Tumor-resident intracellular bacteria benefit metastasis

Emerging evidence has revealed that bacteria are present in a variety of tumor types, including those thought to be sterile, such as brain and renal tumors (1-4). Indeed, tumors contain unique microbial communities that differ according to the tumor type and may persist during metastatic progression. Accordingly, polymorphic microbiomes have been newly assigned as a cancer hallmark (5). Intratumoral microbes, which frequently localize inside tumor cells, can directly or indirectly modulate the effectiveness of anticancer treatments by metabolizing drugs or by regulating antitumor immune responses (6-9). Currently, tumor-resident intracellular bacteria are an emerging field of cancer research; however, how intracellular bacteria regulate tumor progression remains unclear.

Tumor cells metastasize to distant organs in the course of their progression. Individuals with metastatic cancer typically have a poor prognosis; however, other than early treatment intervention, there is no way to avoid metastasis. In order to develop strategies to prevent metastasis, research is often focused on elucidating the mechanisms underlying tumor metastasis and the factors that affect this process. A recent study by Fu et al. (10) demonstrated that tumor-resident intracellular bacteria can improve the survival of circulating tumor cells and promote tumor metastasis, shedding new light on the mechanism by which tumors spread to other organs. Furthermore, Fu et al. (10) explored the functional significance of tumor-resident intracellular bacteria using the spontaneous mouse breast-tumor mouse mammary tumor virus-polyoma middle tumor-antigen (MMTV-PyMT) model. Bacteria were present in both tumorous and non-tumorous breast tissue. Similar species of bacteria were present in both types of tissue, but the number of bacteria in tumorous tissue was nearly 10-fold higher than that in non-tumorous tissue. Further analysis identified different microbial communities in tumorous and non-tumorous breast tissue. Specifically, the tumorous tissue had lower bacterial alpha diversity than the non-tumorous tissue, with Staphylococcus, Enterococcus, Streptococcus, and Lactobacillus forming the main components of the tumor microbiota. Intriguingly, recent research has linked these bacterial species to the production of quorum sensing peptides, which facilitate cancer metastasis (11).

The influence of intratumoral bacteria on tumor growth and progression differs from that of gut bacteria. Stool from colorectal cancer patients gavaged to mice altered the gut microbiome and upregulated genes involved in angiogenesis and metastasis in intestinal cells (12). Further, bacterial infections themselves have the potential to induce angiogenesis, a process that contributes to the formation of cancer metastasis (13). Most intratumoral bacteria inhabit the perinuclear cytoplasm of tumor cells (8,10,14). The elimination of intratumoral bacteria via the intravenous administration of antibiotics reduced the volume of metastatic lung tumors but did not affect primary tumor growth, suggesting that tumor-resident bacteria play a role in tumor metastasis, but not in tumor growth (10). In contrast, the elimination of gut and intratumoral bacteria via the oral administration of antibiotics reduced the tumor volume of both primary and metastatic tumors, indicating the role played by gut bacteria in tumor growth.

Intratumoral bacteria can promote metastatic colonization. When recombinant Staphylococcus xylosus (S. xylosus) was applied to the primary breast tumor, the recombinant clones were observed in most lung areas where metastatic tumors were present but could not be identified in lung tissue without metastases (10). Furthermore, when recombinant S. xylosus was injected via the tail vein, the recombinant clones were detected in the lung only when injected with tumor cells. Indeed, the bacterial injection alone, even at a high dose, did not lead to the formation of colonies in the lung (10). These results suggest that bacteria travel through the circulatory system and settle in distant organs only when combined with tumor cells. When various bacteria, including S. xylosus, Lactobacillus animalis (L. animalis), and Spilopsyllus cuniculi (S. cuniculi), were injected into antibiotic-treated primary tumors, these bacteria invaded the tumor cells and increased the burden of metastatic lung tumors, but had no impact on the growth of the primary tumor (10). These results also suggest the role played by intratumoral bacteria not in tumor growth but in metastatic colonization.

Tumor-resident intracellular bacteria can increase the survival of tumor cells under mechanical stress during circulation. Single-cell RNA sequencing analysis of bacteria-containing cancer cells revealed that the invasion of tumor cells by S. xylosus, L. animalis, S. cuniculi, and Streptococcus sanguinis specifically activated the fluid shear stress pathway (10). When cancer cells enter the bloodstream during metastasis, they frequently undergo apoptosis due to fluid shear stress (15,16). However, bacteria-containing tumor cells exhibit higher viability than tumor cells without bacteria, possibly owing to the role played by intracellular bacteria in modulating the stress response (10). Indeed, stress fiber strength was significantly reduced after bacterial invasion into the tumor cells, suggesting that mechanical stress-induced contraction forces can be relieved by intracellular bacteria (10). Additionally, bacteria-containing tumor cells exhibited increased adherence and spread on a plate, suggesting that intracellular bacteria can modify the construction of the actin cytoskeleton.

