Clinical and therapeutic relevance of cancer-associated fibroblasts

Abstract

Cancer-associated fibroblasts (CAFs) found in primary and metastatic tumours are highly versatile, plastic and resilient cells that are actively involved in cancer progression through complex interactions with other cell types in the tumour microenvironment. As well as generating extracellular matrix components that contribute to the structure and function of the tumour stroma, CAFs undergo epigenetic changes to produce secreted factors, exosomes and metabolites that influence tumour angiogenesis, immunology and metabolism. Because of their putative pro-oncogenic functions, CAFs have long been considered an attractive therapeutic target; however, clinical trials of treatment strategies targeting CAFs have mostly ended in failure and, in some cases, accelerated cancer progression and resulted in inferior survival outcomes. Importantly, CAFs are heterogeneous cells and their characteristics and interactions with other cell types might change dynamically as cancers evolve. Studies involving single-cell RNA sequencing and novel mouse models have increased our understanding of CAF diversity, although the context-dependent roles of different CAF populations and their interchangeable plasticity remain largely unknown. Comprehensive characterization of the tumour-promoting and tumour-restraining activities of CAF subtypes, including how these complex bimodal functions evolve and are subjugated by neoplastic cells during cancer progression, might facilitate the development of novel diagnostic and therapeutic approaches. In this Review, the clinical relevance of CAFs is summarized with an emphasis on their value as prognosis factors and therapeutic targets.

Fig. 1 |. Activation of CAFs.

Schematic illustration of various mechanisms involved in cancer-associated fibroblast (CAF) activation. Potential cellular origins of CAFs include quiescent, resting or specific tissue-resident fibroblasts (stellate cells), bone marrow-derived mesenchymal stem cells (MSCs), endothelial cells and other cell types. ECM, extracellular matrix; ROS, reactive oxygen species.

Fig. 2 |. The heterogeneity and plasticity of CAFs with both tumour-restraining and tumour-promoting functions.

Schematic illustration of heterogeneous cancer-associated fibroblast (CAF) subpopulations with potential tumour-restraining (TR) functions and tumour-promoting (TP) functions through various indicated mechanisms. However, the spectrum of CAF heterogeneity is likely to be non-binary, without distinct polarization, and therefore should not be oversimplified as either tumour restraining or tumour promoting, and might exhibit context-dependent plasticity that needs to be further elucidated. ECM, extracellular matrix; SHH–SMO, sonic hedgehog–smoothened.

Fig. 3 |. Proposed models explaining the diverse functions and phenotypes of CAFs in cancer.

Activation of cancer-associated fibroblasts (CAFs) might lead to heterogeneous CAF compositions according to various possible scenarios (A–D). These distinct models of CAF subset differentiation can be interchangeable and dynamically regulated by the tumour microenvironment. ECM, extracellular matrix.

Fig. 4 |. Interactions between CAFs and other cell types in the tumour microenvironment.

Schematic illustration of the potential regulatory effects of cancer-associated fibroblasts (CAFs) on other cell populations (including cancer cells, lymphocytes, myeloid cells and endothelial cells) and the microbiota within the tumour microenvironment. BMP, bone morphogenetic protein; CCL, CC motif chemokine; CTGF, connective tissue growth factor; CXCL, CXC motif chemokine; ECM, extracellular matrix; EGF, epidermal growth factor; FGF, fibroblast growth factor; HGF, hepatocyte growth factor; IGF, insulin-like growth factor; LOX, lysyl oxidase; M-CSF, macrophage colony-stimulating factor; MMP, matrix metalloproteinase; PDGF, platelet-derived growth factor; PGE₂, prostaglandin E₂; TGFβ, transforming growth factor-β ; TIMPs, tissue inhibitors of metalloproteinases; VEGF, vascular endothelial growth factor.