COLLAGEN MATRIX REMODELLING AS A FACTOR of TUMOUR PROGRESSION AGGRESSIVENESS: THE ROLE OF PROTEASES AND CROSS-LINKING ENZYMES
DOI:
https://doi.org/10.15407/oncology.2026.02.097Keywords:
cancer, collagen, matrix metalloproteinases, cathepsins, meprins, LOX, PLODAbstract
Collagen matrix remodelling is one of the key processes determining the progression of malignant tumours and the development of an aggressive tumour phenotype. This review summarises current data on the role of collagen degradation and cross-linking enzymes in the progression of malignant tumours. It is shown that an imbalance between the processes of degradation and stabilisation of collagen fibres contributes to increased tissue stiffness and the activation of signalling pathways associated with invasion and metastasis. The review focuses on matrix metalloproteinases, cathepsins, meprins, lysyl oxidases and enzymes of the procollagen-lysine family, 2-Oxoglutarate 5-Dioxygenases (PLODs) as enzymes involved in extracellular matrix remodelling, regulation of the epithelial-mesenchymal transition, and the progression of malignant tumours. The results of recent studies demonstrating the link between abnormalities in the expression of collagen-modifying enzymes and the aggressiveness of the tumour process in patients with various types of cancer have been analysed.
References
Neophytou CM, Panagi M, Stylianopoulos T, Papageorgis P. The role of tumor microenvironment in cancer metastasis: molecular mechanisms and therapeutic opportunities. Cancers 2021; 13 (9):2053. https://doi.org/10.3390/cancers13092053.
Reeva H., Mahesh G., Manjunath U., et al. The crucial nexus: unveiling the role of collagen in cancer progression. Semin Oncol 2025; 52 (3): 152346. https://doi.org/10.1016/j.seminoncol.2025.152346.
Gurrala R, Byrne CE, Brown LM, et al. Quantifying breast cancer-driven fiber alignment and collagen deposition in primary human breast tissue. Front Bioeng Biotechnol 2021; 9: 618448. https://doi.org/10.3389/fbioe.2021.618448.
Kader A, Kaufmann JO, Mangarova DB, et al. Collagen-specific molecular magnetic resonance imaging of prostate Cancer. Int J Mol Sci 2022; 24 (1): 711. https://doi.org/10.3390/ijms24010711.
Rømer AMA, Thorseth ML, Madsen DH. Immune modulatory properties of collagen in cancer. Front Immunol 2021; 12: 791453. https://doi.org/10.3389/fimmu.2021.791453.
Fang M, Yuan J, Peng C, et al. Collagen as a double-edged sword in tumor progression. Tumor Biol 2014; 35: 2871–82. https://doi.org/10.1007/s13277-013-1511-7.
Yuan Z, Li Y, Zhang S, et al. Extracellular matrix remodeling in tumor progression and immune escape: from mechanisms to treatments. Mol Cancer 2023; 22 (1): 48. https://doi.org/10.1186/s12943-023-01744-8.
de Almeida LGN, Thode H, Eslambolchi Y, et al. Matrix metalloproteinases: from molecular mechanisms to physiology, pathophysiology, and pharmacology. Pharmacol Rev 2022; 74 (3): 712–68. https://doi.org/10.1124/pharmrev.121.000349.
Laronha H, Caldeira J. Structure and function of human matrix metalloproteinases. Cells 2020; 9 (5): 1076. https://doi.org/10.3390/cells9051076.
Manka SW, Carafoli F, Visse R, et al. Structural insights into triple-helical collagen cleavage by matrix metalloproteinase 1. PNAS 2012; 109 (31) 12461–6. https://doi.org/10.1073/pnas.1204991109.
Singh W, Fields GB, Christov CZ, Karabencheva-Christova TG. Importance of the linker region in matrix metalloproteinase-1 domain interactions. RSC Advances 2016; 6 (28): 23223–32. https://doi.org/10.1039/C6RA03033E.
Hornebeck W, Bellon G, Emonard H. Fibronectin type II (FnII)-like modules regulate gelatinase A activity. Pathologie-biologie 2005; 53 (7): 405–10. https://doi.org/10.1016/j.patbio.2004.12.015.
Trexler M, Briknarová K, Gehrmann M, et al. Peptide ligands for the fibronectin type II modules of matrix metalloproteinase 2 (MMP-2). J Biol Chem 2003; 278 (14): 12241–6. https://doi.org/10.1074/jbc.M210116200
Xu X, Wang Y, Lauer-Fields JL, et al. Contributions of the MMP-2 collagen binding domain to gelatin cleavage. Substrate binding via the collagen binding domain is required for hydrolysis of gelatin but not short peptides. Matrix biology 2004; 23 (3): 171–81. https://doi.org/10.1016/j.matbio.2004.05.002.
Van den Steen PE, Van Aelst I, Hvidberg V, et al. The hemopexin and O-glycosylated domains tune gelatinase B/MMP-9 bioavailability via inhibition and binding to cargo receptors. J Biol Chem 2006; 281 (27): 18626–37. https://doi.org/10.1074/jbc.M512308200.
Wu S, Zhou X, Jin Z. et al. Collagenases and their inhibitors: a review. Collagen Leather 2023; 5: 19. https://doi.org/10.1186/s42825-023-00126-6.
