Intratumoral microbiome: Unlocking the mysteries of tumor development

Microorganisms are not strange to everyone, we are dealing with microorganisms all the time, and there are countless microbial communities in our bodies. A dynamic balance of microbial flora is beneficial to human health, but an unbalanced microbial flora is harmful to the human body. Some microbiomes contribute to carcinogenesis, cancer progression, and the regulation of cancer therapy by inducing cancerous epithelial cells and chronic inflammation. At present, the role of the microbiota in tumourgenesis and clinical efficiency is mostly believed to be related to the gut microbiota. Did you know that there are microbiota in tumors? And these microorganisms may be an important driver of malignant tumor transformation. Over the past few years, research has shown that cancer tissue contains a complete community of bacteria and fungi, but how do the microorganisms in the tumor affect the development of the tumor？

More than 100 years ago, scientists detected bacteria in human tumors. Some believe this suggests that bacteria may have a local role in the tumor's microenvironment; Others point out that the bacteria are present in such low levels that it is difficult to confirm whether they really came from tumor samples or from external contamination, and their presence has not been widely noticed. Until a research paper on the microbiome, published in the journal Science in 2020, knocked on the door to explore the microorganisms in the tumor. In this study[1], the scientists did a more comprehensive analysis to understand the role of bacteria in human tumor samples. To reduce the potential problems caused by external contamination, they used a combination of different methods, not only using gene sequencing of 16S rRNA to look for bacteria, but also microscopy and cell culture to identify different bacteria living in tumors.

The researchers analyzed seven common solid tumors, including brain, bone, breast, lung, ovarian, pancreatic, colorectal, and melanoma, with a sample size of more than 1,500 (Figure 1). The analysis confirmed that the types of bacteria were different for different tumor types. The researchers noted that different tumors have different microbiomes (Figure 2).

In contrast, breast cancer tumors have a more diverse and rich microbiome (Figure 3). The bacteria were also linked to a patient's smoking history and response to immunotherapy, the researchers noted in their paper.

In 2023, Academician Li Lanjuan's team published a review article [2] in Cell Reports Medicine, which briefly summarized the existing research methods on microorganisms in tumors, sorted out the characteristics of microorganisms in tumors (Figure 4) and their roles in various tumors, and discussed the therapeutic potential and current challenges of microorganisms in tumors.

Intratumoral microorganisms are found in esophageal (EC), pancreatic (PC), prostate (PCa), glioma, melanoma, stomach cancer (GC), renal cell carcinoma (RCC), colorectal cancer (CRC), oral squamous cell carcinoma (OSCC), liver cancer, ovarian cancer (OC), cervical cancer (CC), breast cancer (BC) and lung cancer(Table 1).

The difference in the distribution of microorganisms in tumor cells provides a new idea for personalized treatment. The interactions of microbial communities with tumor cells, as well as their role in disease development, provide valuable information for developing more effective treatment options. Therefore, understanding the differences in the distribution of microorganisms in tumor cells not only helps to reveal the pathogenesis of disease, but also provides a key reference for future precision medicine.

Colorectal cancer is a common malignant tumor, and its incidence ranks second among all malignant tumors and first among digestive tract malignant tumors. Early screening, early diagnosis and early treatment are of great significance to reduce the mortality and improve the prognosis of patients with colorectal cancer. A study [3] published in Nature Medicine in 2023 included fresh frozen samples from 348 primary cancer patients for a comprehensive genomic analysis, mapping a comprehensive atlas of colorectal cancer tumors, immunity and microbiome, and developing and validating a mICRoScore. This score identifies a group of patients with a good probability of survival, enabling personalized treatment.

To detect clinically relevant associations between microbiome profiles and clinical outcomes, the researchers used 16S rRNA gene sequencing data to identify microbiome features that predicted survival, comparing the relative abundance of microbiota between matched tumors and healthy colon tissue. In AC-ICAM246, the researchers set up an OS Cox regression model that selected 41 features with non-zero coefficients (associated with differential risk of death, MBR classifier). In this training cohort (ICAM246), a low MBR score (MBR<0, MBR low) was associated with a significantly lower (85%) risk of death. The researchers confirmed the association between low (risk) MBR and prolonged OS in two independent validation cohorts (ICAM42 and TCGA-COAD). There was a significant increase in clostridium in the tumors compared to the healthy samples. There was no significant difference in α diversity (the diversity and abundance of species in a single sample) between tumor samples and healthy samples, and a modest reduction in microbial diversity was observed in ICR-high tumors relative to ICR-low tumors.

The research team identified a microbiome signature with strong prognostic value (MBR risk score). While this feature was derived from tumor samples, there was a strong correlation between healthy colorectal and tumor MBR risk scores, suggesting that the feature may capture the patient's gut microbiome composition. By combining ICR and MBR scores, it was possible to identify and validate a multigroup biomarker that predicts survival in patients with colon cancer. The study's multi-omics data set provides a resource for a better understanding of colon cancer biology that could help in the discovery of personalized treatments.

The tumor microbiome, once a neglected field, is now gradually unlocking its mystery. Their role in the occurrence and development of tumors has amazed people. However, we need to do more than just reveal the microbes in the tumor (Figure 6), but also find a way to solve this problem. A term used to describe the origin and driving force of microorganisms within a tumor. In-depth study of the origin and development of microorganisms in tumors and their relationship with tumors will help us find new ways to prevent and treat tumors. In this process, we need to have a deeper understanding of the microorganisms in the tumor, reveal its mechanism of action in the occurrence and development of tumor, and then provide new ideas for the treatment of tumor.

Looking forward to the future, the study of microorganisms in tumors will bring new hope for tumor treatment [4]. With the continuous development of science and technology, we can foresee that in the near future, microorganisms in tumors will become an important entry point for tumor treatment. By studying the microbes within tumors, we can develop targeted therapies that inhibit tumor growth and spread and improve patients' quality of life and survival. At the same time, we should also pay attention to the balance of the microbial ecosystem, maintain human health, and bring good news to cancer patients. Let's work together to uncover the mystery of the microbes in tumors and move forward for human health.

Reference

[1]Nejman D, Livyatan I, Fuks G, et al. The human tumor microbiome is composed of tumor type-specific intracellular bacteria.?Science. 2020;368(6494):973-980.

[2]Xue C, Chu Q, Zheng Q, et al. Current understanding of the intratumoral microbiome in various tumors. Cell Rep Med. 2023;4(1):100884.

[3]Roelands J, Kuppen PJK, Ahmed EI, et al. An integrated tumor, immune and microbiome atlas of colon cancer. Nat Med. 2023;29(5):1273-1286.

[4]Yang L, Li A, Wang Y, Zhang Y. Intratumoral microbiota: roles in cancer initiation, development and therapeutic efficacy. Signal Transduct Target Ther. 2023;8(1):35.