Research

E. Coli

Illustration of E. coli. from a Science news story covering this research. Credit: Chris Bickel / Science

Programming probiotics

Bioengineers program probiotics for early detection of liver cancer metastases.

Scientists at the Jacobs School and the Massachusetts Institute of Technology (MIT) have described a new method for detecting liver cancer metastases in mice. The approach uses over-the-counter probiotics that are genetically programmed to produce signals easily detectable in urine when liver cancer metastases are present. So far, the results indicate that genetically-programmed probiotics may be useful for detecting liver cancer metastases early on in the progression of the disease.

The metastatic spread of cancer is ultimately responsible for 90 percent of all cancer-related deaths, and liver metastases are particularly challenging for clinicians due in part to their small size and multiplicity. If metastases are detected early, patients have a much higher chance of survival. By using probiotics as a platform for early detection of liver metastases in mice, the researchers took advantage of the ability of certain bacteria to pass from the gastrointestinal tract directly into the liver and target tumors. Over the last 100 years or so, scientists have become increasingly aware of bacteria in environments previously thought to be sterile, such as tumors, indicating that bacteria are part of normal human physiology.

“It was discovered in the early 1900s that certain bacteria selectively colonize tumors,” said Arthur Prindle, one of two first-authors on the study, who performed this research as a bioengineering Ph.D. student at UC San Diego. “No one knows for sure, but this could be due to the lack of immune surveillance and availability of nutrients inside the tumor — the bacteria can grow freely without the interference of the immune system.”

Armed with this knowledge, the researchers set out to develop a simple method for detecting liver metastases using a mouse model

for liver cancer and the widely used probiotic bacterium E. coli Nissle 1917 (EcN). This meant shipping off their probiotic to the study’s other first author, UC San Diego alumnus Tal Danino at the Koch Institute for Integrative Cancer Research at MIT. The group engineered the bacteria to overexpress a LacZ gene reporter to test the idea that a probiotic taken orally would colonize metastases, something that was only previously demonstrated when bacteria were injected directly into the bloodstream. LacZ is a gene that encodes an enzyme that causes bacteria to appear blue when grown on a medium that contains its substrate. When inside an animal, the product of the enzymatic activity is excreted in urine and causes it to change color. If liver metastases were present, the urine of the mice turned red. UC San Diego bioengineering and biological sciences professor Jeff Hasty expects the new method will enable the detection of liver cancer at an earlier stage, increasing the chances that it will be treated successfully.

“There are multiple reasons to use probiotics in the early detection of cancer,” said Hasty. “First, probiotic bacteria are susceptible to antibiotics, which enables their rapid removal from a patient’s system once they’ve done their job. Second, probiotics will do what they do best — grow. That means that patients only need to be given enough probiotic bacteria to ensure that one bacterium arrives at its target location.”

The researchers followed these mice for more than a year after oral delivery and found no deleterious health effects.

Tal Danino

Tal Danino

Arthur Prindle

Arthur Prindle

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