Abstract
Bladder cancer (BLCA) is a tumor that possesses significant heterogeneity, and the tumor microenvironment (TME) plays an important role in the development of BLCA. The TME chiefly consists of tumor cells and tumor-infiltrating immune cells admixed with stromal components. Recent studies have revealed that stromal components, especially cancer-associated fibroblasts (CAFs), affect immune cell infiltration and modulate the extracellular matrix in the TME of BLCA, ultimately impacting the prognosis and therapeutic efficacy of BLCA. Among the subgroups of CAFs, myofibroblasts (myCAFs) were the most abundant and were demonstrated to play an essential role in affecting the prognosis of various tumors, including BLCA. However, the dynamic changes in myCAFs during carcinogenesis and tumor progression have been less discussed previously. With the help of bioinformatics algorithms, we discussed the roles of myCAFs in the carcinogenesis and prognosis of BLCA in this manuscript. Our study highlighted the pathogenesis of BLCA was accompanied by a decrease in the abundance of myCAFs, revealing potential protective properties of myCAFs in the carcinogenesis of BLCA. Meanwhile, the reduced expressions of myCAFs marker genes were highly accurate in predicting tumorigenesis. In contrast, we also demonstrated that myCAFs regulated extracellular matrix remodeling, tumor metabolism, cancer stemness, and oncological mutations, ultimately impacting the treatment responsiveness and prognosis of BLCA patients. Thus, our research revealed the bimodal roles of myCAFs in the development of BLCA, which may be associated with the temporal change of the TME. The in-depth study of myofibroblasts and the TME may provide potential diagnostic biomarkers and therapeutic targets for BLCA.
Highlights
Bladder cancer (BLCA) is a common cancer of the urinary system with two distinct features, frequent recurrence and heterogeneity in tumor progression (Lokeshwar et al, 2020)
After intersecting genes in the yellow module of Weighted Gene Co-Expression Network Analysis (WGCNA) with Differentially Expressed Genes (DEGs), we identified five myCAFs marker genes defined by previous single-cell sequencing (Elyada et al, 2019) that were significantly down-regulated in tumor tissues, including ACTA2, MYL9, TAGLN, TPM1, and TPM2 (Figures 1C,D)
These results indicated the dual roles of myCAFs marker genes in tumorigenesis and BLCA prognosis
Summary
Bladder cancer (BLCA) is a common cancer of the urinary system with two distinct features, frequent recurrence and heterogeneity in tumor progression (Lokeshwar et al, 2020). BLCA can be divided into muscle-invasive bladder cancer (MIBC) and non-muscle-invasive bladder cancer (NMIBC) (Kamoun et al, 2020). Myofibroblasts are present in the vast majority of MIBC sections, suggesting that myofibroblasts play a critical role in the progression and heterogeneity of BLCA. Owing precisely to the highly heterogeneous nature of MIBC, patients with MIBC have limited treatment options and often need to undergo radical cystectomy, which significantly affects patients’ quality of life (Gakis et al, 2017). With the recent development of immunotherapy, immune checkpoint blockade (ICB) therapy is a guideline-recommended treatment for advanced BLCA when chemotherapy fails (Funt and Rosenberg, 2017). ICB therapy still faces many limitations, including multiple adverse effects and unpleasant therapeutic responsiveness (Lopez-Beltran et al, 2021)
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