MyD88 Signaling Accompanied by Microbiota Changes Supports Urinary Bladder Carcinogenesis

Area of Science:

• Uro-oncology
• Immunology
• Microbiome research

Background:

• Urinary bladder cancer (BC) significantly impacts quality of life and mortality.
• BC can be caused by Schistosoma haematobium infection, and urinary microbiota differs in BC patients.
• Bacillus Calmette-Guerin immunotherapy is a primary treatment for non-muscle invasive BC, highlighting the importance of bacterial recognition pathways.

Purpose of the Study:

• To investigate the role of Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) signaling in bladder carcinogenesis.
• To determine the influence of these receptors on the host's response to carcinogens and associated microbiota changes.

Main Methods:

• N-butyl-N-(4-hydroxylbutyl)-nitrosamine (BBN) carcinogen exposure in Toll-like receptor 4 (Tlr4) and myeloid differentiation factor 88 (Myd88) knockout (KO) mice.
• Analysis of gut microbiota composition, gene expression, and urinary bladder pathology.
• Comparison of acute versus chronic BBN exposure effects on bladder cancer development and invasiveness.

Main Results:

• Acute BBN exposure showed no difference in bladder pathology between wild-type and KO mice.
• Chronic BBN treatment led to reduced cancer invasiveness in Myd88-deficient mice.
• Absence of functional Tlr4 did not affect BC development or progression; Myd88 deficiency correlated with increased Faecalibaculum abundance and reduced microbial diversity.

Conclusions:

• MyD88-mediated signaling plays a crucial role in bladder cancer progression, influencing invasiveness.
• TLR4 signaling is not essential for BBN-induced bladder carcinogenesis.
• Microbiota composition and MyD88 signaling are important factors during bladder carcinogenesis.