Uncovering cancer’s deceptive trick

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Cancerous tumours thrive by turning the body’s immune system against itself. By pretending to be damaged tissue, they trigger the body’s immune responses and then exploit the extra oxygen and nutrients the body mistakenly supplies. Now, researchers at Trinity College, Dublin, have demonstrated how tumours are able to do this by manipulating a protein called TRAIL that is secreted by many cells and is commonly found in high numbers in tumour tissues.

Normally, TRAIL is associated with triggering apoptosis, or cell death. A previous study by Seamus Martin’s team at Trinity’s Molecular Cell Biology Laboratory, which investigated cell death processes, showed that some tumours appeared to be immune to TRAIL’s usual effects.

“From our previous work, we had a hint that the cells that didn’t die when treated with TRAIL were actually responding to the cytokine by mounting an inflammatory response — they were secreting molecules that can turn on the body’s immune responses,” says Martin who worked on the project with colleague Conor Henry. “We decided to explore whether this was a common phenomenon in tumour cells.”

Martin and Henry conducted multiple experiments on HeLa cervical cancer cell lines, together with other cell types, and monitored how the cells responded when exposed to TRAIL. While, as expected, TRAIL triggered apoptosis in around 40 per cent of cells in each culture, the researchers found that all the cancer cell types analysed also used TRAIL to trigger the production of multiple pro-inflammatory proteins. Further analysis showed that the TRAIL receptor had been re-wired to induce inflammation.

“We wanted to examine exactly how the pro-inflammatory proteins are produced when the TRAIL receptor engages with cancer cells,” says Martin. “We were surprised to discover the process involves a ‘switched-off’ enzyme called caspase-8, which, instead of its usual enzymatic activity, acted as a scaffold to create a molecular complex with TRAIL.”

In fact, caspase-8 was crucial to the pro-inflammatory response kicking in. The researchers knocked out the caspase-8 gene in the HeLa cells and found that TRAIL-induced protein production stopped completely.

“When we got this result, I asked Conor to check it by repeating the experiment in 10 different ways. Every time the result was absolutely clear, which is quite rare in science!” says Martin. “We then restored the gene and proved that this could reinstate TRAIL-induced pro-inflammatory protein production.”

Their results suggest that, by targeting the pro-inflammatory molecules triggered by TRAIL in cancerous tumours, scientists may find novel ways of treating cancers.

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  1. Molecular Cell 65, 715-729 (2017). doi: 10.1016/j.molcel.2017.01.022