Bacteria in Tumors Promote Metastasis in Mice

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For a long time, tumors were thought to be sterile environments, devoid of bacterial life. Recent research has challenged this dogma, showing that tumors harbor microbiomes. These bacteria residing inside tumor cells may in fact confer an advantage to tumor cells, a study published today in Cell reports. In mice with breast cancer, intracellular bacteria enhanced tumor cells’ ability to metastasize by improving their survival as they exit the primary tumor.

See “Could Cancer’s Microbiome Help Diagnose and Treat the Disease?”

“The report was phenomenal, very timely, and it follows a lot of the work that we’ve seen this year and the years prior, mounting evidence that tumor microenvironments are not sterile,” says Nadim Ajami, a microbiome researcher in MD Anderson’s Program for Innovative Microbiome and Translational Research who was not involved in the studyThe paper also adds to evidence, he says, “that there are differential signals [from the microbiome] and that these signals . . . have some biological relevance, that [they] impact cancer progression.”

Following the discovery of bacteria inside tumor cells in 2017, Shang Cai, a biologist at Westlake University in Hangzhou, China, and his colleagues wanted to find out “whether they are just passengers of drivers for the tumors,” he says. The researchers used a mouse strain that spontaneously develops breast cancer. First, the team confirmed that the mouse tumors harbored intracellular bacteria and found bacterial species that are similar to those found in human breast cancers. 

To find the effects of these bacteria, the researchers injected antibiotics into the tail vein, which eliminated the bacteria inside the tumor while leaving intact the gut microbiota—the bacterial community in the gut which previous studies have shown to contribute to tumor progression. Compared with controls that didn’t receive antibiotics, “we see that lung metastasis has been drastically reduced,” Cai says. The growth of the primary tumor, however, was unchanged. The results suggest that the tumors’ microbes are playing a role in the spread of cancer in the mice, but not their initial growth.

See “How the Microbiome Influences Drug Action”

During metastasis, tumor cells break into the circulatory system and travel to a distant organ. “This is a long journey and a very harsh journey,” Cai says. Some cancer cells survive this perilous trek and seed metastatic growths. The researchers set up a circulation system with a peristaltic pump to mimic the fluid shear stress cells are exposed to in blood vessels, and found that intracellular bacteria enhanced the survival rate of tumor cells. When the team injected infected cancer cells into immunodeficient mice, some types of bacteria increased the survival rate of cancer cells in the lung up to sixfold. 

Cells usually respond to the fluid shear stress they experience when entering the circulatory system by contracting a part of the cytoskeleton called the stress fiber. “When they contract, the cells will die,” Cai says. He and his colleagues stained cancer cells and saw a reduced stress fiber intensity among those with resident bacteria. “These bacteria somehow can release this contraction force—they disassemble the stress fiber, so that they can help the cancer cells to resist this kind of mechanical stress,” he says. Cai now wants to study whether these results also hold true in humans.

illustration of cells metastasizing to the lungs via the bloodstream

Tumor cells with intracellular bacteria are better able to spread to the lung and metastasize. Experiments in the new study suggest that intracellular bacteria affect the cancer cells’ RhoA-ROCK pathway, which in turn inhibits the cytoskeleton reorganization that cells usually undergo in response to mechanical stress.

For Gilad Bachrach, who studies the involvement of bacteria in tumor development at the Hebrew University of Jerusalem and was not involved in this study, the results point toward new approaches for tackling the association between bacteria and cancer therapy, suggesting “that approaches for targeting a broad range of intra-tumor bacteria are in need of development,” he writes in an email to The Scientist. “This might be achieved perhaps using tumor-specific delivery platforms” like the one used in the study, in which antibiotics were delivered to tumors intravenously.

For Ajami, the current study provides “almost a roadmap” for further studies using human samples. However, he suspects that the human situation will be less clear-cut. “Like anything with the microbiome, there’s not a single answer. There’s not a single direction, where microbes may be conferring an exclusively beneficial response or the opposite—there’s a spectrum.”  

See “New Understanding of Metastasis Could Lead to Better Treatments” 

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