The abovementioned findings have increased our understanding of how intratumoral bacteria benefit tumor progression and/or metastasis. Some mechanisms underlying tumor metastasis have been identified and may be targeted early to prevent metastasis (17). A recent study revealed that bacterial distribution within a tumor microenvironment is not random but is organized in microniches with specific tumor-promoting functions of immune and epithelial cells (14). Nevertheless, knowledge of the role of intratumoral bacteria in tumor progression is still limited and warrants further research.

Acknowledgments

Funding: KI was supported financially by the JSPS KAKENHIGrant Number 22H02930, Takeda Science Foundation, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Ichiro Kanehara Foundation, Suzuki Foundation for Urological Medicine, Grant for Lung Cancer Research, Foundation for Promotion of Cancer Research in Japan, and the Yakult Bio-Science Foundation.

Footnote

Provenance and Peer Review: This article was a standard submission to Annals of Translational Medicine. The article has undergone external peer review.

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Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-6209/coif). The authors have no conflicts of interest to declare.

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References

1. Zitvogel L, Ma Y, Raoult D, et al. The microbiome in cancer immunotherapy: Diagnostic tools and therapeutic strategies. Science 2018;359:1366-70. [Crossref] [PubMed]
2. Gopalakrishnan V, Helmink BA, Spencer CN, et al. The Influence of the Gut Microbiome on Cancer, Immunity, and Cancer Immunotherapy. Cancer Cell 2018;33:570-80. [Crossref] [PubMed]
3. Sepich-Poore GD, Zitvogel L, Straussman R, et al. The microbiome and human cancer. Science 2021;371:eabc4552. [Crossref] [PubMed]
4. Inamura K, Hamada T, Bullman S, et al. Cancer as microenvironmental, systemic and environmental diseases: opportunity for transdisciplinary microbiomics science. Gut 2022;gutjnl-2022-327209.
5. Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discov 2022;12:31-46. [Crossref] [PubMed]
6. Geller LT, Barzily-Rokni M, Danino T, et al. Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science 2017;357:1156-60. [Crossref] [PubMed]
7. Yu T, Guo F, Yu Y, et al. Fusobacterium nucleatum Promotes Chemoresistance to Colorectal Cancer by Modulating Autophagy. Cell 2017;170:548-563.e16. [Crossref] [PubMed]
8. Nejman D, Livyatan I, Fuks G, et al. The human tumor microbiome is composed of tumor type-specific intracellular bacteria. Science 2020;368:973-80. [Crossref] [PubMed]
9. Inamura K. Roles of microbiota in response to cancer immunotherapy. Semin Cancer Biol 2020;65:164-75. [Crossref] [PubMed]
10. Fu A, Yao B, Dong T, et al. Tumor-resident intracellular microbiota promotes metastatic colonization in breast cancer. Cell 2022;185:1356-1372.e26. [Crossref] [PubMed]
11. Wynendaele E, Debunne N, Janssens Y, et al. The quorum sensing peptide EntF* promotes colorectal cancer metastasis in mice: a new factor in the host-microbiome interaction. BMC Biol 2022;20:151. [Crossref] [PubMed]
12. Wong SH, Zhao L, Zhang X, et al. Gavage of Fecal Samples From Patients With Colorectal Cancer Promotes Intestinal Carcinogenesis in Germ-Free and Conventional Mice. Gastroenterology 2017;153:1621-1633.e6. [Crossref] [PubMed]
13. Werth N, Beerlage C, Rosenberger C, et al. Activation of hypoxia inducible factor 1 is a general phenomenon in infections with human pathogens. PLoS One 2010;5:e11576. [Crossref] [PubMed]
14. Galeano Niño JL, Wu H, LaCourse KD, et al. Effect of the intratumoral microbiota on spatial and cellular heterogeneity in cancer. Nature 2022;611:810-7. [Crossref] [PubMed]
15. Mitchell MJ, King MR. Fluid Shear Stress Sensitizes Cancer Cells to Receptor-Mediated Apoptosis via Trimeric Death Receptors. New J Phys 2013;15:015008. [Crossref] [PubMed]
16. Follain G, Herrmann D, Harlepp S, et al. Fluids and their mechanics in tumour transit: shaping metastasis. Nat Rev Cancer 2020;20:107-24. [Crossref] [PubMed]
17. Inamura K. Gut microbiota contributes towards immunomodulation against cancer: New frontiers in precision cancer therapeutics. Semin Cancer Biol 2021;70:11-23. [Crossref] [PubMed]