Chinese scientists have confirmed for the first time that bacteria can promote breast cancer metastasis

Recently, the Cai Shang research group of Westlake University published a paper on Tomb-resident intracellular microbiota promotions metastatic colonization in breast cancer on Cell, which for the first time confirmed that intracellular bacteria in breast cancer tissues play a key role in the process of tumor metastasis and colonization[1], which aroused widespread concern as soon as it was published.

Figure 1 Tumor-settled intracellular bacteria promote metastatic colonization of breast cancer

Bacteria in breast cancer promote tumor metastasis

In fact, having bacteria in breast tissue is nothing new.

Some studies have found that there are many different bacteria in the breast tissue of normal people, because the mammary glands are rich in fat, blood vessels, and lymph, providing a favorable environment for the growth of bacteria that promote the development of newborns and the maturation of the immune system [2].

In May 2020, researchers from Israel conducted a comprehensive microbiome analysis of 1526 tumors and adjacent normal tissues, including 7 tumors of breast, lung, ovarian, pancreas, melanoma, bone and brain tumors, and found that each type of tumor has a different microbial composition, with breast cancer being the most abundant and diverse. Most of the bacteria in tumor tissue are intracellular bacteria, which are found in both tumor cells and immune cells [3]. Breast cancer tissues have microbial communities that differ from normal tissues, and these bacteria can modulate the body's response to treatment and can be used as markers for breast cancer staging and diagnosis [4].

Although the above study has determined the presence of microorganisms in breast cancer tissue, the discussion of their biological significance is still incomplete, and whether the microbiota in tumors play a role in the spontaneous progression of tumors under physiological homeostasis is still a problem to be solved.

With questions about related issues, Cai Shang's team first used MMTV-PyM mice to construct a spontaneous mouse breast cancer model, and a large number of bacteria were detected in the modified breast cancer tissue and normal breast tissue, and the bacterial load in the tumor tissue was almost 10 times that of normal tissue. The isolated bacteria are enriched with staphylococcus, lactic acid bacteria, enterococcus and streptococcus, which are consistent with human breast tissue. High-resolution electron microscopy showed that the bacterial-like structure was mainly distributed in the cytoplasm (97.25%), rather than the extracellular fluid. Moreover, these bacteria are alive, surviving treatment with antibiotics that cannot penetrate cell membranes (ampicillin and gentamicin), but not under the treatment of antibiological (doxycycline) that can penetrate cell membranes.

Through a combination of different antibiotics and routes of administration, the authors removed microbes from breast cancer tissue and found that they did not affect the growth of primary tumors. However, in the advanced stage of disease development, most tumor-bearing mice have lung metastases, which can reduce lung metastasis to less than one-third of the original lung metastasis by removing the intracellular microflora in breast cancer tissue, suggesting that the bacteria in the tumor play a key role in breast cancer metastasis. Since most of the identified bacteria came from within the cell, the authors speculated that during the transfer process, the bacteria inside the cell may migrate to the distal organ through the circulatory system, and this hypothesis was verified experimentally.

To further understand the microbes in the cytoplasm and how they promote cancer cell invasion, the authors performed single-cell RNA sequencing of bacterially invaded tumor cells and found that although bacterial invasion did not change the heterogeneity of cancer cells, it enhanced their stem. KeGG pathway enrichment analysis showed that tumor cells invaded by bacteria upregulated many immune-related pathways, while the invasion of certain strains also specifically activated the fluid shear stress pathway, which may cause apoptosis of cancer cells metastatic in blood vessels. The above results suggest that bacteria may regulate the survival of circulating tumor cells by modulating the stress response. Further studies have found that bacteria in tumors can enhance the cell's resistance to fluid stress by remodeling the actin cytoskeleton.

In summary, this study found that the microbiota that resides within breast cancer cells, despite having a low load, plays an important role in tumor metastasis, so interventions with these bacteria are likely to inhibit tumor metastasis to improve the prognosis of breast cancer patients.

Good bacteria or bad bacteria?

Today, with the high development of medicine, oncological diseases are still one of the diseases with the highest mortality rate in the world. The development of tumors is thought to be related to many genetic and environmental factors, including physical, chemical and biological factors. In the early days, it was generally believed that cancer was not contagious, and bacteria were the cause of many infectious diseases, and the concept of bacteria causing cancer was not accepted by most people, but scientific discoveries revolutionized this concept, and the relationship between bacteria and cancer was further analyzed. Today, the relationship between certain viral and bacterial infections and tumor development has become a consensus, such as the incidence of human papillomavirus (HPV) and cervical cancer, while the infection of Helicobacter pylori is associated with the occurrence of stomach cancer.

However, bacterial infection is not always a bad thing for cancer patients, and the study found that bacteria play a dual role in the development of tumors, both carcinogenic and promote the treatment of tumors.

Figure 3 Bacteria play a dual role in tumors

In 1868, the German doctor Bush discovered that a patient with sarcoma had a tumor that quickly subsided due to infection with streptococcus. Later, william Colly, the "father of immunotherapy", also met a special patient in clinical practice, whose sarcoma had a suprated streptococcus infection after surgery, resulting in a delay in healing of his wounds, but the patient's tumor miraculously shrunk - his tumor healed itself. Curley guessed that this was due to the fact that the bacterial infection activated the patient's immune system, which led to the killing of the tumor.

In 1972, a study published in the New England Journal of Medicine analyzed the effect of empyema on the survival of lung cancer patients after surgery, and the results showed that the overall 5-year survival rate of 18 patients in the postoperative infection (empyema) group was as high as 50%, compared with only 18% in the control group, and the researchers believed that the protective effect of postoperative empyema on recurrent cancer may be achieved by activating the immune system, and the response between immune cells and bacteria released a large number of cytokines and activated macrophages. Non-specifically inhibits the growth of residual tumor cells [5].

Abandon evil and promote good, bacteria help tumor treatment

The ideal treatment for tumors should be to selectively eradicate tumors while minimizing side effects on normal tissues, while using bacteria is considered a potential tumor treatment. Various preclinical and clinical trials have shown that different strains of bacteria have the ability to selectively spread to tumor sites and mediate efficient and specific therapeutic responses. In addition to the above-mentioned methods that may be able to inhibit tumor metastasis and activate the immune system through bacterial infection by targeting intracellular bacteria in tumor tissues, the use of gene-edited bacteria to deliver anti-cancer drugs to tumor sites is also a method that has been studied, and I believe that with the deepening of research, we will develop more bacterial treatment methods.

Figure 4 Different types of tumor treatments

Source| the frontline of tumors in the health community

The author | Yin Qilei

Resources

1.Fu A, Yao B, Dong T, et al. Tumor-resident intracellular microbiota promotes metastatic colonization in breast cancer. Cell 2022;185:1356-72.e26.

2.Al-Hilu SA, Al-Shujairi WH. Dual Role of Bacteria in Carcinoma: Stimulation and Inhibition. International Journal of Microbiology 2020;2020:4639761.

3.Nejman D, Livyatan I, Fuks G, et al. The human tumor microbiome is composed of tumor type–specific intracellular bacteria. Science (New York, NY) 2020;368:973-80.

4.O'Connor H, MacSharry J, Bueso YF, et al. Resident bacteria in breast cancer tissue: pathogenic agents or harmless commensals? Discovery medicine 2018;26:93-102.

5.Ruckdeschel JC, Codish SD, Stranahan A, McKneally MF. Postoperative Empyema Improves Survival in Lung Cancer. New England Journal of Medicine 1972;287:1013-7.