Cancer-associated fibroblasts and clinical and morphological features of prostate cancer

Introduction. In recent years, researchers have been paying special attention to the structure of the tumor microenvironment, which is assumed to be able to modulate the tumor behavior due to various paracrine factors and, thereby, act as a marker of the course and prognosis of prostate cancer (PCa). One of the components of the tumor microenvironment are cancer-associated fibroblasts (CAFs). Fibroblast activation protein (FAP) and plateletderived growth factor receptors α and β (PDGFR α and β) can be used as markers of CAFs.

Objective. To evaluate the association between the clinical and morphological features of PCa and CAFs markers, FAP and PDGFRα + β.

Materials & methods. The study used surgical material obtained from 34 patients with PCa. The age of the patients ranged from 52 to 77 years (mean age 64.1). The surgical material was stained with CAFs – FAP and PDGFRa + β markers. Subsequently, the relationship between these markers and the clinical and morphological features of PCa was analyzed using the RStudio software in the R programming language.

Results. A higher Gleason grade in the presence of FAP was noted: in 81.3% of cases, PCa was classified as Gleason 4 + 3 = 7 and higher, while in the absence of FAP, only 33.3% of tumors belonged to this category (p=0.014). In addition, patients with FAP were significantly more likely to have lymphatic invasion, which was detected in 43.8% of cases, while in the absence of FAP it was detected only in 5.6% (0.015). In the presence of FAP, patients were more likely to have a lesion of the prostate according to MRI, and lymph nodes were also more often affected (31.2% and 5.6%), however, this parameter had a borderline significance level (p = 0.078). With moderate/high PDGFRa + β expression, a higher Gleason grade was noted: in 80.0% of cases, PCa was classified as Gleason 4 + 3 = 7 and higher, while with no/ weak PDGFRa + β expression, only 36.8% of tumors belonged to this category (p = 0.030). In patients with moderate/ high PDGFRa + β expression, there was a more frequent probability of involvement of lymph nodes in the process (according to the MSKCC nomogram) and more likely to have lesions according to MRI at the borderline significance level of these parameters (p = 0.097 and p = 0.063, respectively).

Conclusion. The presence and severity of expression of stromal CAFs markers are associated with unfavorable clinical and morphological features of prostate cancer with a higher Gleason grade, more frequent lesions on MRI and the presence of invasion into the lymphatic vessels.

1. Cancer Taday. (Accessed on November 23, 2024) URL: https://gco.iarc.fr/today/home

2. James ND, Tannock I, N’Dow J, Feng F, Gillessen S, Ali SA, Trujillo B, AlLazikani B, Attard G, Bray F, Compérat E, Eeles R, Fatiregun O, Grist E, Halabi S, Haran Á, Herchenhorn D, Hofman MS, Jalloh M, Loeb S, MacNair A, Mahal B, Mendes L, Moghul M, Moore C, Morgans A, Morris M, Murphy D, Murthy V, Nguyen PL, Padhani A, Parker C, Rush H, Sculpher M, Soule H, Sydes MR, Tilki D, Tunariu N, Villanti P, Xie LP. The Lancet Commission on prostate cancer: planning for the surge in cases. Lancet. 2024;403(10437):1683-1722. Erratum in: Lancet. 2024;403(10437):1634. DOI: 10.1016/S0140-6736(24)00651-2

3. Kaprin A.D., Alekseev B.I., Matveev V.B., Pushkar’ D.I., Govorov A.V., Gorban’ N.A., Kirichek A.A., Biriukov V.A., Volkova M.I., Gulidov I.A., Gumenetskaia I.V., Krylov V.V., Kariakin O.B., Krasheninnikov A.A., Mardynskii I.S., Niushko K.M., Zakharova T.I., Kostin A.A., Khmelevskii E.V., Fedenko A.A., Bolotina L.V., Falaleeva N.A., Filonenko E.V., Nevol’skikh A.A., Ivanov S.A., Khailova Z.V., Gevorkian T.G. Prostate cancer. Journal of Modern Oncology. 2021;23(2):211-247. (In Russian). DOI: 10.26442/18151434.2021.2.200959

