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Review
. 2025 Jan 13;23(1):50.
doi: 10.1186/s12967-025-06071-8.

Cancer-associated fibroblasts in carcinogenesis

Shufen Zhou #  1   2 , Zekun Zhao #  3 , Zhaojun Wang #  4 , Hanzheng Xu  1   2 , Yijie Li  1 , Ke Xu  5   6 , Wei Li  7 , Jiahua Yang  8
Affiliations
Review

Cancer-associated fibroblasts in carcinogenesis

Shufen Zhou et al. J Transl Med. .

Abstract

In contemporary times, cancer poses the most significant threat to human life and safety. Scientists have relentlessly pursued the intricacies of carcinogenesis and explored ways to prevent and treat cancer. Carcinogenesis is a complex, multi-faceted, and multi-stage process, with numerous underlying causes, including inflammation and fibrosis. Cancer-associated fibroblasts (CAFs), however, occupy a pivotal and substantial role within the tumor microenvironment, facilitating carcinogenesis through diverse mechanisms such as creating inflammation, fostering a fibrotic tumor microenvironment, and immunosuppression. In this paper, we introduce the concept of carcinogenesis, explain its causes, describe the characteristics of CAFs and their sources, and highlight the roles and mechanisms of CAFs in promoting carcinogenesis. Ultimately, our aim is to contribute to the development of novel therapeutic strategies for cancer treatment.

Keywords: Breast cancer; Cancer-associated fibroblasts; Carcinogenesis; Colorectal cancer.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
“Drivers” of carcinogenesis. Figure was created with https://www.biorender.com/
Fig. 2
Fig. 2
The role of CAFs involved in carcinogenesis in breast cancer and colorectal cancer. Figure was created with https://www.biorender.com/
Fig. 3
Fig. 3
CAFs in breast cancer carcinogenesis. (A) In 3D co-culture with NFs, breast cancer cells exhibit formation of glandular structures with a mid-lumen. Adapted with permission from [73], copyright 2013, International Institute of Anticancer Research. (B) When co-cultured with CAFs rather than NFs, precancerous breast epithelial cells showed a mesenchymal morphology. Adapted with permission from [74], copyright 2013, Elsevier. C.(i) BRCA1+/mut fibroblasts exhibited a CAF phenotype; (ii)MMP3-expressing fibroblasts drive BRCA1+/mut breast tumorigenesis in vivo. Adapted with permission from [77], copyright 2023, Springer Nature. D.(i) Scheme of organotypic 3D co-culture of primary mammary fibroblasts and mammary epithelial cells; (ii) Treatment with nitric oxide synthase inhibitor L-8 caused the aberrant morphologies of mammary gland epithelia and fibroblasts in vivo as well as in organotypic 3D co-cultures. Adapted with permission from [79], copyright 2021, MDPI (Basel, Switzerland)
Fig. 4
Fig. 4
CAFs in colorectal cancer carcinogenesis. A. (i) Knockdown of Imp1 in the matrix increases inflammation and matrix components; (ii) Imp1 in stroma promotes enhanced tumorigenesis. Adapted with permission from [84], copyright 2015, the American Association for Cancer Research. B.(i) Hic-5 is more highly expressed in the mesenchymal compartment of all colorectal cancer samples compared to the resident fibroblasts of normal colonic mucosa; (ii) CAFs lacking Hic-5 block colorectal carcinogenesis. Adapted with permission from [90], copyright 2018, Springer Nature. C.(i) Removing MyD88 from intestinal stromal cells can alter the immune microenvironment of sporadic colorectal cancer; (ii) Deletion of MyD88 in intestinal mesenchymal cells reduces tumorigenesis in the Apcmin/+ model of sporadic intestinal cancer. Adapted with permission from [93], copyright 2019, Elsevier
See this image and copyright information in PMC

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