A light blue Japanese tree frog found in farmland in Sasaguri, Fukuoka Prefecture (photo courtesy of Daiichi University of Pharmacy High School, Fukuoka City).
A naturally occurring bacterium discovered in common Japanese tree frogs may hold promise as a breakthrough cancer treatment.
In experiments involving mice with induced colon cancer, a single intravenous injection caused the bacterium to accumulate at the tumor site and attack cancer cells. It led to the complete disappearance of the tumor within one to two days. The bacterium then died off on its own and did not colonize organs or produce adverse effects.
A research team at the Japan Advanced Institute of Science and Technology (JAIST) described the discovery as a "groundbreaking bacterium."
The team is now moving swiftly to verify its effectiveness against other types of cancer and to explore safer methods of administration, as well as potential combinations with existing therapies.
Bacteria as Cancer Fighters
The three pillars of cancer treatment are surgery, chemotherapy, and radiation therapy. In recent years, immunotherapy — which works by reactivating the body's immune system, the natural defender against foreign threats — has emerged as a new option.
A leading example is the immune checkpoint inhibitor, which blocks the protein PD-1 that normally suppresses immune activity. By doing so, it restores the immune system's natural ability to attack cancer.
Tasuku Honjo, a distinguished professor at Kyoto University who contributed to the inhibitor's development, was awarded the Nobel Prize in Physiology or Medicine in 2018.
However, while immunotherapy is highly effective for some patients, it remains ineffective for many others. Challenges include the time it takes for treatment effects to appear, immune-related side effects, and high costs. To that end, identifying which combinations of treatments will work for which patients has become increasingly important.
New approaches are being explored one after another. These include using genetically modified viruses to destroy cancer cells and stimulate the immune system, or rapidly generating and administering large numbers of immune cells derived from induced pluripotent stem cells (iPS cells).
Within this context, bacteria stand out as somewhat unique. Cancer treatments using bacteria have been studied for over 150 years, but interest has surged recently. Researchers found that certain bacteria can thrive in the low-oxygen, immune-suppressed environments characteristic of tumors.
Nature Over Engineering
In the United States, a treatment using live, attenuated tuberculosis bacteria, which are also used in tuberculosis vaccines, was approved in 1991 to stimulate the immune system in bladder cancer patients. Other bacterial therapies are also advancing to the final phase of clinical trials for practical use.
In contrast, bacterial preparations are not used in Japan, and regulatory approval has yet to be obtained.
Many studies today focus on genetically modifying bacteria such as E coli and Salmonella to weaken them and turn them into carriers for delivering drugs. However, genetic modification brings regulatory and cost challenges. There is also a risk that the bacteria's properties could become unstable during cultivation.
Intending to find naturally occurring bacteria that do not require genetic modification, the JAIST research team turned to amphibians and reptiles, which have remarkably few reported cases of cancer.
They hypothesized that there must be a biological explanation for their low susceptibility.
The Experiment
The research team collected bacteria from the intestines of the Japanese tree frog, fire-bellied newt, and the Japanese grass lizard, isolating a total of 45 strains.
These were administered intravenously to mice with induced colon cancer to ensure they did not cause significant health deterioration. The team then carried out a painstaking process, testing the effect of each strain on cancer one by one.
As a result of this screening, nine strains showed antitumor effects. But the degree and nature of their effectiveness varied. For instance, among the bacteria derived from tree frogs, one strain had no noticeable impact. In another strain, tumor growth was temporarily suppressed, only to resume increasing after several days.
Some bacteria derived from fire-bellied newts caused tumors to disappear within just a few days after administration. However, tumors sometimes recurred over time, highlighting challenges for long-term suppression. Bacteria from Japanese grass lizards also suppressed tumor growth, though their ability to induce complete disappearance varied by strain.
This suggests that making a careful selection is essential, considering factors such as effectiveness and safety. That said, the identification of nine effective strains was both a jackpot discovery and a starting point for further study.
Strain With Exceptional Potency
Based on these experimental results, the research team concluded that among the nine selected strains, the bacterium E americana, found in the intestines of tree frogs, showed an exceptional ability to target and kill colorectal cancer cells.
In mouse experiments, a single intravenous administration completely eradicated colorectal cancer tumors, achieving a 100% complete response rate. Each mouse received a dose of 200 microliters, containing roughly 1 billion bacteria.
For comparison, this bacterium showed even greater tumor-eliminating potency than widely used immune checkpoint inhibitors and standard anticancer drugs tested under the same conditions. This is one reason the research team describes it as "groundbreaking."
So why do these bacteria work against cancer? The key lies in their dual action. First, they have an inherent ability to accumulate within tumors and directly attack cancer cells. Within 24 hours of administration, the number of bacteria inside the tumor surged roughly 3,000-fold, enabling a rapid and effective attack.
Bacteria accumulate in tumors because they can detect specific substances secreted by cancer cells and move toward them. Moreover, cancer cells release substances that suppress immune function as a survival strategy. Bacteria are believed to utilize this immune suppression, allowing them to evade attacks and gather more effectively.
Another is their ability to activate the body's immune system. The presence of bacteria serves as a stimulus, drawing immune cells such as T cells, B cells, and neutrophils to the tumor and intensifying the attack on cancer cells. The bacteria enter the tumor first to ignite the fire, followed by the immune system rushing in to join the assault.
Promising, But With Caution
Of course, safety verification is crucial when introducing bacteria intravenously. According to the research team, these bacteria were rapidly cleared from the bloodstream and became undetectable within 24 hours.
While bacteria in the bloodstream can circulate throughout the body, the liver and spleen act like a mesh, filtering them out. Once trapped, the immune system processes the bacteria, reducing their numbers.
There was no colonization in normal organs such as the liver or kidneys, and inflammatory responses were mild, returning to normal within 72 hours. No chronic toxicity was observed during a 60-day follow-up period.
Success in mice is only the beginning, however. Safety in mice does not guarantee the same outcome in humans. "If used in humans, toxicity and safety tests must be conducted with extreme caution," said Professor Eijiro Miyako of JAIST.
Still, the impact of seeing tumors vanish is immense. "I've been researching cancer for over 20 years, but I've never seen anything this effective," Miyako added.
From Nature to the Clinic
Three major challenges lie ahead. First, researchers need to confirm whether the same effect can be achieved against other types of cancer, such as breast or pancreatic cancer.
Second, they must explore safer and more effective administration methods, including fractionated dosing or direct intratumoral injection. Third, it's necessary to determine whether combining this bacterium with immune checkpoint inhibitors or conventional anticancer drugs can produce synergistic effects.
That does not mean tree frogs should be overharvested. Once the bacteria are isolated and properly stored, they can be multiplied indefinitely. Moreover, E americana is not present in the intestines of all tree frogs. The ones collected this time were purely coincidental. Encounters with such bacteria are genuinely once-in-a-lifetime opportunities.
What is needed is not to exploit nature, but to uncover its hidden gems and find ways to turn them into medicines. "We must think carefully about social implementation," Miyako stressed. "When it comes to human use, safety, safety, safety, is absolutely paramount."
If used for medicinal purposes, should we use the bacteria themselves, or isolate and use the compounds they produce? Using the bacteria directly raises challenges of safety and control, while relying on their components presents the difficulty of replicating the same level of efficacy.
Research on these naturally occurring intestinal bacteria of tree frogs has begun to advance carefully yet steadily. This work represents a potential step forward that could transform conventional approaches to cancer treatment.
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Author: Juichiro Ito, The Sankei Shimbun
(Read this in Japanese)
