Fibroblast ERα Promotes Bladder Cancer Invasion Via Increasing the CCL1 and IL-6 Signals in the Tumor Microenvironment

Epidemiological studies indicate that women have a higher chance of developing muscle invasive bladder cancer (BCa) than men, suggesting that estrogen and estrogen receptors (ERs) may play critical roles in BCa progression. However, the ERs roles in the bladder tumor microenvironment and impacts on BCa progression remain largely unclear. Using IHC staining in human BCa samples, we found that higher ERα expression in the stromal compartment of BCa may be correlated with unfavorable clinical outcomes. Results from cell line studies revealed that co-culturing with fibroblasts could promote BCa T24, UMUC3 and 5637 cells invasion. Importantly, addition of ERα in fibroblasts further enhanced the BCa cell invasion and knock-down of ERα in fibroblasts could then partially reduce the fibroblasts-enhanced BCa invasion. Mechanism dissection suggested that ERα could function through modulating the CCL cytokines expression in fibroblasts to increase the BCa IL-6 expression. An interruption approach using IL-6 neutralizing antibody then reversed the fibroblast ERα-enhanced BCa cell invasion. Together, these data suggest that the higher expression of ERα in fibroblasts may be the result of modulating the CCL1 expression in fibroblasts and/or IL-6 production in BCa cells to enhance BCa cells invasion. Targeting these individual molecules in this newly identified ERα-stimulated CCL1 and IL-6 signal pathways may become an alternative therapy to better suppress the BCa cell invasion.