Research performed by a South Korean team at Chonnam National University was recently published, to much excitement. These scientists claim to have discovered a way to flag up cancerous cells, using Salmonella as a “Trojan Horse” of sorts (sneaking into mutated cells via the body’s immune system, and attacking them).
Tumours have the propensity to be overlooked by our natural immune defences; this is either due to cancerous cells not appearing as foreign invaders (rather, just as askew normal tissues), or due to the cells having evolved new methods to evade defence mechanisms. Hence, a great challenge lies in finding a means by which to identify tumour cells as being ‘non-self’ – here lies the ingenuity of the recruitment of these bacteria (paired with the fact that necrotic, oxygen-deprived tissue is their optimum habitat – the conditions found in most compacted tumours) as a means of targeting tumour cells. Unfortunately (whether the problem arises due to the pathological bacteria, or the persistence of cancerous cells), most of the time this technique does not work as expected.
Over recent years, a large chunk of research has been geared towards trying to infect cancerous tissue with bacteria that are loaded with anti-cancer drugs. Roy Curtiss III (of the University of Florida in Gainesville) has tried several times to elucidate bacterial techniques to have the potential to fight cancer. He has admitted that “…until now, attempts to use bacteria as anti-cancer therapies have had limited success, both in the laboratory and in the clinic.” Nonetheless, scientists have recently tried to alter Salmonella on a molecular level, later implanting them within mice in order to trigger a particularly powerful immune response against human cancer cells. The outcome was unexpected, but very happily received – the melanoma shrank, and (even more surprisingly) the bacteria seemed to prevent the cancer cells from metastasising.
Strikingly, the actual discovery arose from a disparate study. In 2006, South Korean researchers were seeking to produce a novel agent to fight cancer, as well as a vaccine for the microbe Vibrio Vulnificus (a bacteria that contaminates shellfish on the South Korean coast). Whilst working with Vibrio, they observed that a protein (FlaB) the microbe expressed was able to elicit a particularly strong immune response. What was the problem? Salmonella is too powerful to be inserted into a human body, without poisoning the recipient. Drawing on this, Korean engineers have managed to produce a relatively ‘harmless’ strain of the bacteria; this strain is one million times less virulent than that commonly known as a cause of severe food poisoning. Neither noxiousness nor inflammation in either organs or systems are observed within patients, but the innocuous modified Salmonella typhimurium can still be spotted easily.
The team consequently began to examine the effect that the modified Salmonella could have on a tumour, through various different stages. Their experiments consisted of inserting human colon cancers in mouse models, following which modified bacteria were inserted into a proportion of them (which were then compared to mice hosting non-modified Salmonella Typhimurium, and untreated mice). After a couple of days, the scientists observed that even though there were no more signs of tumours within the mice, organs earlier affected were filled with Salmonella. After a month, the two latter groups exhibited different cancerous growths, but those mice bearing the modified bacteria had only minor cancers. After four months had passed, half of the starting mouse models were noted to be ‘healthy’, with any previous signs of cancer untraceable. The control mice, on the other hand, surrendered to their melanomas in death. Thus, it was confirmed – the FlaB protein may potentially be able to stop tumour growth and tag cancer cells, as well as stimulating TLR5 (a molecule which triggers the strengthening of body’s immune system). Similar studies have confirmed these results, reinforcing the success of FlaB.
The modified colonising Salmonella facilitated infiltration of the tumour by immune cells, such as macrophages, through the signalling by the Toll-like receptors (TLR). When engineered Salmonella expressed FlaB, white blood cells appeared in the tumour: M1 (macrophage 1) phenotype encouraged inflammation and M2 (macrophage 2) phenotype reduced inflammation and encouraged tissue repair. These results showed that the innocuous version of Salmonella extricates molecules bound to TLR, which are proteins playing a key function in the immune system and thus in immunotherapies that are used to fight cancer.
At the University of Swansea, Professor Paul Dyson is also working on the use of modified Salmonella Typhimurium as a means of defeating cancer. Reaffirming popular hopes, he says “we believe there is huge mileage in pursuing research into this type of treatment – existing evidence indicates there would be few or no side effects.” Accordingly, in order to prove that FlaB has the potential to work as an active anticancer agent, scientists are hoping to speed through to organising human clinical trials.
If found to be effective even within a human body, this FlaB-enhanced Salmonella Typhimurium therapy may in fact provide a step forward in the ceaseless battle against cancer.