Cancer-associated Fibroblasts in Bladder Cancer: Origin, Biology, and Therapeutic Opportunities

Cancer-associated fibroblasts are a major component of the tumour microenvironment. The clinical and molecular heterogeneity of bladder cancer is reflected in the microenvironment. This review emphasises these aspects and the need to acquire further knowledge on the role of cancer-associated fibroblasts in tumour biology, tumour heterogeneity, and response to therapy. Bladder cancer (BLCA) is a highly prevalent tumour and a health problem worldwide, especially among men. Recent work has highlighted the relevance of the tumour microenvironment (TME) in cancer biology with translational implications. Cancer-associated fibroblasts (CAFs) are a prominent, heterogeneous population of cells in the TME. CAFs have been associated with tumour development, progression, and poor prognosis in several neoplasms. However, their role in BLCA has not yet been exploited deeply. To review the role of CAFs in BLCA biology and provide an understanding of CAF origin, subtypes, markers, and phenotypic and functional characteristics to improve patient management. A PubMed search was performed to review manuscripts published using the terms “cancer associated fibroblast” and “bladder cancer” or “urothelial cancer”. All abstracts were reviewed, and the full content of all relevant manuscripts was analysed. In addition, selected manuscripts on CAFs in other tumours were considered. CAFs have been studied less extensively in BLCA than in other tumours. Thanks to new techniques, such as single-cell RNA-seq and spatial transcriptomics, it is now possible to accurately map and molecularly define the phenotype of fibroblasts in normal bladder and BLCA. Bulk transcriptomic analyses have revealed the existence of subtypes among both non–muscle-invasive and muscle-invasive BLCA; these subtypes display distinct features regarding their CAF content. We provide a higher-resolution map of the phenotypic diversity of CAFs in these tumour subtypes. Preclinical studies and recent promising clinical trials leverage on this knowledge through the combined targeting of CAFs or their effectors and the immune microenvironment. Current knowledge of BLCA CAFs and the TME is being increasingly applied to improve BLCA therapy. There is a need to acquire a deeper understanding of CAF biology in BLCA. Tumour cells are surrounded by nontumoural cells that contribute to the determination of the behaviour of cancers. Among them are cancer-associated fibroblasts. The “neighbourhoods” established through these ce