ERα-dependent crosstalk between macrophages and cancer cells potentiates vasculogenic mimicry and M2 macrophage polarization in bladder cancer.

Gender related differences in the occurrence and progression of bladder cancer are affected by sex hormones and their receptor signaling pathways. Angiogenesis inhibitors targeting vascular endothelial growth factor do not show therapeutic effectiveness in bladder cancer patients. In this study, we found that the expression of ERα is positively correlated with vascular mimicry (VM) formation as well as the infiltration of M2 type tumor associated macrophages (TAM). However, it is unclear how this connection between ERα and macrophages affects VM and its detailed mechanism. Our in vitro results showed that macrophage-induced upregulation of ERα promotes VM in BLCA cells by transcriptionally upregulating CDH5. Further research has found that upregulated ERα in BLCA cells induces polarization of M2 macrophages by activating the PTEN/PI3K/pAKT pathway through exosomes derived from tumor cells. Mechanistic investigations have revealed that exosomal miR-642a-5p upregulated by ERα in BLCA cells downregulate PTEN expression in macrophages by directly targeting the 3’UTR of PTEN mRNA. Preclinical experiments involving in vitro BLCA cell lines and an in vivo mouse xenograft model confirm this newly identified pathway and its feedback circuit, offering new perspectives for the development of innovative treatment strategies for BLCA.