Rethinking Salmonella: from food poisoning culprit to cancer-fighting agent

What would you look for in an ideal cancer treatment? You’d probably want something that would only kill cancer cells and leave healthy cells unharmed. It would also be nice if this drug could penetrate deep inside tumours, even if the tumours are dispersed across multiple sites in the body.

What if that anti-cancer treatment was a dose of Salmonella? Would you try it?

Scientists are developing ways to transform bacteria like Salmonella into lean, mean tumour-fighting machines. A new study published this week in Proceedings of the National Academy of Sciences describes a new and innovative way to turn Salmonella into highly specific vehicles that can deliver anti-cancer compounds into the heart of a tumour.

Salmonella has a reputation of being an unpleasant and unwanted bacterium. Fair enough: it is one of the most common causes of food poisoning. The same characteristics that make Salmonella a successful gastrointestinal pathogen are also what makes it a potentially great anti-cancer vector. These include its abilities to survive in both oxygen-rich and –poor environments and to invade different human cell types. To add to its list of attractive qualities, Salmonella seems to preferentially grow inside tumours. Earlier studies found that Salmonella counts are significantly higher in some human and mouse tumours than in the surrounding healthy tissues. One study reported as much as 10,000 times more Salmonella in tumour tissue compared to healthy tissue!

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If Salmonella can be engineered to produce cancer-fighting compounds when it is in a tumour, then it could, in theory, be an effective way of delivering targeted therapies to tumour sites. Luckily, because Salmonella has been studied for so long, there is a wealth of tools with which we can genetically manipulate the bacteria to do our bidding. The first step in using Salmonella as a potential cancer treatment is to make it safe for human consumption by taking away its disease-causing ability. These weakened strains of Salmonella can then be engineered to express tumour-killing compounds like bacterial toxins. While highly effective, bacterial toxins are indiscriminate killers, causing any cell that ingests them to die.

The challenge is that while Salmonella are enriched in tumours, low numbers of the bacteria are still found in healthy tissues. If those bacteria also produced the cancer-fighting compounds, they would risk damaging healthy tissues. Since many of the debilitating side effects of chemotherapies and radiation therapies are caused by damage to healthy tissues and organs, finding a way to minimize the off-target effects of using a Salmonella anti-cancer vector has been a key focus of this research field.

Figuring out how to limit the production of these tumour-killing compounds to only tumour-residing Salmonella has been tricky. Several strategies have been tested (including using radiation, low oxygen levels or external compounds to turn on production) but none of them have been ideal. Now, a group of scientists led by Dr. Neil Forbes at University of Massachusetts Amherst has devised a clever way of using a pre-existing bacterial system to control gene expression in tumour-residing Salmonella.

Bacteria communicate to each other by sending out chemical signals. How much chemical signals are in a given environment is a good indicator of how many bacteria are living there – the higher the signal level, the denser the bacterial community. This strategy, called quorum sensing, is widely used in some bacteria to control the expression of genes that should only be turned on when the community reaches a certain population size. Given that Salmonella levels are often higher in tumour tissues than in neighbouring healthy tissues, the researchers tried to co-opt the quorum-sensing system and use population density as a trigger to turn on gene expression.

To test their idea, the researchers engineered a weakened strain of Salmonella with a quorum sensing system to control production of the green fluorescent protein (GFP). They confirmed that their system worked by showing that the bacteria only made GFP once their communities had reached a certain density. At densities higher than the minimum threshold, the bacteria continued to make GFP and acquired a bright green glow. When these bacteria were injected into mice that had tumours, Salmonella density in the tumour tissue was almost 90 times higher than in the healthy liver tissue. The Salmonella residing within the tumour were brightly fluorescent because the high bacterial density in the tumour tissue triggered the production of GFP. The researchers also used mathematical models to show that the density threshold for the quorum sensing system was high enough that sporadic Salmonella dispersed randomly in healthy tissues would not turn on GFP production.

Even though the researchers did not directly test whether the quorum sensing system is effective in controlling production of tumour-killing compounds, this study was an important proof of principle because it showed that this strategy can successfully trigger Salmonella to make certain proteins only when it is in a tumour environment. Using bacteria as anti-cancer vectors is a promising area of research but there is still a long way to go before these ideas can reach the clinic. In moving forward, there are many other important questions to consider. For example, could these bacterial anti-cancer treatments be given to patients with a weakened immune system? Even though the bacteria are weakened and should (in theory) be no longer capable of causing disease, they may still pose a health threat to immunocomprised individuals. With more research, we may one day help Salmonella achieve “frenemy” status – a new friend in the fight against cancer, but a perpetual enemy in food safety.

Reference:
Swofford CA, Van Dessel N, & Forbes NS (2015). Quorum-sensing Salmonella selectively trigger protein expression within tumors. Proceedings of the National Academy of Sciences of the United States of America, 112 (11), 3457-62 PMID: 25737556

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