The features of cancer-associated fibroblasts as components of tumor stroma in bladder cancer

Sycheva I.N.; Oleynikova N.A.

doi:https://doi.org/10.17116/patol20268802187

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Abstract:

The subject of the study is the data from the world literature on tumor-associated fibroblasts (CAF) and their target markers, on the relationship of this group of cells with clinical and prognostic characteristics. Tumor-associated fibroblasts are a heterogeneous group of cells of the mesenchymal microenvironment in the tumor stroma that play a significant role in tumor development and disease progression, and are also directly related to treatment tactics. Current trends in bladder cancer (BC) research include the investigation of these cell groups and their target markers. The following open internet resources were used to search for literature sources: PubMed, National Library of Medicine, and The Human Protein Atlas. Sources were selected using keywords (indicated in the appropriate field) and publication dates. CAFs and their immunohistochemical markers can be used not only to improve diagnostic panels of urothelial carcinomas, but also to potentially improve the selection criteria for patient groups for the application of various treatment strategies, including minimally invasive methods.

Keywords:

bladder cancer

urothelial carcinoma

cancer-associated fibroblasts

targeted therapy

immunohistochemistry

mesenchymal microenvironment

tumor stroma

Authors:

Sycheva I.N.

Lomonosov Moscow State University — Medical Research and Educational Institute, Moscow, Russia

ORCID: 0009-0004-3905-8709

Oleynikova N.A.

Lomonosov Moscow State University — Medical Research and Educational Institute, Moscow, Russia

SPIN RSCI: 4076-2637
Scopus AuthorID: 57193513523
ResearcherID: H-7672-2014
ORCID: 0000-0001-8564-8874

Received:

09.07.2025

Accepted:

22.12.2025

Close metadata

References:

