A bacterium from the intestines of Japanese tree frogs has "exhibited remarkably potent" tumor-killing abilities when administered intravenously, outperforming current standard therapies and paving the way for an entirely new approach to treating cancer.

Researchers at the Japan Advanced Institute of Science and Technology (JAIST) had taken a keen interest in amphibian and reptile gut microbes for several reasons – spontaneous tumors are very rare in these wild animal types, and when they do appear they’re generally linked to pollutants or lab conditions. In other words, direct external environmental factors. In addition to this, these animals have long lifespans relative to size, and naturally endure extreme cellular stress – think metamorphosis, regeneration – and live in pathogen-rich habitats, which would normally be considered things to elevate cancer risk, not lower it.

The researchers suspected that part of their apparent protection from cancer might come from microbes, not just the cells themselves. The team isolated 45 bacterial strains from the tree frogs, Japanese fire belly newts (Cynops pyrrhogaster) and Japanese grass lizards (Takydromus tachydromoides), and intensive screening narrowed the list down to nine microbes that demonstrated anti-tumor effects – with the tree frogs’ Ewingella americana exhibiting the strongest response.

"Ewingella americana exhibited remarkably potent cytotoxic activity with selective tumor-targeting ability characteristic of facultative anaerobic bacteria," the researchers noted. "Mechanistic investigations revealed that E. americana functions through a dual-action mechanism: direct tumor cell killing and robust activation of host immunity, leading to enhanced T cell, neutrophil, and B cell-mediated tumor attack. Treatment with E. americana significantly outperformed standard therapies, including anti-PD-L1 antibody and doxorubicin, in tumor regression studies."

The team administered a single shot of E. americana intravenously to mice with colorectal cancer, and it completely eliminated tumors in every treated animal. What’s more, the response wasn’t just rapid but appeared to provide ongoing protection. When the mice were later re-exposed to cancer cells, none developed new tumors, suggesting the treatment had triggered long-lasting immune memory.

The scientists soon found out why this one bacterium was so successful in completely clearing out tumors. E. americana has a two-pronged mechanism to topple cancer cells – first, it has a natural affinity for the low-oxygen environment inside solid tumors, so within just 24 hours it had increased its numbers by around 3,000-fold, but it also didn’t drift over to impact any other healthy organs or tissue. Then it’s able to directly kill the growth thanks to toxins it secretes inside the tumor.

At the same time, the bacterial invasion triggered a natural immune response, and the tumors soon became flooded with immune cells – particularly neutrophils, and T and B cells – alongside increases in inflammatory signaling molecules. The combined effect was widespread tumor cell death driven both by direct bacterial action from the foreign gut bug and by the host’s own immune system.

"These findings suggest that gut microbiomes of lower vertebrates harbor numerous uncharacterized bacterial species with exceptional therapeutic potential," the team wrote. "Our study establishes a foundation for developing naturally occurring, non-pathogenic bacterial therapeutics and underscores the critical importance of microbial biodiversity in advancing cancer treatment strategies."

Importantly, this mechanism appears to also be highly tumor-specific, with *E. americana *sticking only to the tumor environment. The researchers believe this selectivity arises from a combination of factors unique to tumors – insufficient oxygen (hypoxia), leaky blood vessels, altered metabolism and locally suppressed immune defenses that allow the bacterial colony to thrive where they are also most destructive.

But extensive testing showed that E. americana was rapidly cleared from the bloodstream, becoming undetectable within 24 hours, and caused only short-lived inflammatory effects that resolved within 72 hours. Over two months of observation, treated mice showed no signs of organ damage or chronic toxicity. Importantly, the bacterium was also sensitive to antibiotics, providing intervention options if problems were to arise following treatment.

"Comprehensive safety evaluations in murine models demonstrated that the gut-derived E. americana strain exhibits minimal pathogenicity and exerts no significant adverse effects at therapeutically effective doses, contrasting favorably with genetically modified bacterial therapeutics," the researchers added.

Of course, these findings are preliminary and experimental – and in mice. While human and mice tumors share many of the same molecular markers, including many shared genes, there are differences, including our natural immune responses and our immune systems in general. However, it’s a promising new pathway for a novel cancer therapy using natural bacteria that has the potential to completely wipe out tumors for good.

The researchers will now investigate its efficacy in breast cancer, pancreatic cancer, melanoma and other malignancies, and fine tune delivery and dosage methods. They’re also interested in seeing how this could work as a complementary therapy alongside existing immunotherapy and chemotherapy treatments.

"The successful identification of E. americana as a potent, naturally occurring anticancer agent establishes a proof-of-concept for microbiome-derived bacterial therapeutics and provides a foundation for the development of a new class of cancer treatments," the researchers concluded. "These discoveries may ultimately lead to transformative advances in precision oncology and offer new hope for patients with treatment-refractory cancers."

The study was published in the journal Gut Microbes.

Source:Japan Advanced Institute of Science and Technology via MedicalXpress