4. EAU Guidelines. Prostate cancer. Edn. presented at the EAU Annual Congress Milan 2023. ISBN 978-94-92671-19-6.

5. López-Abad A, Server Gómez G, Loyola Maturana JP, Giménez Andreu I, Collado Serra A, Wong Gutiérrez A, Boronat Catalá J, de Pablos Rodríguez P, Gómez-Ferrer Á, Casanova Ramón-Borja J, Ramírez Backhaus M. Comparative evaluation of continence and potency after radical prostatectomy: Robotic vs. laparoscopic approaches, validating LAP-01 trial. Surg Oncol. 2024;55:102098. DOI: 10.1016/j.suronc.2024.102098

6. Bangma C, Doan P, Zhu L, Remmers S, Nieboer D, Helleman J, Roobol MJ, Sugimoto M, Chung BH, Lee LS, Frydenberg M, Klotz L, Peacock M, Perry A, Bjartell A, Rannikko A, Van Hemelrijck M, Dasgupta P, Moore C, Trock BJ, Pavlovich C, Steyerberg E, Carroll P, Koo KC, Hayen A, Thompson J; Movember Foundation’s Global Action Plan Prostate Cancer Active Surveillance (GAP3) Consortium. Has Active Surveillance for Prostate Cancer Become Safer? Lessons Learned from a Global Clinical Registry. Eur Urol Oncol. 2025;8(2):324-337. DOI: 10.1016/j.euo.2024.07.003

7. Pakula H, Pederzoli F, Fanelli GN, Nuzzo PV, Rodrigues S, Loda M. Deciphering the Tumor Microenvironment in Prostate Cancer: A Focus on the Stromal Component. Cancers (Basel). 2024;16(21):3685. DOI: 10.3390/cancers16213685

8. Lopez-Bujanda ZA, Hadavi SH, Ruiz De Porras V, Martínez-Balibrea E, Dallos MC. Chemotactic signaling pathways in prostate cancer: Implications in the tumor microenvironment and as potential therapeutic targets. Int Rev Cell Mol Biol. 2024;388:162-205. DOI: 10.1016/bs.ircmb.2024.03.008

9. El Alaa RSA, Al-Mannai W, Darwish N, Al-Mansoori L. Adipose-Derived Stromal Cells and Cancer-Associated Fibroblasts: Interactions and Implications in Tumor Progression. Int J Mol Sci. 2024;25(21):11558. DOI: 10.3390/ijms252111558

10. Yu S, Wang S, Wang X, Xu X. The axis of tumor-associated macrophages, extracellular matrix proteins, and cancer-associated fibroblasts in oncogenesis. Cancer Cell Int. 2024;24(1):335. DOI: 10.1186/s12935-024-03518-8

11. Fotsitzoudis C, Koulouridi A, Messaritakis I, Konstantinidis T, GouvasN, Tsiaoussis J, Souglakos J. Cancer-Associated Fibroblasts: The Origin, Biological Characteristics and Role in Cancer-A Glance on Colorectal Cancer. Cancers (Basel). 2022;14(18):4394. DOI: 10.3390/cancers14184394

12. Bughda R, Dimou P, D’Souza RR, Klampatsa A. Fibroblast Activation Protein (FAP)-Targeted CAR-T Cells: Launching an Attack on Tumor Stroma. Immunotargets Ther. 2021;10:313-323. DOI: 10.2147/ITT.S291767

13. Kraxner A, Braun F, Cheng WY, Yang TO, Pipaliya S, Canamero M, Andersson E, Harring SV, Dziadek S, Bröske AE, Ceppi M, Tanos T, Teichgräber V, Charo J. Investigating the complex interplay between fibroblast activation protein α-positive cancer associated fibroblasts and the tumor microenvironment in the context of cancer immunotherapy. Front Immunol. 2024;15:1352632. DOI: 10.3389/fimmu.2024.1352632

