Scientists at Westlake Laboratory of Life Sciences and Biomedicine reported the results of a study in a mouse model of breast cancer, which suggest that bacteria in tumors can promote cancer metastasis by bolstering the strength of host cells against mechanical stress in the bloodstream, to promote cell survival during tumor progression. The study results showed that intracellular bacteria act to reorganize the actin cytoskeleton in circulating tumor cells (CTCs), and this promotes CTC survival by enhancing resistance to mechanical stress in the circulation. The studies also indicated that these tumor-resident intracellular bacteria promoted metastasis, but were not required for primary tumor growth.

“Our study reveals that the cancer cell’s behavior is also controlled by the microbes hiding inside tumors, the majority of which were originally thought to be sterile,” said senior author Shang Cai, PhD. “This microbial involvement is distinct from the genetic, epigenetic, and metabolic components that most cancer drugs target.”

However, Cai stressed, “Our study does not mean that using antibiotics during cancer treatment will benefit patients … it is still an important scientific question of how to manage the intratumor bacteria to improve cancer treatment in the future.”

The researchers reported on their findings in Cell, in a paper titled, “Tumor-resistant intracellular microbiota promotes metastatic colonization in breast cancer,” in which they concluded, “Our findings suggest that tumor-resident microbiota, albeit at low biomass, play an important role in promoting cancer metastasis, intervention of which might therefore be worth exploring for advancing oncology care.”

Microbes play a critical role in affecting cancer susceptibility and tumor progression, particularly in colorectal cancers, the authors noted. “These microbial organisms exert their functions notably through indirect pathways (including metabolites and the immune system) on distant or proximal tumor tissues, particularly in colorectal cancers where they are in intimate contact with the gut microbiota.”

Emerging evidence suggests that microbiota are also integral components of the tumor tissue itself in a broad range of cancer types, such as pancreatic cancer, lung cancer, and breast cancer, which were originally thought to be “sterile.” However, the team noted, “Although studies have shown that gut microbiota contributes to the tumor progression in various tumor systems, the biological significance of intratumor microbiota remains largely unknown.”

Studies have suggested that features of such tissue-resident microbiota are linked to cancer risk, prognosis, and treatment responses, yet the biological functions of tumor-resident microbes in tumor progression remain unclear, the team further pointed out. Whether these microbes are passengers or drivers of tumor progression has been an intriguing question.

“Whereas a growing body of evidence indicates the importance of intratumor microbiota, whether the low-biomass tumor-resident microbiota in its physiological homeostatic state plays any significant biological roles in spontaneous tumor progression is still an open question,” the investigators stated.

“Tumor cells hijacked by microbes could be more common than previously thought, which underscores the broad clinical value of understanding the exact role of the tumor-resident microbial community in cancer progression,” Cai added.

To address this gap in understanding, Cai and his collaborators used a mouse model of breast cancer with significant amounts of bacteria inside cells, “resembling that in human breast cancer,” they wrote. Their work demonstrated that these intratumoral microbes can travel through the circulatory system with the cancer cells and play critical roles in tumor metastasis. Specifically, these passenger bacteria were able to modulate the cellular actin network and promoted cell survival against mechanical stress in circulation. “During metastatic colonization, intratumor bacteria carried by circulating tumor cells promoted host-cell survival by enhancing resistance to fluid shear stress by reorganizing actin cytoskeleton,” they wrote. “We were surprised initially at the fact that such a low abundance of bacteria could exert such a crucial role in cancer metastasis,” Cai noted.

Further experiments also showed that directly administering bacteria strains isolated from tumor-resident microbiota directly into a tumor promoted metastasis in two murine tumor models with significantly different levels of metastasis potential. “Intriguingly, when we performed this experiment on an MMTV-Wnt tumor mouse model, which is known to rarely metastasize and contained low abundance microbiota, the tumor started to metastasize after one shot of the on-site administration of bacteria, reinforcing the role of certain bacteria in promoting metastasis

Cai continued, “What is even more astonishing is that only one shot of bacteria injection into the breast tumor can cause a tumor that originally rarely metastasizes to start to metastasize.” Conversely, other experiments showed that depleting intratumor bacteria using antibiotics led to reduced lung metastasis, without impacting on primary tumor growth.

“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,” Cai suggested.

Although the study revealed a clear role of intratumor bacteria in promoting cancer cell metastatic colonization, the authors did not exclude the possibility that the gut microbiome and immune system may act together with intratumor bacteria to determine cancer progression. 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.

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