Liotta LA, Kohn EC. The microenvironment of the tumour-host interface. Nature. 2001;411(6835):375-9. https://doi.org/10.1038/35077241
Lambrechts D, Wauters E, Boeckx B, Aibar S, Nittner D, Burton O, Bassez A, Decaluwé H, Pircher A, Van den Eynde K, et al. Phenotype molding of stromal cells in the lung tumor microenvironment. Nat Med. 2018;24(8):1277-1289. https://doi.org/10.1038/s41591-018-0096-5
Domínguez-Cejudo MA, Gil-Torralvo A, Cejuela M, Molina-Pinelo S, Salvador Bofill J. Targeting the Tumor Microenvironment in Breast Cancer: Prognostic and Predictive Significance and Therapeutic Opportunities. Int J Mol Sci. 2023;24(23):16771. https://doi.org/10.3390/ijms242316771
Huang X, Ding L, Liu X, Tong R, Ding J, Qian Z, Cai L, Zhang P, Li D. Regulation of tumor microenvironment for pancreatic cancer therapy. Biomaterials. 2021;270:120680. https://doi.org/10.1016/j.biomaterials.2021.120680
Song H, Weinstein HNW, Allegakoen P, Wadsworth MH 2nd, Xie J, Yang H, Castro EA, Lu KL, Stohr BA, Feng FY, et al. Single-cell analysis of human primary prostate cancer reveals the heterogeneity of tumor-associated epithelial cell states. Nat Commun. 2022;13(1):141. https://doi.org/10.1038/s41467-021-27322-4
de Visser KE, Joyce JA. The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth. Cancer Cell. 2023;41(3):374-403. https://doi.org/10.1016/j.ccell.2023.02.016
Bremnes RM, Dønnem T, Al-Saad S, Al-Shibli K, Andersen S, Sirera R, Camps C, Marinez I, Busund Lill-T. The role of tumor stroma in cancer progression and prognosis: emphasis on carcinoma-associated fibroblasts and non-small cell lung cancer. Journal of Thoracic Oncology. 2011;6(1):209-217. https://doi.org/10.1097/JTO.0b013e3181f8a1bd
Dudas J, Ladanyi A, Ingruber J, Steinbichler TB, Riechelmann H. Epithelial to Mesenchymal Transition: A Mechanism that Fuels Cancer Radio/Chemoresistance. Cells. 2020;9(2):428. https://doi.org/10.3390/cells9020428
Zhuang J, Lu Q, Shen B, Huang X, Shen L, Zheng X, Huang R, Yan J, Guo H. TGFβ1 secreted by cancer-associated fibroblasts induces epithelial-mesenchymal transition of bladder cancer cells through lncRNA-ZEB2NAT. Sci Rep. 2015;5:11924 https://doi.org/10.1038/srep11924
Caramelo B, Zagorac S, Corral S, Marqués M, Real FX. Cancer-associated Fibroblasts in Bladder Cancer: Origin, Biology, and Therapeutic Opportunities. Eur Urol Oncol. 2023;6(4):366-375. https://doi.org/10.1016/j.euo.2023.02.011
Yamamoto Y, Kasashima H, Fukui Y, Tsujio G, Yashiro M, Maeda K. The heterogeneity of cancer-associated fibroblast subpopulations: Their origins, biomarkers, and roles in thetumor microenvironment. Cancer Sci. 2023;114(1):16-24. https://doi.org/10.1111/cas.15609
Ma Z, Li X, Mao Y, Wei C, Huang Z, Li G, Yin J, Liang X, Liu Z. Interferon-dependent SLC14A1+ cancer-associated fibroblasts promote cancer stemness via WNT5A in bladder cancer. Cancer Cell. 2022;40(12):1550-1565. https://doi.org/10.1016/j.ccell.2022.11.005
Liang T, Tao T, Wu K, Liu L, Xu W, Zhou D, Fang H, Ding Q, Huang G, Wu S. Cancer-Associated Fibroblast-Induced Remodeling of Tumor Microenvironment in Recurrent Bladder Cancer. Adv. Sci. 2023;10,2303230. https://doi.org/10.1002/advs.202303230
Burley A, Rullan A, Wilkins A. A review of the biology and therapeutic implications of cancer-associated fibroblasts (CAFs) in muscle-invasive bladder cancer. Front Oncol. 2022;12:1000888. https://doi.org/10.3389/fonc.2022.1000888
Gil-Julio H, Perea F, Rodriguez-Nicolas A, Cozar JM, González-Ramirez AR, Concha A, Garrido F, Aptsiauri N, Ruiz-Cabello F. Tumor Escape Phenotype in Bladder Cancer Is Associated with Loss of HLA Class I Expression, T-Cell Exclusion and Stromal Changes. Int J Mol Sci. 2021;22(1):7248. https://doi.org/10.3390/ijms22147248
