Comprehensive analysis of angiogenesis and stemness-related genes in chemotherapy and immunotherapy of bladder cancer

Abstract

Tumor angiogenesis and cancer stem cells (CSCs) are critical features of malignancies. Research has shown that CSCs promote blood vessel formation, while increased vasculature, in turn, supports CSC proliferation—creating a detrimental feedback loop that drives disease progression. However, studies investigating vascularization and stem-like properties in bladder cancer (BLCA) remain limited. In our investigation, we applied clustering techniques and LASSO methodology to assess the significance of vascularization- and stemness-related genes in predicting responses to chemotherapy and immunotherapy in BLCA. Using multivariate Cox regression analysis, we identified Von Hippel–Lindau (VHL) as the primary prognostic marker associated with both vascularization and stem-like traits. Tissue array analysis of 40 BLCA specimens, combined with molecular docking simulations, revealed interactions between HDAC6 and VHL that influence stem-like behavior and angiogenesis in BLCA. Additionally, VHL showed strong correlations with treatment responses to both chemotherapy and immunotherapy in BLCA. In conclusion, our findings highlight the critical role of vascularization- and stemness-related genes in determining therapeutic outcomes in BLCA and underscore the regulatory relationship between VHL and HDAC6 in modulating treatment response.