Acute and chronic hypoxia differentially predispose lungs for metastases

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

doi:10.1038/s41598-019-46763-y

Moritz Reiterer, Renato Colaço + Show 5 more

Open Access

https://doi.org/10.1038/s41598-019-46763-y

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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.

Highlights

Oscillations in oxygen levels affect malignant cell growth, survival, and metastasis, and somatic cell behaviour
Hypoxia Inducible factors (HIF)-1α activation is seen at the shorter exposure time-points, peaking at 4 h and starting to decline after 8 h, when increased stabilization of HIF-2α becomes more evident (Fig. 1A), consistent with what has recently been reported for microvascular cells of human lung and other organs[30]
To investigate whether this pattern of HIF isoform expression is seen in vivo, animals were exposed to environmental hypoxia (10% O2)

Summary

Introduction

Oscillations in oxygen levels affect malignant cell growth, survival, and metastasis, and somatic cell behaviour. 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 prometastatic environment. 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. A number of groups have shown that each HIF isoform has downstream physiological consequences that are cell-type specific[22,27,28], and the stabilization of either in different contexts can determine disease outcome

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