of pages15
JournalScientific Reports
Volume9
DOIs
Publication statusPublished - 15 Jul 2019

Fingerprint

Endothelial cells
Neoplasm Metastasis
Lung
Tumors
Endothelial Cells
Protein Isoforms
Blood Vessels
Cell growth
Cell death
Cell Survival
Growth
Transcription Factors
Stabilization
Chemical activation
Cells
Hypoxia
Tissue
Oxygen
Vascular Endothelium
Capillary Permeability

Keywords

  • Metastases
  • Endothelial cell
  • Hypoxia
  • HIF transcription factors
  • Pre-disposition

Cite this

Reiterer, M., Colaço, R., Emrouznejad, P., Jensen, A., Rundqvist, H., Johnson, R. S., & Branco, C. (2019). Acute and chronic hypoxia differentially predispose lungs for metastases. Scientific Reports, 9, [10246]. https://doi.org/10.1038/s41598-019-46763-y
Reiterer, Moritz ; Colaço, Renato ; Emrouznejad, Pardis ; Jensen, Anders ; Rundqvist, Helene ; Johnson, Randall S ; Branco, Cristina. / Acute and chronic hypoxia differentially predispose lungs for metastases. In: Scientific Reports. 2019 ; Vol. 9.
@article{2c253bd38df84934b3ac0c084f0358e2,
title = "Acute and chronic hypoxia differentially predispose lungs for metastases",
abstract = "Oscillations in oxygen levels affect malignant cell growth, survival, and metastasis, but also somatic cell behaviour. In this work, we studied the effect of the differential expression of the two primary hypoxia inducible transcription factor isoforms, HIF-1α and HIF-2α, and pulmonary hypoxia to investigate how the hypoxia response of the vascular endothelium remodels the lung pre-metastatic niche. Molecular responses to acute versus chronic tissue hypoxia have been proposed to involve dynamic HIF stabilization, but the downstream consequences and the extent to which differential lengths of exposure to hypoxia can affect HIF-isoform activation and secondary organ pre-disposition for metastasis is unknown. We used primary pulmonary endothelial cells and mouse models with pulmonary endothelium-specific deletion of HIF-1α or HIF-2α, to characterise their roles in vascular integrity, inflammation and metastatic take after acute and chronic hypoxia. We found that acute hypoxic response results in increased lung metastatic tumours, caused by HIF-1α-dependent endothelial cell death and increased microvascular permeability, in turn facilitating extravasation. This is potentiated by the recruitment and retention of specific myeloid cells that further support a pro-metastatic environment. We also found that chronic hypoxia delays tumour growth to levels similar to those seen in normoxia, and in a HIF-2α-specific fashion, correlating with increased endothelial cell viability and vascular integrity. Deletion of endothelial HIF-2α rendered the lung environment more vulnerable to tumour cell seeding and growth. These results demonstrate that the nature of the hypoxic challenge strongly influences the nature of the endothelial cell response, and affects critical parameters of the pulmonary microenvironment, significantly impacting metastatic burden. Additionally, this work establishes endothelial cells as important players in lung remodelling and metastatic progression.",
keywords = "Metastases, Endothelial cell, Hypoxia, HIF transcription factors, Pre-disposition",
author = "Moritz Reiterer and Renato Cola{\cc}o and Pardis Emrouznejad and Anders Jensen and Helene Rundqvist and Johnson, {Randall S} and Cristina Branco",
year = "2019",
month = "7",
day = "15",
doi = "10.1038/s41598-019-46763-y",
language = "English",
volume = "9",
journal = "Nature Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",

}

Reiterer, M, Colaço, R, Emrouznejad, P, Jensen, A, Rundqvist, H, Johnson, RS & Branco, C 2019, 'Acute and chronic hypoxia differentially predispose lungs for metastases', Scientific Reports, vol. 9, 10246. https://doi.org/10.1038/s41598-019-46763-y

Acute and chronic hypoxia differentially predispose lungs for metastases. / Reiterer, Moritz; Colaço, Renato; Emrouznejad, Pardis; Jensen, Anders; Rundqvist, Helene; Johnson, Randall S; Branco, Cristina.

