CAMBRIDGE, Mass.—Engineers at the Massachusetts Institute of Technology (MIT) and the University of California, San Diego (UCSD) have devised a new way to detect cancer that has spread to the liver—by enlisting help from probiotics.
Many types of cancer, including colon and pancreatic, tend to metastasize to the liver. The earlier doctors can find these tumors, the more likely it is that they can successfully treat them.
In an article that appeared earlier this year in Science Translational Medicine, the MIT/UCSD researchers reported that “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 have a higher survival rate, so there’s a particular need for detecting early metastasis in the liver,” wrote Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Electrical Engineering and Computer Science at MIT. Bhatia and Jeff Hasty, a professor of bioengineering at UCSD, were the senior authors of the paper describing the new approach, along with lead authors MIT postdoc Tal Danino and UCSD postdoc Arthur Prindle.
An E. coli strain was carefully engineered to carry β-galactosidase, an enzyme that can metabolize numerous substrates. When fed to mice, these bacteria transited the gut epithelium to enter the bloodstream and then traveled to the liver, where they take up residence in any tumor colonies that are present. At that point, the mice were fed LuGal, a combined luciferin and galactose molecule. When the LuGal reached the bacteria in the tumors, the bacterial β-galactosidase metabolized it to luciferin, which was then excreted in the urine. The amount of luciferin, an easily detectible molecule, revealed the tumor burden carried in the liver. It remains to be seen whether this noninvasive approach to cancer detection can be applied to other tumor types and locations, but the versatility conferred by control of the enzymes in the E. coli and the substrates fed to the animal bodes well for future application.
Previous studies had shown that bacteria can penetrate and grow in the tumor 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.
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 tumors all over the body, but they do predictably zero in on liver tumors because the hepatic portal vein carries them from the digestive tract to the liver.
“We realized that if we gave a probiotic, we weren’t going to be able to get bacteria concentrations high enough to colonize the tumors all over the body, but we hypothesized that if we had tumors in the liver, they would get the highest dose from an oral delivery,” says Bhatia, who is a member of MIT’s Koch Institute for Integrative Cancer Research and the Institute for Medical Engineering and Science.
This allowed the team to develop a diagnostic specialized for liver tumors. In tests in mice with colon cancer that has spread to the liver, the probiotic bacteria colonized nearly 90 percent of the metastatic tumors.
In the mouse experiments, animals that were given the engineered bacteria did not exhibit any harmful side effects.
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, making it difficult to diagnose metastatic tumors there.
With the new system, the researchers can detect liver tumors 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 tumor removed, because they are at risk for recurrence in the liver, Bhatia says.
The MIT team is now pursuing the idea of using probiotic bacteria to treat cancer, as well as for diagnosing it.
The research was funded by the Ludwig Center for Molecular Oncology at MIT, a Prof. Amar G. Bose Research Grant, the National Institutes of Health through the San Diego Center for Systems Biology and the Koch Institute Support Grant from the National Cancer Institute.