Baker LE, Carrel A. Action on fibroblasts of the protein fraction of embryonic tissue extract. J Exp Med. 1926;44(3):387-395. https://doi.org/10.1084/jem.44.3.387
Liu F, Qi L, Liu B, Liu J, Zhang H, Che D, Cao J, Shen J, Geng J, Bi Y, Ye L, Pan B, Yu Y. Fibroblast activation protein overexpression and clinical implications in solid tumors: A meta-analysis. PLoS ONE. 2025;10(3):e0116683. https://doi.org/10.1371/journal.pone.0116683
Privé BM, Boussihmad MA, Timmermans B, van Gemert WA, Peters SMB, Derks YHW, van Lith SAM, Mehra N, Nagarajah J, Heskamp S, Westdorp H. Fibroblast activation protein-targeted radionuclide therapy: background, opportunities, and challenges of first (pre)clinical studies. Eur J Nucl Med Mol Imaging. 2023;50(7):1906-1918. https://doi.org/10.1007/s00259-023-06144-0
Shahvali S, Rahiman N, Jaafari MR, Arabi L. Targeting fibroblast activation protein (FAP): advances in CAR-T cell, antibody, and vaccine in cancer immunotherapy. Drug Deliv Transl Res. 2023;13(7):2041-2056. https://doi.org/10.1007/s13346-023-01308-9
Mona CE, Benz MR, Hikmat F, Grogan TR, Lueckerath K, Razmaria A, Riahi R, Slavik R, Girgis MD, Carlucci G, et al. Correlation of 68Ga-FAPi-46 PET biodistribution with FAP expression by immunohistochemistry in patients with solid cancers: a prospective translational exploratory study. J Nucl Med. 2022;63(7):1021-1026. https://doi.org/10.2967/jnumed.121.262426
Hemida AS, Aiad HAES, Hassan NA, Al Sharaky DR. Fibroblast activation protein (FAP) expression in CK5/6 expressed (Basal subtype) & CK20 expressed (Luminal subtype) urothelial bladder carcinoma: an immunohistochemical study. J Immunoassay Immunochem. 2022;43(6):618-633. https://doi.org/10.1080/15321819.2022.2095208
Choi W, Porten S, Kim S, Willis D, Plimack ER, Hoffman-Censits J, Roth B, Cheng T, Tran M, Lee IL, et al. Identification of Distinct Basal and Luminal Subtypes of Muscle-Invasive Bladder Cancer with Different Sensitivities to Frontline Chemotherapy. Cancer Cell. 2014;25(2):152-165. https://doi.org/10.1016/j.ccr.2014.01.009
Kriajevska MV, Cardenas MN, Grigorian MS, Ambartsumian NS, Georgiev GP, Lukanidin EM. Non-muscle myosin heavy chain as a possible target for protein encoded by metastasis-related mts-1 gene. J Biol Chem. 1994;269(31):19679-82.
Ford HL, Salim MM, Chakravarty R, Aluiddin V, Zain SB. Expression of mts-1, a metastasis-associated gene, increases motility but not invasion of a nonmetastatic mouse mammary adenocarcinoma cell line. Oncogene. 1995;11:2067-2075.
Davies BR, O’Donnell M, Durkan GC, Rudland PS, Barraclough R, Neal DE, Kilian Mellon J. Expression of SI00A4 protein is associated with metastasis and reduced survival in human bladder cancer. J Pathol. 2022;196(3):292-299. https://doi.org/10.1002/path.1051
Schulte, J., Weidig, M., Balzer, P., Richter, P., Franz, M., Junker, K., Gajda, M., Friedrich, K., et al. Expression of the E-cadherin repressors Snail, Slug and Zeβ1 in urothelial carcinoma of the urinary bladder: Relation to stromal fibroblast activation and invasive behaviour of carcinoma cells. Histochem Cell Biol. 2012;138(6):847-60. https://doi.org/10.1007/s00418-012-0998-0
Sauzay C, Voutetakis K, Chatziioannou A, Chevet E, Avril T. CD90/Thy-1, a cancer-associated cell surface signaling molecule. Front Cell Dev Biol. 2019;7:66. https://doi.org/10.3389/fcell.2019.00066
Zareinejad M, Faghih Z, Ariafar A, Safaei A, Ghaderi A. Establishment of a bladder cancer cell line expressing both mesenchymal and epithelial lineage-associated markers. Hum Cell. 2021;34(2):675-687. https://doi.org/10.1007/s13577-020-00456-1
