A review of the biology and therapeutic implications of cancer-associated fibroblasts (CAFs) in muscle-invasive bladder cancer

Abstract

Cancer-associated fibroblasts (CAFs) play a fundamental role in the development of cancers and their response to therapy. In recent years, CAFs have returned to the spotlight as researchers work to unpick the mechanisms by which they impact tumour evolution and therapy responses. However, study of CAFs has largely been restricted to a select number of common cancers, whereas research into CAF biology in bladder cancer has been relatively neglected. In this review, we explore the basics of CAF biology including the numerous potential cellular origins of CAFs, alongside mechanisms of CAF activation and their diverse functionality. We find CAFs play an important role in the progression of bladder cancer with significant implications on tumour cell signaling, epithelial to mesenchymal transition and the capacity to modify components of the immune system. In addition, we highlight some of the landmark papers describing CAF heterogeneity and find trends in the literature to suggest that the iCAF and myCAF subtypes defined in bladder cancer share common characteristics with CAF subtypes described in other settings such as breast and pancreatic cancer. Moreover, based on findings in other common cancers we identify key therapeutic challenges associated with CAFs, such as the lack of specific CAF markers, the paucity of research into bladder-specific CAFs and their relationship with therapies such as radiotherapy. Of relevance, we describe a variety of strategies used to target CAFs in several common cancers, paying particular attention to TGFβ signaling as a prominent regulator of CAF activation. In doing so, we find parallels with bladder cancer that suggest CAF targeting may advance therapeutic options in this setting and improve the current poor survival outcomes in bladder cancer which sadly remain largely unchanged over recent decades.

Keywords: bladder cancer; caf; cancer-associated fibroblast; immunotherapy; muscle-invasive bladder cancer; radiotherapy.

Figure 1

Bladder cancer staging and the role of fibroblasts. (A) An illustration of the human bladder, including the tumour (T stages) of bladder cancer. Commencing in the urothelium, NMIBCs describe carcinoma in situ (in the inner most layer of the urothelium) Ta (urothelium only) and T1 tumours. T1 tumours have infiltrated the first sub-urothelial layer known as the lamina propria. To progress to stages T2-4, invasion into the muscle layer is required and is the determining factor in the diagnosis of MIBC. (B) A representation of the physiological histology observed in the human bladder. Of note, fibroblasts found in the lamina propria function to produce and maintain collagen and other fibres that make up the loose connective tissue. (C) Interactions between tumour cells and tissue resident fibroblasts are one of the likely origins of cancer-associated fibroblasts (CAFs). (D) The illustration depicts the histological changes observed in bladder cancer including the presence of CAFs. In addition, there is an increase in extracellular matrix deposition and remodelling. Abbreviations: non-muscle invasive bladder cancer (NMIBC), muscle invasive bladder cancer (MIBC), cancer-associated fibroblasts (CAFs). Figure created with Biorender.com.

Figure 2

A simplified schematic of CAF subtypes centred around bladder cancer and their similarity with CAFs reported in other common cancers. Derived from a common CAF progenitor (25) and activated by IL-1 and TGFβ (26), in bladder cancer inflammatory CAFs (iCAFs) and myofibroblast CAFs (myCAFs) are delineated by PDGFRα and RGS5 (56). These CAF subtypes and others have been described in other common cancers, such as pancreatic (24), head and neck (55) and breast (53) with their own respective protein markers or transcriptional profiles. Figure adapted from Obradovic et al., 2022. Figure created with Biorender.com.