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Review
, 146 (4), 895-905

In Search of Definitions: Cancer-associated Fibroblasts and Their Markers

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Review

In Search of Definitions: Cancer-associated Fibroblasts and Their Markers

Martin Nurmik et al. Int J Cancer.

Abstract

The tumor microenvironment has been identified as one of the driving factors of tumor progression and invasion. Inside this microenvironment, cancer-associated fibroblasts (CAFs), a type of perpetually activated fibroblasts, have been implicated to have a strong tumor-modulating effect and play a key role in areas such as drug resistance. Identification of CAFs has typically been carried based on the expression of various "CAF markers", such as fibroblast activation protein alpha (FAP) and alpha smooth muscle actin (αSMA), which separates them from the larger pool of fibroblasts present in the body. However, as outlined in this Review, the expression of various commonly used fibroblast markers is extremely heterogeneous and varies strongly between different CAF subpopulations. As such, novel selection methods based on cellular function, as well as further characterizing research, are vital for the standardization of CAF identification in order to improve the cross-applicability of different research studies in the field. The aim of this review is to give a thorough overview of the commonly used fibroblast markers in the field and their various strengths and, more importantly, their weaknesses, as well as to highlight potential future avenues for CAF identification and targeting.

Keywords: cancer-associated fibroblasts; fibroblast heterogeneity; fibroblast markers; tumor microenvironment.

Figures

Figure 1
Figure 1
Molecular crosstalk between CAFs and tumor cells. Secretion of numerous cytokines by both epithelial tumor cells and cancer‐associated fibroblasts forms a complex network of intratumoral crosstalk between the two cell types, affecting numerous different cellular processes. The list of interactions depicted is not exhaustive. Abbreviations: FAP, fibroblast activation protein α; ACTA2(αSMA), alpha smooth muscle actin; MFAP5, microfibril‐associated protein 5; COL11A1, collagen type XI alpha 1 chain; TNC, tenascin‐C; PDGFRα/β, platelet derived growth factor receptor alpha/beta; VIM, vimentin; S100A4 (FSP1), S100 calcium‐binding protein A4; POSTN, periostin; EPCAM, epithelial cell adhesion molecule; KRT20, keratin 20; WNT7a, Wnt family member 7A; PDGF, platelet derived growth factor; SHH, sonic hedgehog; IL1β, interleukin 1β; TGF‐β, transforming growth factor beta; IL17A, interleukin 17A; WNT10b, Wnt family member 10B; WNT2, Wnt family member 2; IGF2, insulin like growth factor 2; CXCL6, C‐X‐C motif chemokine ligand 6; HGF, hepatocyte growth factor; IL11, interleukin 11; MMPs, matrix metalloproteinases; IL6, Interleukin 6; SDF‐1, stromal cell‐derived factor 1; CXCL1, chemokine (C‐X‐C motif) ligand 1. [Color figure can be viewed at http://wileyonlinelibrary.com]
Figure 2
Figure 2
Subtypes of cancer‐associated fibroblasts. An outline of different types of CAFs found in breast, pancreatic, and colon cancer. The figure does not display an exhaustive list of all CAF subtypes and additional subtypes can be suspected to be present in the TME (and in other cancer types). Abbreviations: myCAF, myofibroblastic CAF; iCAF, inflammatory CAF; FAP, fibroblast activation protein α; ACTA2 (αSMA), alpha smooth muscle actin; MMP2, matrix metalloproteinase 2; DCN, decorin; COL1A2, collagen type I alpha 2 chain; PDGFA, platelet derived growth factor subunit A; TAGLN, transgelin; IL6, interleukin 6; IL11, Interleukin 11; LIF, interleukin 6 family cytokine; CCL11, C‐C motif chemokine ligand 11; CXCL12, C‐X‐C motif chemokine ligand 12; CD29, integrin beta‐1. [Color figure can be viewed at http://wileyonlinelibrary.com]
Figure 3
Figure 3
Expression of common markers in patient‐derived fibroblasts. Immunofluorescent staining of primary colon cancer fibroblasts (Neuromics, #CAF05), reveals a heterogeneous expression pattern for both αSMA/ACTA2 (abcam #ab7817, 1/200) and FAP (Santa‐Cruz Biotechnology #sc‐65,398, 1/200), while PDGFRα (abcam #ab61219, 1/200) expression in tested cells remains relatively homogenous. Nuclei of fibroblasts were stained using DAPI (DAPI Fluoromount‐G® Mounting Medium). Image is representative of three independent biological experiments. Cells were imaged using a Zeiss LSM 510 Meta laser scanning confocal microscope (Carl Zeiss, Jena, Germany) with a Plan‐Apochromat 63x/1.40 Oil DIC M27 objective (x60). Images were processed using NIS elements software (Nikon) and ImageJ 1.51 s. Abbreviations: FAP: Fibroblast Activation Protein α, αSMA: Alpha Smooth Muscle Actin, PDGFRα: Platelet Derived Growth Factor Receptor Alpha, DAPI: 4′,6‐diamidino‐2‐phenylindole.

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