The collagen-containing connective tissue component of breast and prostate cancer as a key determinant of the risk of metastatic progression

Authors

DOI:

https://doi.org/10.26641/1997-9665.2025.2.37-46

Keywords:

invasive ductal breast cancer, prostate cancer, parenchymal and stromal components of tumors, degree of malignancy, collagen-containing fibrillar structures.

Abstract

Introduction. Numerous studies in recent decades have confirmed that, alongside the parenchymal component of tumors, the fibrous collagen-containing stroma plays a critical role in determining the course and progression of cancer. Objective. To identify morphological features that highlight the significance of the stromal, particularly the collagen-containing component, in shaping the malignant phenotype and metastatic potential of the most common hormone-dependent tumors — invasive breast cancer (BCa) and prostate cancer (PCa). This was achieved by correlating these features with the clinicopathological characteristics of patients. Methods. Histological material of primary tumors was examined from individuals of the Kyiv population — of 120 womens with stage I–II invasive ductal BCa with moderate differentiation (G2), and 69 mens with PCa with Gleason scores of 6–9, including both cases without metastatic progression and cases with lymph node and bone metastases. To verify collagen-containing structures and quantify the distribution of variously shaped collagen fibrils around epithelial structures in the parenchyma, histological sections were stained using Van Gieson’s method. Results. A comparative analysis of the features of collagen-containing fibrous structures in the primary tumors of BCa and PCa patients — considering the proportions of parenchymal and stromal components, the degree of desmoplasia in adjacent and surrounding connective tissue, and the ratio of differently shaped collagen fibrils around parenchymal structures — together with the clinicopathological data, supports the conclusion that the observed differences and patterns, specifically: a shift towards more aligned collagen fibrils around epithelial structures, an increase in the overall mass of collagen in the adjacent and surrounding tumor stroma, thickening and widening of fibrils, and their denser and more parallel arrangement against varying degrees of desmoplasia, should be emphasized by pathologists in pathological reports as indicators of metastatic progression risk. This would help clinicians develop more personalized prognoses and select optimal therapeutic strategies.

