Queen's University Belfast, Centre for Cancer Research and Cell Biology, Belfast, UK.
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
Sci Rep. 2019 Jul 15;9(1):10246. doi: 10.1038/s41598-019-46763-y.
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.
氧水平的波动会影响恶性细胞的生长、存活和转移，也会影响体细胞行为。在这项工作中，我们研究了两种主要缺氧诱导转录因子同工型 HIF-1α 和 HIF-2α 的差异表达以及肺部缺氧对血管内皮重塑肺转移前生态位的影响。据报道，急性和慢性组织缺氧的分子反应涉及动态 HIF 稳定化，但下游后果以及缺氧暴露时间的长短如何影响 HIF 同工型激活和次要器官转移倾向尚不清楚。我们使用原代肺内皮细胞和肺内皮细胞特异性缺失 HIF-1α 或 HIF-2α 的小鼠模型，来表征它们在血管完整性、炎症和急性和慢性缺氧后转移前器官易感性中的作用。我们发现，急性缺氧反应会导致 HIF-1α 依赖性内皮细胞死亡和微血管通透性增加，从而导致肺部转移性肿瘤增加，进而促进细胞外渗。这种情况因特定髓样细胞的募集和保留而加剧，这些细胞进一步支持了促转移环境。我们还发现，慢性缺氧会延迟肿瘤生长，使其达到与常氧相似的水平，并且以 HIF-2α 特异性的方式，与内皮细胞活力和血管完整性的增加相关。内皮细胞中 HIF-2α 的缺失使肺部环境更容易受到肿瘤细胞播种和生长的影响。这些结果表明，缺氧挑战的性质强烈影响内皮细胞反应的性质，并影响肺部微环境的关键参数，显著影响转移负担。此外，这项工作确立了内皮细胞作为肺重塑和转移进展的重要参与者。
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