14. Wang J, You J, Gong D, Xu Y, Yang B, Jiang C. PDGF-BB induces conversion, proliferation, migration, and collagen synthesis of oral mucosal fibroblasts through PDGFR-β/PI3K/ AKT signaling pathway. Cancer Biomark. 2021;30(4):407-415. DOI: 10.3233/CBM-201681

15. Strell C, Rodríguez-Tomàs E, Östman A. Functional and clinical roles of stromal PDGF receptors in tumor biology. Cancer Metastasis Rev. 2024;43(4):1593-1609. DOI: 10.1007/s10555-024-10194-7

16. Solek J, Braun M, Sadej R, Romanska HM. FGFR related phenotypic and functional profile of CAFs in prognostication of breast cancer (Review). Int J Oncol. 2024;65(4):94. DOI: 10.3892/ijo.2024.5682

17. Cui M, Dong H, Duan W, Wang X, Liu Y, Shi L, Zhang B. The relationship between cancer associated fibroblasts biomarkers and prognosis of breast cancer: a systematic review and meta-analysis. PeerJ. 2024;12:e16958. DOI: 10.7717/peerj.16958

18. Yu Y, Lyu C, Li X, Yang L, Wang J, Li H, Xin Z, Xu X, Ren C, Yang G. Remodeling of tumor microenvironment by extracellular matrix protein 1a differentially regulates ovarian cancer metastasis. Cancer Lett. 2024;596:217022. DOI: 10.1016/j.canlet.2024.217022

19. Akinjiyan FA, Dave RM, Alpert E, Longmore GD, Fuh KC. DDR2 Expression in Cancer-Associated Fibroblasts Promotes Ovarian Cancer Tumor Invasion and Metastasis through Periostin-ITGB1. Cancers (Basel). 2022;14(14):3482. DOI: 10.3390/cancers14143482

20. Zhang M, Chen Z, Wang Y, Zhao H, Du Y. The Role of Cancer-Associated Fibroblasts in Ovarian Cancer. Cancers (Basel). 2022;14(11):2637. DOI: 10.3390/cancers14112637

21. Zheng H, An M, Luo Y, Diao X, Zhong W, Pang M, Lin Y, Chen J, Li Y, Kong Y, Zhao Y, Yin Y, Ai L, Huang J, Chen C, Lin T. PDGFRα+ITGA11+ fibroblasts foster early-stage cancer lymphovascular invasion and lymphatic metastasis via ITGA11-SELE interplay. Cancer Cell. 2024;42(4):682-700. e12. DOI: 10.1016/j.ccell.2024.02.002

22. Sha M, Shen C, Jeong S, Xu N, Chen C, Hang HL, Tong Y, Cao J. Novel discovery of PDPN-positive CAFs contributing to tumor-associated lymphangiogenesis through mesenchymal to lymphatic endothelial transition in intrahepatic cholangiocarcinoma. Genes Dis. 2023;10(6):2226- 2228. DOI: 10.1016/j.gendis.2023.02.023

23. Shah R, Johnson KA, Lippert AEL, Kraus SG, Emmerich PB, Pasch CA, Zhang W, Matkowskyj KA, LeBeau AM, Deming DA. Cancer-Associated Fibroblast Proteins as Potential Targets against Colorectal Cancers. Cancers (Basel). 2024;16(18):3158. DOI: 10.3390/cancers16183158

24. Wu Z, Shi J, Lai C, Li K, Li K, Li Z, Tang Z, Liu C, Xu K. Clinicopathological significance and prognostic value of cancer-associated fibroblasts in prostate cancer patients. Urol Oncol. 2021;39(7):433.e17-433.e23. DOI: 10.1016/j.urolonc.2021.05.004