In: Scientific Reports, Vol. 9, 10246, 15.07.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Acute and chronic hypoxia differentially predispose lungs for metastases

AU - Reiterer, Moritz

AU - Colaço, Renato

AU - Emrouznejad, Pardis

AU - Jensen, Anders

AU - Rundqvist, Helene

AU - Johnson, Randall S

AU - Branco, Cristina

PY - 2019/7/15

Y1 - 2019/7/15

N2 - Oscillations in oxygen levels affect malignant cell growth, survival, and metastasis, but also somatic cell behaviour. In this work, we studied the effect of the differential expression of the two primary hypoxia inducible transcription factor isoforms, HIF-1α and HIF-2α, and pulmonary hypoxia to investigate how the hypoxia response of the vascular endothelium remodels the lung pre-metastatic niche. Molecular responses to acute versus chronic tissue hypoxia have been proposed to involve dynamic HIF stabilization, but the downstream consequences and the extent to which differential lengths of exposure to hypoxia can affect HIF-isoform activation and secondary organ pre-disposition for metastasis is unknown. We used primary pulmonary endothelial cells and mouse models with pulmonary endothelium-specific deletion of HIF-1α or HIF-2α, to characterise their roles in vascular integrity, inflammation and metastatic take after acute and chronic hypoxia. We found that acute hypoxic response results in increased lung metastatic tumours, caused by HIF-1α-dependent endothelial cell death and increased microvascular permeability, in turn facilitating extravasation. This is potentiated by the recruitment and retention of specific myeloid cells that further support a pro-metastatic environment. We also found that chronic hypoxia delays tumour growth to levels similar to those seen in normoxia, and in a HIF-2α-specific fashion, correlating with increased endothelial cell viability and vascular integrity. Deletion of endothelial HIF-2α rendered the lung environment more vulnerable to tumour cell seeding and growth. These results demonstrate that the nature of the hypoxic challenge strongly influences the nature of the endothelial cell response, and affects critical parameters of the pulmonary microenvironment, significantly impacting metastatic burden. Additionally, this work establishes endothelial cells as important players in lung remodelling and metastatic progression.

AB - Oscillations in oxygen levels affect malignant cell growth, survival, and metastasis, but also somatic cell behaviour. In this work, we studied the effect of the differential expression of the two primary hypoxia inducible transcription factor isoforms, HIF-1α and HIF-2α, and pulmonary hypoxia to investigate how the hypoxia response of the vascular endothelium remodels the lung pre-metastatic niche. Molecular responses to acute versus chronic tissue hypoxia have been proposed to involve dynamic HIF stabilization, but the downstream consequences and the extent to which differential lengths of exposure to hypoxia can affect HIF-isoform activation and secondary organ pre-disposition for metastasis is unknown. We used primary pulmonary endothelial cells and mouse models with pulmonary endothelium-specific deletion of HIF-1α or HIF-2α, to characterise their roles in vascular integrity, inflammation and metastatic take after acute and chronic hypoxia. We found that acute hypoxic response results in increased lung metastatic tumours, caused by HIF-1α-dependent endothelial cell death and increased microvascular permeability, in turn facilitating extravasation. This is potentiated by the recruitment and retention of specific myeloid cells that further support a pro-metastatic environment. We also found that chronic hypoxia delays tumour growth to levels similar to those seen in normoxia, and in a HIF-2α-specific fashion, correlating with increased endothelial cell viability and vascular integrity. Deletion of endothelial HIF-2α rendered the lung environment more vulnerable to tumour cell seeding and growth. These results demonstrate that the nature of the hypoxic challenge strongly influences the nature of the endothelial cell response, and affects critical parameters of the pulmonary microenvironment, significantly impacting metastatic burden. Additionally, this work establishes endothelial cells as important players in lung remodelling and metastatic progression.

KW - Metastases

KW - Endothelial cell

KW - Hypoxia

KW - HIF transcription factors

KW - Pre-disposition

U2 - 10.1038/s41598-019-46763-y

DO - 10.1038/s41598-019-46763-y

M3 - Article

C2 - 31308473

VL - 9

JO - Nature Scientific Reports

JF - Nature Scientific Reports

SN - 2045-2322

M1 - 10246

ER -

Reiterer M, Colaço R, Emrouznejad P, Jensen A, Rundqvist H, Johnson RS et al. Acute and chronic hypoxia differentially predispose lungs for metastases. Scientific Reports. 2019 Jul 15;9. 10246. https://doi.org/10.1038/s41598-019-46763-y