References

  1. Vickman RE, Faget DV, Beachy Ph, Beebe D, Bhowmick NA, Cukierman E, Deng W-M, Granneman JG, Hildesheim J, Kalluri R, Lau KS, Ernst Lengyel E. Deconstructing tumor heterogeneity: the stromal perspective. Oncotarget. 2020;11(40):3621–32. doi: 10.18632/oncotarget.27736.
  2. Buruiană A, Gheban BA, Gheban-Roșca TA, Georgiu C, Crișan D and Crișan M. The Tumor Stroma of Squamous Cell Carcinoma: A Complex Environment That Fuels Cancer Progression. Cancers. 2024;16(9):1727. doi: 10.3390/cancers16091727.
  3. Frankenstein Z, Basanta D, Franco O, Anderson ARA. Stromal reactivity differentially drives tumour cell evolution and prostate cancer progression. Nature Ecology & Evolution. 2020;4(6):870–84. doi: 10.1038/s41559-020-1157-y.
  4. Poonja Sh, Forero Pinto A, Lloyd MC, Damaghi M, Rejniak KA. Editors: Wilson MR, Kalyuzhny AE. Dynamics of Fibril Collagen Remodeling by Tumor Cells: A Model of Tumor-Associated Collagen Signatures. Cells. 2023;12(23):2688. doi: 10.3390/cells12232688.
  5. Martino DD, Bravo-Cordero JJ. Collagens in cancer: structural regulators and guardians of cancer progression. Cancer Res. 2023;83(9):1386–92. doi: 10.1158/0008-5472.CAN-22-2034.
  6. Song K, Yu Zh, Zu X, Li G, Hu Zh and Xue Yu. Collagen Remodeling along Cancer Progression Providing a Novel Opportunity for Cancer Diagnosis and Treatment. Int. J. Mol. Sci. 2022;23(18):10509. doi: 10.3390/ijms231810509.
  7. Nguyen TH, Zhang J, Hipp J, Chhor G, Griffin M, Le N, Kartik D, Zhang Yi, Mirzadeh M, Varao J, Allay J, Sweeney M, Rivera V, Johnson B, Brosnan-Cashman J, Bronnimann M, Pokkalla H, Glass B, Beck AH, Lee J, Egger R. Quantification of collagen and associated features from H&E-stained whole slide pathology images across cancer types using a physics-based deep learning model. bioRxiv. 2025;03. doi: 10.1101/2025.03.17.643273.
  8. Ouellette JN, Drifka CR, Pointer KB, Liu Yu. Navigating the Collagen Jungle: The Biomedical Potential of Fiber Organization in Cancer. Bioengineering. 2021;8(2):17.doi: bioengineering8020017.
  9. Bourgot I, Bourgot I, Primac I, Primac I, Louis T, Noël A, Maquoi E. Reciprocal Interplay Between Fibrillar Collagens and Collagen-Binding Integrins: Implications in Cancer Progression and Metastasis. Front. Oncol. Sec. Molecular and Cellular Oncology. 2020;10. doi: 10.3389/fonc.2020.01488.
  10. Yuan Zh, Li Yi, Zhang S, Wang Xu, Dou H, Yu X, Zhang Zh, Yang Sh & Xiao M. Extracellular matrix remodeling in tumor progression and immune escape: from mechanisms to treatments. Molecular Cancer. 2023;22: https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-023-01744-8.
  11. Su H, Karin M. Collagen architecture and signaling orchestrate cancer development. Trends in Cancer. 2023;9(9):764-773. doi: 10.1016/j.trecan.2023.06.002.
  12. Naleskina LA, Luk’yanova NY, Zadvorny TV, Kunska LM, Chehun VF. [Peculiarities of the architectonics of collagen structures in tumors of breast cancer patients with different manifestations of remodeling of the stromal component]. Oncology. 2021;4(90):195-200. Ukrainian.
  13. Almagro J, Messal HA, Elosegui-Artola A, van Rheenen J, Behrens A. Tissue architecture in tumor initiation and progression. Trends in Cancer. 2022;8(6):494-505. doi: 10.1016/j.trecan.2022.02.007.
  14. Naleskina L, Lukianova N, Zadvornyi T, Kunska L, Mushii O, Chekhun V. Remodelling the architecture of collagen-containing connective tissue fibers of metastatic prostate cancer. Cytology and Genetics 2023;57(5):406–412. doi: 10.3103/ S0095452723050031.
  15. Bourgot I, Bourgot I, Primac I, Primac I, Louis T, Noël A, Maquoi E. Reciprocal Interplay Between Fibrillar Collagens and Collagen-Binding Integrins: Implications in Cancer Progression and Metastasis. Front. Oncol. Sec. Molecular and Cellular Oncology. 2020;10. doi: 10.3389/fonc.2020.01488.
  16. Heydari S, Tajik F, Safaei S, Kamani F, Karami B, Dorafshan Sh, Madjd Z, Ghods R. The association between tumor-stromal collagen features and the clinical outcomes of patients with breast cancer: a systematic review. Breast Cancer Res. 2025;27(1):69. doi: 10.1186/s13058-025-02017-6.
  17. Baruah A, Bhuyan G, & Saikia P. Histopathological categorization of desmoplastic reaction in gallbladder carcinoma: its relation to cancer invasiveness and prognostic utility. Egyptian Liver Journal. 2023;13. https://eglj.springeropen.com/articles/10.1186/s43066-023-00253-z.
  18. Imanbayev NM, Iztleuov YeM, Kamyshanskiy YeK, Zhumasheva AiV. Diagnostic and prognostic significance of keloid-like collagen remodeling patterns in the extracellular matrix of colorectal cancer. Pathol. Oncol. Res. 2024;30. doi: 10.3389/ pore.2024.1611789.
  19. Maneshi P, Mason J, Dongre M, Öhlund D. Targeting Tumor-Stromal Interactions in Pancreatic Cancer: Impact of Collagens and Mechanical Traits. Front. Cell Dev. Biol. Sec. Molecular and Cellular Pathology. 2021;9. doi: 10.3389/fcell.2021.787485.
  20. Egnell L, VidićI, Jerome NP, Bofin AM, Bathen TF, Goa PE. Stromal Collagen Content in Breast Tumors Correlates With In Vivo Diffusion-Weighted Imaging: A Comparison of Multi b-Value DWI With Histologic Specimen From Benign and Malignant Breast Lesions. 2019. doi: 10.1002/ jmri.27018.
  21. Morkunas M, Zilenaite D, Laurinaviciene A, Treigys P & Laurinavicius A. Tumor collagen framework from bright-field histology images predicts overall survival of breast carcinoma patients. Scientific Reports. 2021;11. https://www.nature.com/articles/s41598-021-94862-6.
  22. Nissen NI, Karsdal M, Willumsen N. Collagens and Cancer associated fibroblasts in the reactive stroma and its relation to Cancer biology. J Exp Clin Cancer Res. 2019;38(1):115. doi: 10.1186/s13046-019-1110-6.
  23. Atallaha NM, Wahabc N, Tossa MS, Minhasc F, Rajpootc MN, Emad Rakhaa E. Deciphering the Morphology of Tumor-Stromal Features in Invasive Breast Cancer Using Artificial Intelligence. Modern Pathology. 2023;36:10100254. https:// www.modernpathology.org/article/S0893-3952(23)00159-X/fulltext.
  24. Xi G, Guo W, Kang D, Ma J, Fu F, Qiu L, Zheng L, He J, Fang N, Chen J, Li J, Zhuo Sh, Liao X, Tu H, Li L, Zhang Q, Wang Ch, Boppart SA, Chen J. Large-scale tumor-associated collagen signatures identify high-risk breast cancer patients. Theranostics. 2021;11(7):3229–43. doi: 10.7150/ thno.55921.
  25. Provenzano PP, Eliceiri KW, Campbell JM, Inman DR, White JG, Keely PJ. Collagen reorganization at the tumor-stromal interface facilitates local invasion. BMC Med. 2006;4(1):38. doi: 10.1186/1741-7015-4-38.
  26. Liu Yu, Xu Sh, Kang D, Huang X, Xu Sh, Li L, Zheng L, Qiu L , Zhan Z, Han X, Chen J. Guest Editors: Ding Z, Liu Z. Quantitative analysis of collagen morphology in breast cancer from millimeter scale using multiphoton microscopy. Journal of Innovative Optical Health Sciences. 2023;16(4):2243003. doi: 10.1142/S1793545822430039.
  27. Fan Yi, Chiu A, Zhao F, George JT. Understanding the interplay between extracellular matrix topology and tumor-immune interactions: Challenges and opportunities. Oncotarget. 2024;15:768-81. doi: 10.18632/oncotarget.28666.
  28. Xi G, Qiu L, Xu Sh, Guo W, Fu F, Kang D, Zheng L, He Ji, Zhang Q, Li L, Wang Ch, Chen J. Computer-assisted quantification of tumor-associated collagen signatures to improve the prognosis prediction of breast cancer. BMC Med. 2021;19:273. doi: 10.1186/s12916-021-02146-7.
  29. Ghannam SF, Rutland CS, Allegrucci C, Mather ML, Alsaleem M, Bateman-Price TD, Patke R, Ball G, Mongan NP, Rakha E. Geometric characteristics of stromal collagen fibres in breast cancer using differential interference contrast microscopy. Journal of Microscopy. 2025;297(2):135-52. doi: 10.1111/jmi.13361.
  30. Pavlova IP, Nair SS, Lundon D, Sobotka S, Roshandel R, Treacy P-J, Ratnani P, Brody R, Epstein JI, Ayala GE, Kyprianou N, Tewari AK. Multiphoton Microscopy for Identifying Collagen Signatures Associated with Biochemical Recurrence in Prostate Cancer Patients. J Pers Med. 2021;11(11):1061. doi: 10.3390/jpm11111061.
  31. Shah RB. Current perspectives on the Gleason grading of prostate cancer. Arch Pathol Lab Med. 2009;133(11):1810-6. doi: 10.5858/ 133.11.1810.
  32. Epstein JI, Egevad L, Amin MB, et al. The 2014 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma: Definition of Grading Patterns and Proposal for a New Grading System. The American Journal of Surgical Pathology. 2016;40(2):244-52. doi: 10.1097/pas.0000000000000530.