25. Ageeli W, Zhang X, Ogbonnaya CN, Bray SE, Kernohan NM, Wilson J, Li C, Nabi G. Multimodality Characterization of Cancer-Associated Fibroblasts in Tumor Microenvironment and Its Correlation With Ultrasound Shear Wave-Measured Tissue Stiffness in Localized Prostate Cancer. Front Oncol. 2022;12:822476. DOI: 10.3389/fonc.2022.822476

26. Hesterberg AB, Rios BL, Wolf EM, Tubbs C, Wong HY, Schaffer KR, Lotan TL, Giannico GA, Gordetsky JB, Hurley PJ. A distinct repertoire of cancer-associated fibroblasts is enriched in cribriform prostate cancer. J Pathol Clin Res. 2021;7(3):271-286. DOI: 10.1002/cjp2.205

27. Linxweiler J, Hajili T, Körbel C, Berchem C, Zeuschner P, Müller A, Stöckle M, Menger MD, Junker K, Saar M. Cancer-associated fibroblasts stimulate primary tumor growth and metastatic spread in an orthotopic prostate cancer xenograft model. Sci Rep. 2020;10(1):12575. DOI: 10.1038/s41598-020-69424-x

28. Shen T, Li Y, Wang D, Su Y, Li G, Shang Z, Niu Y, Tan X. YAP1-TEAD1 mediates the perineural invasion of prostate cancer cells induced by cancer-associated fibroblasts. Biochim Biophys Acta Mol Basis Dis. 2022;1868(12):166540. DOI: 10.1016/j.bbadis.2022.166540

29. Sun DY, Wu JQ, He ZH, He MF, Sun HB. Cancer-associated fibroblast regulate proliferation and migration of prostate cancer cells through TGF-β signaling pathway. Life Sci. 2019;235:116791. DOI: 10.1016/j.lfs.2019.116791

30. Bedeschi M, Marino N, Cavassi E, Piccinini F, Tesei A. Cancer-Associated Fibroblast: Role in Prostate Cancer Progression to Metastatic Disease and Therapeutic Resistance. Cells. 2023;12(5):802. DOI: 10.3390/cells12050802

31. Kakarla M, ChallaSivaKanaka S, Dufficy MF, Gil V, Filipovich Y, Vickman R, Crawford SE, Hayward SW, Franco OE. Ephrin B Activate Src Family Kinases in Fibroblasts Inducing Stromal Remodeling in Prostate Cancer. Cancers (Basel). 2022;14(9):2336. DOI: 10.3390/cancers14092336

32. Orr B, Grace OC, Brown P, Riddick AC, Stewart GD, Franco OE, Hayward SW, Thomson AA. Reduction of pro-tumorigenic activity of human prostate cancer-associated fibroblasts using Dlk1 or SCUBE1. Dis Model Mech. 2013;6(2):530-536. DOI: 10.1242/dmm.010355

33. Vitale G, Caraglia M, Jung V, Kamradt J, Gentilini D, Di Martino MT, Dicitore A, Abate M, Tagliaferri P, Itro A, Ferro M, Balsamo R, De Sio M, Facchini G, Persani L, Schmitt K, Saar M, Stöckle M, Unteregger G, Zappavigna S. Molecular Characterization of Cancer Associated Fibroblasts in Prostate Cancer. Cancers (Basel). 2022;14(12):2943. DOI: 10.3390/cancers14122943

34. Talia M, Cesario E, Cirillo F, Scordamaglia D, Di Dio M, Zicarelli A, Mondino AA, Occhiuzzi MA, De Francesco EM, Belfiore A, Miglietta AM, Di Dio M, Capalbo C, Maggiolini M, Lappano R. Cancer-associated fibroblasts (CAFs) gene signatures predict outcomes in breast and prostate tumor patients. J Transl Med. 2024;22(1):597. DOI: 10.1186/s12967-024-05413-2