Mezheyeuski A, Segersten U, Leiss LW, Malmström PU, Hatina J, Östman A, Strell C. Fibroblasts in urothelial bladder cancer define stroma phenotypes that are associated with clinical outcome. Sci Rep. 2020;10:281. https://doi.org/10.1038/s41598-019-55013-0
Li Y, Zheng H, Luo Y, Lin Y, An M, Kong Y, Zhao Y, Yin Y, Ai L, Huang J, Chen C. An HGF-dependent positive feedback loop between bladder cancer cells and fibroblasts mediates lymphangiogenesis and lymphatic metastasis. Cancer Commun (Lond). 2023;43(12):1289-1311. https://doi.org/10.1002/cac2.12470
Zhao K, Xu G, Jin J, Peng C, Chen J, Li Y, Wang W, Pan S. Integrated prognostic assessment of apoptosis and chemotherapy related gene in bladder cancer: a prognostic signature. Discov Oncol. 2025;16:718. https://doi.org/10.1007/s12672-025-02581-5
Yan J, Xiao G, Yang C, Liu Q, Lv C, Yu X, Zhou Z, Lin S, Bai Z, Lin H, Zhang R, Liu C. Cancer-Associated Fibroblasts Promote Lymphatic Metastasis in Cholangiocarcinoma via the PDGF-BB/PDGFR-β Mediated Paracrine Signaling Network. Aging Dis. 2024;15(1):369-389. https://doi.org/10.14336/AD.2023.0420
Wang KJ, Wang C, Dai LH, Yang J, Huang H, Ma XJ, Zhou Z, Yang ZY, Xu WD, Hua MM, et al. Targeting an Autocrine Regulatory Loop in Cancer Stem-like Cells Impairs the Progression and Chemotherapy Resistance of Bladder Cancer. Clin Cancer Res. 2019;25(3):1070-1086. https://doi.org/10.1158/1078-0432.CCR-18-0586
Song H, Lu T, Han D, Zhang J, Gan L, Xu C, Liu S, Li P, Zhang K, Hu Z, et al. YAP1 Inhibition Induces Phenotype Switching of Cancer-Associated Fibroblasts to Tumor Suppressive in Prostate Cancer Running Title: YAP1 inhibition switches CAF phenotypes. Cancer Res. 2024;84(22):3728-3742. https://doi.org/10.1158/0008-5472.CAN-24-0932
Kamali Zonouzi S, Pezeshki PS, Razi S, Rezaei N. Cancer-associated fibroblasts in colorectal cancer. Clin Transl Oncol. 2022; 24(5):757-769. https://doi.org/10.1007/s12094-021-02734-2
Athavale D, Balch C, Zhang Y, Yao X, Song S. The role of Hippo/YAP1 in cancer-associated fibroblasts: Literature review and future perspectives. Cancer Let. 2024;604: 217244. https://doi.org/10.1016/j.canlet.2024.217244
Cheng X, Lou K, Ding L, Zou X, Huang R, Xu G, Zou J, Zhang G. Clinical potential of the Hippo-YAP pathway in bladder cancer. Front Oncol. 2022;12:925278. https://doi.org/10.3389/fonc.2022.925278
Qiu D, Zhu Y, Cong Z. Yap triggers bladder cancer proliferation by affecting the MAPK pathway. Cancer Manag Res. 2020;12:12205-12214. https://doi.org/10.2147/CMAR.S273442
Santini D, Banna GL, Buti S, Isella L, Stellato M, Roberto M, Iacovelli R. Navigating the Rapidly Evolving Advanced Urothelial Carcinoma Treatment Landscape: Insights from Italian Experts. Curr Oncol Rep. 2023;25(11):1345-1362. https://doi.org/10.1007/s11912-023-01461-x
Johnson DC, Greene PS, Nielsen ME. Surgical advances in bladder cancer: At what cost? Urol Clin North Am. 2015; 42(2):235-52, ix. https://doi.org/10.1016/j.ucl.2015.01.005
Xylinas E, Kent M, Kluth L, Pycha A, Comploj E, Svatek RS, Lotan Y, Trinh QD, Karakiewicz PI, Holmang S, et al. Accuracy of the EORTC risk tables and of the CUETO scoring model to predict outcomes in non-muscle-invasive urothelial carcinoma of the bladder. Br J Cancer. 2013;109(6):1460-6. https://doi.org/10.1038/bjc.2013.372
Gong YW, Wang YR, Fan GR, Niu Q, Zhao YL, Wang H, Svatek R, Rodriguez R, Wang ZP. Diagnostic and prognostic role of BTA, NMP22, survivin and cytology in urothelial carcinoma. Transl Cancer Res. 2021;10(7):3192-3205. https://doi.org/10.21037/tcr-21-386
Ng K, Stenzl A, Sharma A, Vasdev N. Urinary biomarkers in bladder cancer: A review of the current landscape and future directions. Urol Oncol. 2021;39(1):41-51. https://doi.org/10.1016/j.urolonc.2020.08.016