Researchers in China have discovered that bacteria promote cancer metastasis by bolstering the strength of host cells against mechanical stress in the bloodstream, promoting cell survival during tumor progression.

A cancer cell's behavior is also controlled by the microbes hiding inside tumors, the majority of which were originally thought to be sterile, according to the study that was published in Cell, April 7.

"In the future, we may have a new way to block cancer metastases by modulating the microbiota," lead study author Shang Cai of the Westlake University School of Life Sciences in Hangzhou, China, told BioWorld.

Microbes play a critical role in affecting cancer susceptibility and tumor progression, particularly in colorectal cancers. However, emerging evidence suggests that they are also integral components of the tumor tissue itself in in a broad range of cancer types, such as pancreatic cancer, lung cancer and breast cancer. Microbial features are linked to cancer risk, prognosis and treatment responses, yet the biological functions of tumor-resident microbes in tumor progression remain unclear, study authors said.

Using a spontaneous mouse breast tumor (BT) model, Cai's lab characterized the BT microbiota profile and developed methods to dissect the different roles of breast tumor-resident microbiota and gut-resident microbiota.

Researchers showed that the intracellular microbiota plays crucial roles in tumor metastasis by "modulating cellular cytoskeleton and cell viability upon mechanical stress," the study said.

Cai conducted his post doc studies at Stanford University from 2010 to 2017, where he was involved in trying to knock out a certain gene using tetracycline as an inducer to determine if this gene was involved in cancer progression.

"When I induced the knockout of the gene, I observed that the tumor metastases were greatly inhibited, and I got really excited about this result," he said.

But when he tried to check the control by using the inducer without knocking out the gene, he also observed significant reduction of metastases.

"The results were confusing," he said, "because it wasn't clear what was happening."

He checked literature to see if antibiotics could kill cancer cells, and he found some studies that mentioned doxycycline killing cancer cells.

"But I didn't observe primary tumor shrinkage. The primary tumor grew fine; I only observed the metastases. I realized that doxycycline on one hand is inducing the gene knockout, but on the other hand, the antibiotic kills the bacteria. That made me wonder if it was possible that the bacteria are also involved in this process," he said.

Cai returned to China in 2017, and he established his own lab and got to work putting these questions to the test in mouse models.

He and his team used a mouse model of breast cancer with significant amounts of bacteria inside cells, similar to human breast cancer. They found that the microbes can travel through the circulatory system with the cancer cells and play critical roles in tumor metastasis. Specifically, these passenger bacteria are able to modulate the cellular actin network and promoted cell survival against mechanical stress in circulation.

Bacteria hide from immune system in tumor cells

"The most fascinating thing is that the majority of those bacteria hide themselves within the tumor cells," he said, which explains why most people believed it was a sterile environment for the tumor, because there shouldn't be any bacteria within the tumor because the immune system would clear it.

Further studies confirmed the bacteria were important for tumor metastases. Additional questions emerged such as what the function of the bacteria are and whether the bacteria are drivers or passengers for the tumor progression.

"When the tumor cells go into the circulatory system, they experience fluid sheer stress and all kinds of mechanical stress, and more than 99% of the cells will die when they travel through the circulatory system."

"But when the tumor cells are invaded by the bacteria, amazing things happen, because they reorganize the cytoskeleton and make the tumor cells more robust, and they can resist the fluid sheer stress, so they greatly enhance their ability to survive during the harsh journey to the distal organ, and then they colonize there and give rise to metastases.

"If you kill the bacteria specifically, leaving the gut microbiome intact, then the tumor metastases will be greatly inhibited."

The same type of tumor in different patients will have different prognoses, and the study suggests that intratumor microbiota could be one of the things that affect prognosis and tumor progression. Profiling the microbiota within specific patients could help clinicians provide better prognoses.

"In the future, we may have a new way to block the cancer metastases by modulating the microbiota."

Next steps

"We demonstrated with very strong evidence in this mouse model (a spontaneous tumor that closely mimicked human cancer progression) that the bacteria have a function there, and we also showed evidence that in humans the primary tumor and the lymph node metastases tumor have similarities with the microbiome profile.

But functional evidence is still lacking, he said, so next steps will be to figure out how to control the intratumor microbiota.

Different antibiotics have different properties in clearing bacteria, and some antibiotics can enter cells, but some cannot, he said, and some bacteria have become resistant to antibiotics.

Fluorescence microscopy analysis showed that Staphylococcus, Lactobacillus and Streptococcus had the ability to stimulate metastases, but not Enterococcus.

"We need to figure out the best combination of antibiotics and other tools to kill these bacteria," he said, noting that different types of antibiotics and bacteria will need to be studied further.

In humans, this will become more difficult to understand because of the overuse of antibiotics, while the mouse study was clear because the mice had not been exposed to antibiotics.

"Our study clearly demonstrates the importance of the microbiota within the tumor, but it doesn't mean that using antibiotics can cure the cancer," he said.

"Intracellular microbiota could be a potential target for preventing metastasis in broad cancer types at an early stage, which is much better than to have to treat it later on."

In the future, further in-depth analysis of how bacteria invade tumor cells, how intracellular bacteria are integrated into the host cell system, and how bacteria-containing tumor cells interact with the immune system will provide insights on how to properly implement antibiotics for cancer therapeutics in the clinic.