Cancer-associated fibroblasts promote cisplatin resistance in bladder cancer cells by increasing IGF-1/ERß/Bcl-2 signalling.

ABSTRACT

While cancer-associated fibroblasts (CAFs) in the tumour microenvironment may play important roles in bladder cancer (BCa) progression, their impacts on BCa chemoresistance remain unclear. Using human BCa samples, we found that tumour tissues possessed more CAFs than did adjacent normal tissues. Both the presence of CAFs in the BCa stroma and the expression of ERß in BCa contribute to chemoresistance, and CAFs and BCa cells interact to affect ERß expression. In vitro co-culture assays demonstrated that compared with normal bladder cells, BCa cells had a higher capacity to induce the transformation of normal fibroblasts into CAFs. When BCa cells were co-cultured with CAFs, their viability, clone formation ability and chemoresistance were increased, whereas their apoptotic rates were downregulated. Dissection of the mechanism revealed that the recruited CAFs increased IGF-1/ERß signalling in BCa cells, which then led to the promotion of the expression of the anti-apoptotic gene Bcl-2. Blocking IGF-1/ERß/Bcl-2 signalling by either an shRNA targeting ERß or an anti-IGF-1 neutralizing antibody partially reversed the capacity of CAFs to increase BCa chemoresistance. The in vivo data also confirmed that CAFs could increase BCa cell resistance to cisplatin by increasing ERß/Bcl-2 signalling. The above results showed the important roles of CAFs within the bladder tumour microenvironment, which could enhance BCa chemoresistance.