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Review Open Access

Cancer‑associated fibroblasts in human malignancies, with a particular emphasis on sarcomas (Review)

  • Authors:
    • Iva Benesova
    • Katerina Kalkusova
    • Yea Seo Kwon
    • Pavla Taborska
    • Dmitry Stakheev
    • Katerina Krausova
    • Jitka Smetanova
    • Andrej Ozaniak
    • Jirina Bartunkova
    • Daniel Smrž
    • Zuzana Ozaniak Strizova
  • View Affiliations / Copyright

    Affiliations: Department of Immunology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague 5, Czech Republic, Third Department of Surgery, First Faculty of Medicine, Charles University and University Hospital Motol, Prague 5, Czech Republic
    Copyright: © Benesova et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 79
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    Published online on: August 6, 2025
       https://doi.org/10.3892/ijo.2025.5785
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Abstract

Over the course of the last 10 years, clinical oncology has seen significant changes. Although there has been much interest in targeting cancer cells with immunotherapy, the initial enthusiasm has waned as clinical trial results have not met the initial expectations, especially for solid tumors. As a result, research efforts are now shifting towards the study of other cells in the tumor microenvironment. Cancer‑associated fibroblasts (CAFs) are one of the main adversarial cell types that help cancer cells to resist oncological treatment. However, although CAFs have been extensively studied in different types of carcinomas, their role in sarcomas remains poorly understood. Despite this topic being of especial importance, to the best of the authors' knowledge, no literature review currently addresses and summarizes the up‑to‑date knowledge on the role of CAFs in sarcomas. The present review article aimed to address this literature gap by summarizing our current understanding of CAFs in carcinomas and integrating this information with what is currently known about CAFs in sarcomas. The review also suggested novel approaches for targeting CAFs, and outlines new avenues for identifying novel therapeutic targets, which may markedly impact future research in this field.
View Figures

Figure 1

Basic classification of CAFs into
iCAFs, myCAFs and apCAFs. The iCAFs are induced by IL-6 and LIF,
leading to the upregulation of NF-κB signaling. TGF-β promotes the
differentiation of iCAFs into myCAFs. The IL-1/JAK/STAT signaling
pathway promotes the transformation of myCAFs into iCAFs. Finally,
apCAFs induce Tregs. This figure was created with Biorender (ref.
no. SB28IWEZUV). α-SMA, α-smooth muscle actin; apCAFs,
antigen-presenting CAFs; CAFs, cancer-associated fibroblasts;
iCAFs, inflammatory cancer-associated fibroblasts; IL, interleukin;
LIF, leukemia inhibitory factor; JAK, Janus kinase; MHC II, major
histocompatibility complex II; myCAFs, myofibroblastic CAFs; STAT,
signal transductor and activator of transcription protein; TGF-β,
transforming growth factor-β; Treg, regulatory T cell.

Figure 2

Role of CAFs in sarcoma. The diverse
functions of CAFs within the soft tissue and bone sarcoma are
shown. CAFs in liposarcoma, leiomyosarcoma and osteosarcoma support
cancer cells, whereas their role in Ewing sarcoma is unclear and
CD73+ CAF-like tumor cells have been described.
According to current knowledge, CAFs may have a minor role in tumor
progression in rhabdomyosarcoma. The figure was created with
Biorender (ref. no. AW288QL477). CAFs, cancer-associated
fibroblasts; apCAFs, antigen-presenting CAFs; α-SMA, α-smooth
muscle actin; ECM, extracellular matrix; EVs, extracellular
vesicles; iCAFs, inflammatory cancer-associated fibroblasts; TGF-β,
tumor growth factor-β.

Figure 3

CAF-mediated regulation of cancer (on
the left) and immune cells (on the right) with emphasis on sarcomas
(shown by the yellow star) and therapeutic targets (shown by the
red star). CAFs are able to enhance tumor progression by inducing
angiogenesis and invasiveness via the production of VEGF, MMPs and
cytokines. In addition, CAFs promote tumor growth and stemness
through the cytokine production and secretion of EVs. As described
in sarcomas, CAFs can regulate the immune cells of the TME by
producing diverse cytokines and proteins of ECM, favoring
immunosuppressive TME and preventing immune infiltration and
promoting the immune escape. CAFs also promote the recruitment of
M2 macrophages, FoxP3+ regulatory T cells and MDSCs, and
prevent immune infiltration through ECM production and T cell
exhaustion. The figure was created with Biorender (ref. no.
UH288QLJIP). CAFs, cancer-associated fibroblasts; CAR, chimeric
antigen receptor; CXCL12, chemokine (C-X-C motif) ligand; ECM,
extracellular matrix; EMT, epithelial-mesenchymal transition; EVs,
extracellular vesicles; FAP, fibroblast activation protein; FoxP3,
forkhead box P3; IL, interleukin; MDSCs, myeloid-derived suppressor
cells; MΦ2, M2 macrophage; miRNA, micro RNA; MMPs, matrix
metalloproteases; TGF-β, tumor growth factor beta; TME, tumor
microenvironment; VEGF, vascular endothelial growth factor; Wnt,
wingless-related integration site.

