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Page 8 of 17 Peng et al. Microbiome Res Rep 2024;3:5 https://dx.doi.org/10.20517/mrr.2023.47

Figure 2. Possible overview of microbiota in the TME of bladder cancer. Extracellular microbiota may directly influence tumor cells
through metabolites [53] or ECM remodeling [54] . Gut microbiota is able to produce a remote effect through systemic microbial
metabolites [55-58] . Furthermore, the microbiota can interplay with the immune compartment in the TME and result in
immunomodulation [59] . Notably, the intracellular microbiota may influence the gene expression or intracellular signal pathways to
manipulate the behavior of tumor cells [52] . The blue metabolites refer to the systemic microbiota metabolites. ECM: Extracellular matrix;
TME: tumor microenvironment.

ECM remodeling in the TME could be regulated by tumor cells, cancer-associated fibroblasts (CAFs),
inflammatory cells, etc. and was highlighted to a significance of cancer development, especially invasion and
metastasis. As discussed before, some microbiota can produce virulence factors that cause ECM
degradation, suggesting a potential mechanism that intratumoral microbiota influence the tumor cells in an
ECM remodeling-dependent manner. Matrix metalloproteinases (MMPs), the proteolytic enzymes inducing
ECM degradation and remodeling, are vital for the progression of bladder cancer, and influence tumor cell
proliferation, apoptosis, invasion, and metastasis . Eubacterium sp. cocultured with bladder cancer
[77]
organoids, which has been proved to retain the histological and genomic features of parental tumors , can
[78]
promote tumor cell proliferation through the ECM1/ERK1/2 phosphorylation/MMP9 pathway, and this
[54]
microbe is found related to bladder cancer in NMIBC cohort clinically .