Researchers engineer probiotics to detect liver tumours

Engineers at MIT and the University of California at San Diego (UCSD) have devised a way to detect cancer that has spread to the liver, by enlisting the help of probiotics.

Many types of cancer, including colon and pancreatic, tend to metastasize to the liver. The earlier doctors can find these tumours, the more likely that they can successfully treat them.

“There are interventions, like local surgery or local ablation, that physicians can perform if the spread of disease in the liver is confined, and because the liver can regenerate, these interventions are tolerated. New data are showing that those patients may have a higher survival rate, so there’s a particular need for detecting early metastasis in the liver,” says Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Electrical Engineering and Computer Science at MIT.

Using a harmless strain of E. coli that colonises the liver, the researchers programmed the bacteria to produce a luminescent signal that can be detected with a simple urine test.

Previous studies had shown that bacteria can penetrate and grow in the tumour microenvironment, where there are lots of nutrients and the body’s immune system is compromised. Because of this, scientists have been trying for many years to develop bacteria as a possible vehicle for cancer treatment. The MIT and UCSD researchers began exploring this idea a few years ago, but soon expanded their efforts to include the concept of creating a bacterial diagnostic.

To turn bacteria into diagnostic devices, the researchers engineered the cells to express the gene for a naturally occurring enzyme called lacZ that cleaves lactose into glucose and galactose. In this case, lacZ acts on a molecule injected into the mice, consisting of galactose linked to luciferin, a luminescent protein naturally produced by fireflies. Luciferin is cleaved from galactose and excreted in the urine, where it can easily be detected using a common laboratory test.

Researchers founds that orally delivered bacteria zero in on liver tumours

At first, the researchers were interested in developing these bacteria for injection into patients, but then decided to investigate the possibility of delivering the bacteria orally, just like the probiotic bacteria found in yogurt. To achieve that, they integrated their diagnostic circuits into a harmless strain of E. coli called Nissle 1917, which is marketed as a promoter of gastrointestinal health.

In tests with mice, the researchers found that orally delivered bacteria do not accumulate in tumours all over the body, but they do predictably zero in on liver tumours because the hepatic portal vein carries them from the digestive tract to the liver.

“We realised that if we gave a probiotic, we weren’t going to be able to get bacteria concentrations high enough to colonise the tumours all over the body, but we hypothesized that if we had tumours in the liver they would get the highest dose from an oral delivery,” Bhatia explained.

This allowed the team to develop a diagnostic specialised for liver tumours. In tests in mice with colon cancer that has spread to the liver, the probiotic bacteria colonised nearly 90% of the metastatic tumours. Animals that were given the engineered bacteria did not exhibit any harmful side effects.

Researchers can detect liver tumours larger than one cubic millimeter using the new technique

The researchers focused on the liver not only because it is a natural target for these bacteria, but also because the liver is hard to image with conventional imaging techniques like CT scanning or magnetic resonance imaging (MRI), making it difficult to diagnose metastatic tumours there. With the new system, the researchers can detect liver tumours larger than about one cubic millimeter, offering more sensitivity than existing imaging methods.

“This kind of diagnostic could be most useful for monitoring patients after they have had a colon tumour removed because they are at risk for recurrence in the liver”, Bhatia says.

Andrea Califano, a professor of biological sciences at Columbia University, says the study is “seminal and thought-provoking in terms of clearing a new path for investigating what can be done for early detection of cancer,” adding that the therapeutic possibilities are also intriguing.

“These bacteria could be engineered to cause genetic disruption of cancer cell function, deliver drugs, or reactivate the immune system,” says Califano, who was not involved in the research.

The MIT team is now pursuing the idea of using probiotic bacteria to treat cancer, as well as for diagnosing it.