Downloads

Published

2025-07-30

How to Cite

Naleskina , L., Lukianova , N., Zadvornyi , T., Kunska , L., & Chekhun , V. (2025). The collagen-containing connective tissue component of breast and prostate cancer as a key determinant of the risk of metastatic progression. Морфологія / Morphologia / Morfologìâ, 19(2), 37–46. https://doi.org/10.26641/1997-9665.2025.2.37-46

Issue

Vol. 19 No. 2 (2025)

Section

Статті

License

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

 The authors reserve the right to authorship of their work and transfer to the Journal the right to the first publication of this work under the terms of a license Creative commons Attribution 4.0 International (CC BY 4.0), which allows other people to freely distribute the published work with a mandatory reference to the authors of the original work and the first publication of the work in this journal.
        By submitting a manuscript to the editorial office of the Journal ‘Morphologia’ authors agree to transfer the rights to protect and use the manuscript (all supplemental materials, particularly protected objects such as photos, drawings, diagrams, tables, etc.), including the reproduction in the press and distribution via the Internet; translation of the manuscript into any language; export and import of journal copies with the Authors’ article in order to make it available for public. Authors convey the rights mentioned above to the editorial office without any temporal or territorial limitation all over the world. 
        The Authors guarantee that they have the exclusive rights to use the material transferred to editorial office. Editors are not responsible to third parties for contraventions of warranty given by the Authors. The considered rights are transferred to the editorial office since the moment when the current issue is signed for publishing. Reproduction of materials published in the Journal by other individuals and legal entities is possible only with the consent of Editorial office, with the obligatory indication of the full bibliographic reference of the primary publication. The Authors reserve the right to use the published material, its fragments and parts for teaching materials, oral presentations, dissertation thesis prepararion with obligatory bibliographic citation of the original paper. Electron copy of the published article, downloaded from official journal web-site in .pdf format may be put by authors on the official web-site of their institutions, any other official resources with open access.