Introduction: Bisphenol A (BPA) acts as an endocrine disruptor and is found in 90% of urine samples. Exposure to BPA is associated with tumor progression. The bladder is not recognized as a hormone-sensitive tissue, but the activation of hormone receptors plays a role in bladder cancer initiation and progression. We hypothesiezed that chronic exposure of urothelial (UCs) and cancer cells to physiological concentrations of BPA should increase the invasive phenotype of cancer cells, and potentiate the induction of healthy bladder fibroblasts (HBFs) in cancer-associated fibroblasts (CAFs), thus promoting tumor invasion.

Methods: UCs and non-invasive (RT4) and invasive (T24) cancer cells were exposed to 10^-8 M BPA, which corresponds to the concentrations found in urine. The impact of BPA on energy metabolism, proliferation, and migration was measured. The expression of α-SMA, associated with invasion potential, of RT4 and T24±BPA was analyzed by flow cytometry. HBFs were used and induced into CAFs with media conditioned with RT4 or T24. The impact of BPA on HBF/CAF metabolism was also measured.

Results: After chronic exposure to BPA, energy metabolism, proliferation, and migration of cancer cells are increased, while these parameters are reduced for UCs. RT4 exposed to BPA express more α-SMA. The metabolism of HBFs exposed to BPA is also reduced. CAFs conditioned with BPA demonstrated an enhanced metabolic reprogramming, characterized by increased glycolysis.

Conclusions: Chronic exposure to BPA decreases the energy metabolism of healthy cells (UCs and HBFs), which could impact tissue repair and extracellular matrix production. The increased physiological activity of cancer cells and α-SMA expression in RT4+BPA may promote tumor invasion. The increased glycolytic metabolism of CAFs+BPA leads to the acidification of the extracellular environment, promoting tumor invasion. Our unique 3D bladder cancer model will allow us to confirm these results in more physiological conditions.