Fig. 1 |. Bladder TME components and their interactions with urothelial cells during bladder tumour progression.

a | In a nonmalignant bladder, the multilayered urothelium is supported by a stroma (the lamina propria) that contains nerve fibres, vasculature, interstitial extracellular matrix (ECM), intercalated by a few fibroblasts and interstitial cells of Cajal within the stroma. The lamina propria is further surrounded by inner longitudinal, middle circular and outer longitudinal smooth muscle layers (the muscularis propria or detrusor muscle), as well as perivesical adipose tissue and the peritoneum. b | In premalignant lesions or carcinoma in situ (CIS), stromal fibroblasts initially secrete inhibitory signals (such as transforming growth factor β1 (TGFβ1)) and differentiation signals (such as bone morphogenetic proteins (BMPs)) to impede uncontrolled cellular proliferation and aberrant differentiation, respectively. As the tumour progresses, these stromal fibroblasts and/or other cell types (types 1–5, that is type 1, normal fibroblasts; types 2 and 3, fibrocytes or monocytes; type 4, epithelial cancer cells; and type 5, endothelial cells) are converted into myofibroblasts or other cancer-associated fibroblast (CAF) types in a cascade highly reminiscent of the wound-healing response. c | At an advanced stage (that is, invasive cancer), stromal cells and ECM in the tumour microenvironment (TME) co-evolve and communicate with cancer cells to promote cancer progression and cause drug resistance. CAFs promote bladder cancer progression through secreting chemoattractants, growth factors (such as basic fibroblast growth factor 2 (FGF2), epidermal growth factor receptor (EGFR) ligands, colony-stimulating factors, TGFβ1 and hepatocyte growth factor (HGF)^57–59, angiogenic factors (vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF)), and ECM-degrading proteases (such as matrix metalloproteinase (MMP)) and ECM. αSMA, α-smooth muscle actin; SHH, sonic hedgehog.