Figure 4

CAF study models. 2D and 3D models
can both be utilized for in vitro experiments. 3D models are
created using soft hydrogels, collagen scaffolds or 3D-printed
scaffolds and they are used to study the association between CAFs
and cancer cells, including sarcomas. Depending on the type of
experiment, CAF spheroids alone or the co-cultivation models are
used. In vivo models are categorized into transgenic mice
and xenograft models. Xenograft models can be mice or zebrafish,
and these are used to study the role of CAFs in tumors, including
sarcomas. The figure was created with Biorender (ref. no.
GW28IWDQOO). CAFs, cancer-associated fibroblasts.
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Copy and paste a formatted citation
Spandidos Publications style
Benesova I, Kalkusova K, Kwon YS, Taborska P, Stakheev D, Krausova K, Smetanova J, Ozaniak A, Bartunkova J, Smrž D, Smrž D, et al: Cancer‑associated fibroblasts in human malignancies, with a particular emphasis on sarcomas (Review). Int J Oncol 67: 79, 2025.
APA
Benesova, I., Kalkusova, K., Kwon, Y.S., Taborska, P., Stakheev, D., Krausova, K. ... Strizova, Z.O. (2025). Cancer‑associated fibroblasts in human malignancies, with a particular emphasis on sarcomas (Review). International Journal of Oncology, 67, 79. https://doi.org/10.3892/ijo.2025.5785
MLA
Benesova, I., Kalkusova, K., Kwon, Y. S., Taborska, P., Stakheev, D., Krausova, K., Smetanova, J., Ozaniak, A., Bartunkova, J., Smrž, D., Strizova, Z. O."Cancer‑associated fibroblasts in human malignancies, with a particular emphasis on sarcomas (Review)". International Journal of Oncology 67.4 (2025): 79.
Chicago
Benesova, I., Kalkusova, K., Kwon, Y. S., Taborska, P., Stakheev, D., Krausova, K., Smetanova, J., Ozaniak, A., Bartunkova, J., Smrž, D., Strizova, Z. O."Cancer‑associated fibroblasts in human malignancies, with a particular emphasis on sarcomas (Review)". International Journal of Oncology 67, no. 4 (2025): 79. https://doi.org/10.3892/ijo.2025.5785
Copy and paste a formatted citation
x
Spandidos Publications style
Benesova I, Kalkusova K, Kwon YS, Taborska P, Stakheev D, Krausova K, Smetanova J, Ozaniak A, Bartunkova J, Smrž D, Smrž D, et al: Cancer‑associated fibroblasts in human malignancies, with a particular emphasis on sarcomas (Review). Int J Oncol 67: 79, 2025.
APA
Benesova, I., Kalkusova, K., Kwon, Y.S., Taborska, P., Stakheev, D., Krausova, K. ... Strizova, Z.O. (2025). Cancer‑associated fibroblasts in human malignancies, with a particular emphasis on sarcomas (Review). International Journal of Oncology, 67, 79. https://doi.org/10.3892/ijo.2025.5785
MLA
Benesova, I., Kalkusova, K., Kwon, Y. S., Taborska, P., Stakheev, D., Krausova, K., Smetanova, J., Ozaniak, A., Bartunkova, J., Smrž, D., Strizova, Z. O."Cancer‑associated fibroblasts in human malignancies, with a particular emphasis on sarcomas (Review)". International Journal of Oncology 67.4 (2025): 79.
Chicago
Benesova, I., Kalkusova, K., Kwon, Y. S., Taborska, P., Stakheev, D., Krausova, K., Smetanova, J., Ozaniak, A., Bartunkova, J., Smrž, D., Strizova, Z. O."Cancer‑associated fibroblasts in human malignancies, with a particular emphasis on sarcomas (Review)". International Journal of Oncology 67, no. 4 (2025): 79. https://doi.org/10.3892/ijo.2025.5785
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