Cancer-associated fibroblasts promote cell proliferation and invasion via paracrine Wnt/IL1ß signaling pathway in human bladder cancer.

Bladder cancer (BC) is the most common urinary system malignancy worldwide. However, the molecular mechanisms underlying its progression remain largely unexplored. Accumulating evidence indicates that the cancer-associated fibroblasts (CAFs), major constituents of tumor stroma, play a key role in tumor development. Herein, we have successfully isolated CAFs and paired normal fibroblasts (NFs) from bladder cancer tissues. We observed that the conditional medium from bladder cancer (CM-CAF) could significantly enhance cell proliferation (p<0.01) and invasion capacity (p<0.01) of bladder cancer cell lines T24 and J82, compared to the conditional medium from NFs or 5637 cells (bladder epithelial cell control). We subsequently identified cytokine IL1ß is enriched in CM-CAF, and a further functional study showed CAF-derived IL1ß contributes to the aggressiveness of T24 cells. In mechanisms, we demonstrated that a high level of IL1ß is capable of activating Wnt signaling in T24 cells, and Wnt signaling upregulates the expression of IL1ß, therefore forming a paracrine Wnt/IL1ß signaling feedback to enhance the aggressive phenotype of bladder cancer cells. In addition, we treated T24 cells with CM-CAF alone, or together with Wnt signaling inhibitor XAV939. We found that the inhibition of Wnt signaling could sufficiently abolish the oncogenic effect of CAFs on bladder cancer. In conclusion, our data revealed a novel mechanism that CAFs promote cell proliferation and invasion of human BC cells through Wnt/IL1ß signaling feedback. Inhibition of the Wnt signaling pathway may provide a promising target to block the interaction between CAF and bladder cancer cells.