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HIF1-alpha expressing cells induce a hypoxic-like response in neighbouring cancer cells

Hannah Harrison, Henry J Pegg, Jamie Thompson, Christian Bates, Paul Shore

Preprint posted on March 18, 2018 https://www.biorxiv.org/content/early/2018/03/18/266213

A new hypoxic-inducible system reveals non-localised effects of oxygen deprivation

Selected by Anh Hoang Le

What did the authors discover?

Studying hypoxia in cell culture systems has been frequently speculated to not reflect the natural heterogeneity within a tumour. This is because cultured cells are usually exposed to a homogenous condition to induce hypoxia in all of them. This is far from reality since, within a tumour, hypoxic regions are scattered randomly. Thus the way we used to study hypoxia can lead to loss of information that may well be vital to understanding the biology of tumours.

To overcome this, the authors have created an HIF1-inducible system based on the fact that the transcription factor Hypoxia-inducible factor 1 (HIF1) is one of the main response routes the cell uses to cope with hypoxic stress.  They attached a destabilising domain to HIF1 and upon the addition of a chemical called TMP, the HIF1-fusion protein is stabilised. By forcing the cell to express HIF1,  conditions of low oxygen are mimicked. Since this engineered protein is stable, induced cells can be mixed with non-induced cells, and this allows the authors to study a more heterogeneous population, recreating the kind of environment found inside a real tumour.

A surprising finding is that HIF1-expressing cells – in this case, two breast cancer cell lines – somehow influence surrounding cells; they even change the gene expression patterns of these cells, similar to what hypoxia would cause.

 

What I found interesting

I personally think the system is rather simple but elegant. This allows us to better model a more physiologically relevant system in a petri dish, which is highly accessible compared to systems like intravital imaging.  As shown by the authors, a heterogeneous environment of cells can easily be mimicked, and we can learn a lot just from this simple technique.

 

Unanswered questions

Nevertheless, there are a few questions that need to be answered. Thinking of complex biological systems, hypoxia is an intricate response by cells; thus, only expressing one protein may not be reflecting the entire hypoxic response mechanism.

Crosstalk between cells is a common mechanism cancer cells use to communicate. What mediates this paracrine signalling pathway between hypoxic cells and non-hypoxic cells? One interesting hypothesis is that this occurs through exosomes. Exosomes are vesicular structures released by cells, including cancer cells. It has been shown that hypoxia can increase the release of these vesicles [1]. However, what components are carried with them that cause cells to react in a certain way is largely unknown. By using this system, we may just be able to take a closer look at this.

[1] King, WM. (2012) Hypoxic enhancement of exosome release by breast cancer cell. BMC Cancer, 12:421 DOI: 10.1186/1471-2407-12-421

Tags: cancer model, heterogenous, hif1, hypoxia, intratumoural

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