A bird’s eye view of fibroblast heterogeneity: A pan‐disease, pan‐cancer perspective

Abstract

Classically, fibroblasts are defined as non-epithelial, nonimmune cells of mesenchymal origin with a spindle-shaped morphology, dwelling in interstitial spaces or near blood vessels, and capable of extracellular matrix (ECM) deposition and remodeling. 1 Embedded in the tissue parenchyma, fibroblasts are active participants in biological processes not only by shaping tissue architecture via ECM remodeling, but also through regulating immune cell recruitment, wound-healing responses, inflammation, and fibrosis. 2-4 Recent reviews 1 have proposed an organizational framework chiefly consisting of the following flavors of fibroblasts: (a) spindle-shaped quiescent or resting fibroblasts that are metabolically inactive and occupy the interstitial space in the ECM; (b) stellate-shaped normal activated fibroblasts (NAFs), which are epigenetically reversible, and influenced by various stimuli such as stress, wounding, and inflammation; and (c) cancer-associated fibroblasts or fibrosis-associated fibroblasts (CAFs or FAFs), which are generated in response to unrelenting chronic stimuli

Cancer-Associated Fibroblasts Influence the Biological Properties of Malignant Tumours via Paracrine Secretion and Exosome Production

“…Notably, TGF-β signalling can drive several of these phenotypes, e.g., contractile CAFs and desmoplastic CAFs. Interestingly, the comparison of CAF heterogeneity demonstrated some similarities across different types of tumour [79][80][81]. This confirms earlier observations of the functional similarities among CAFs of various origins in vitro [82].…”

Cancer-Associated Fibroblasts: Mechanisms of Tumor Progression and Novel Therapeutic Targets

“…Such heterogeneity, made more evident by data obtained by single-cell RNA seq analysis (reviewed in [ 3 ]), contributes to the uncertainty as to the specific cell type or types that give rise to the CAF cohort or cohorts in various human malignancies. This likely reflects the overall difficulty in defining a “fibroblast” since there are no unique biomarkers that provide an unambiguous identification and strategies utilizing exclusion criteria may underestimate the diversity in fibroblast origins [ 17 , 18 ]. Several additional confounders complicate a precise molecular definition of CAF derivation.…”

“…Several additional confounders complicate a precise molecular definition of CAF derivation. Among the most significant is the absence of specific lineage tracing-adaptable Cre drivers for normal fibroblasts or their CAF counterparts in mouse models of tumorigenesis and the realization that subsets of fibroblasts differ as a function of tissue localization and mobilization state [ 8 , 18 , 19 ].…”

Inflammatory Microenvironment of Skin Wounds

“…For example, before circulating macrophages arrive, some tissue resident macrophages are already involved in the inflammatory response ( 16 ). Although different fibroblast subsets in human skin have been revealed, the unique gene expression changes in this population in skin wounds, especially in the inflammatory microenvironment, remain unknown ( 167 ). In addition, a wide range of cell types in wounds have significant plasticity under the influence of the ECM, which complicates the dynamic study of different cell subsets and their effects on wound healing.…”