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.
Cancer-associated fibroblasts (CAFs) are found in both primary and metastatic tumours; studies using modern cell sorting and sequencing technologies have provided exciting new insights into the potential therapeutic and prognostic value of CAFs.
In particular, studies using single-cell RNA sequencing and genetically engineered mouse models have begun to reveal the heterogeneity and functional roles of CAFs, which are dynamic and context dependent.
The precise functional roles of various CAF subtypes remain largely undefined, which requires future investigations integrating functional studies using multiple model systems with transcriptomic and/or proteomic data at single-cell resolution.
The identification and precise characterization of the tumour-promoting and tumour-restraining functions of different CAF populations might provide opportunities to develop novel diagnostic and therapeutic approaches.
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The CAF-related work of the authors is supported by MD Anderson Cancer Center, and was supported by the Cancer Prevention and Research Institute of Texas (CPRIT) award RP150231. The NIH National Cancer Institute grant P01CA117969 supports ECM-related research in the Kalluri laboratory.
The authors declare no competing interests.
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Chen, Y., McAndrews, K.M. & Kalluri, R. Clinical and therapeutic relevance of cancer-associated fibroblasts. Nat Rev Clin Oncol (2021). https://doi.org/10.1038/s41571-021-00546-5