Pérez-García S, Carrión M, Gutiérrez-Cañas I, et al. Profile of matrix-remodeling proteinases in osteoarthritis: impact of fibronectin. Cells 2019; 9 (1): 40. https://doi.org/10.3390/cells9010040
Atanasova T, Stankova T, Bivolarska A, Vlaykova T. Matrix Metalloproteinases in oral health-special attention on MMP-8. Biomedicines 20023; 11 (6): 1514. https://doi.org/10.3390/biomedicines11061514.
Li S, Pritchard DM, Yu LG. Regulation and function of matrix metalloproteinase-13 in cancer progression and metastasis. Cancers 2022; 14 (13): 3263. https://doi.org/10.3390/cancers14133263.
Shoari A. Potential of MMP-2 and MMP-9 gelatinase blockade as a therapeutic strategy in fibrosarcoma treatment: a decadal review. Targets 2024; 2 (2): 104–25. https://doi.org/10.3390/targets2020007.
Wang Y, Zheng L, Zhang L, et al. Roles of MMP-2 and MMP-9 and their associated molecules in the pathogenesis of keloids: a comprehensive review. Front Pharmacol 2024; 15: 1444653. https://doi.org/10.3389/fphar.2024.1444653.
Wolosowicz M, Prokopiuk S, Kaminski TW. The complex role of matrix metalloproteinase-2 (MMP-2) in health and disease. Int J Mol Sci 2024; 25 (24): 13691. https://doi.org/10.3390/ijms252413691.
Wolosowicz M, Prokopiuk S, Kaminski TW. Matrix Metalloproteinase-9 (MMP-9) as a therapeutic target: insights into molecular pathways and clinical applications. Pharmaceutics 2025; 17 (11): 1425. https://doi.org/10.3390/pharmaceutics17111425.
Gorantla KR, Krishnan A, Waheed SO, et al. Novel insights into the catalytic mechanism of collagenolysis by Zn(II)-dependent matrix metalloproteinase-1. Biochemistry 2024; 63 (15): 1925–40. https://doi.org/10.1021/acs.biochem.4c00076.
Henke E, Nandigama R, Ergün S. Extracellular matrix in the tumor microenvironment and its impact on cancer therapy. Front Mol Biosci 2020; 6: 160. https://doi.org/10.3389/fmolb.2019.00160.
Mook OR, Frederiks WM, Van Noorden CJ. The role of gelatinases in colorectal cancer progression and metastasis. Biochim Biophys Acta – Rev Cancer 2004; 1705 (2): 69–89. https://doi.org/10.1016/j.bbcan.2004.09.006.
Ricard‐Blum S, Salza R. Matricryptins and matrikines: biologically active fragments of the extracellular matrix. Exp Dermatol 2014; 23 (7): 457–63. https://doi.org/10.1111/exd.12435.
Maquart FX, Pasco S, Ramont L, et al. An introduction to matrikines: extracellular matrix-derived peptides which regulate cell activity: implication in tumor invasion. Crit Rev Oncol Hematol 2004; 49 (3): 199–202.
Wells JM, Gaggar A, Blalock JE. MMP generated matrikines. Matrix Biol 2015; 44-46: 122–9. https://doi.org/10.1016/j.matbio.2015.01.016.
Gilles C, Newgreen DF, Sato H, Thompson EW. Matrix metalloproteases and epithelial-to-mesenchymal transition. Rise and Fall of Epithelial Phenotype 2005; 297–315. https://doi.org/10.1007/0-387-28671-3.
Quintero-Fabián S, Arreola R, Becerril-Villanueva E, et al. Role of matrix metalloproteinases in angiogenesis and cancer. Front Oncol 2019; 9: 1370. https://doi.org/10.3389/fonc.2019.01370.
Wang Q, Wang K, Tan X, et al. Immunomodulatory role of metalloproteases in cancers: Current progress and future trends. Front Immunol 2022; 13: 1064033. https://doi.org/10.3389/fimmu.2022.1064033.
Juurikka K, Butler GS, Salo T, et al. The role of MMP8 in cancer: a systematic review. Int J Mol Sci 2019; 20 (18): 4506. https://doi.org/10.3390/ijms20184506.
Zhao K, Sun Y, Zhong S, Luo JL. The multifaceted roles of cathepsins in immune and inflammatory responses: implications for cancer therapy, autoimmune diseases, and infectious diseases. Biomarker Res 2024; 12 (1): 165. https://doi.org/10.1186/s40364-024-00711-9.
Pečar Fonović U, Kos J, Mitrović A. Compensational role between cathepsins. Biochimie 2024; 226: 62–76. https://doi.org/10.1016/j.biochi.2024.04.010.
Yadati T, Houben T, Bitorina A, Shiri-Sverdlov R. The Ins and Outs of cathepsins: physiological function and role in disease management. Cells 2020; 9 (7); 1679. https://doi.org/10.3390/cells9071679.
Fujii Y, Asadi Z, Mehla K. Cathepsins: emerging targets in the tumor ecosystem to overcome cancers. Semin Cancer Biol 2025; 112: 150–66. https://doi.org/10.1016/j.semcancer.2025.04.001.
Senjor E, Kos J, Nanut MP. Cysteine cathepsins as therapeutic targets in immune regulation and immune disorders. Biomedicines 2023; 11 (2): 476. https://doi.org/10.3390/biomedicines11020476.
Petushkova AI, Savvateeva LV, Zamyatnin AA Structure determinants defining the specificity of papain-like cysteine proteases. Comput Struct Biotechnol J 2022; 20: 6552–69. https://doi.org/10.1016/j.csbj.2022.11.040.
Turk V, Stoka V, Vasiljeva O, et al. Cysteine cathepsins: from structure, function and regulation to new frontiers. Biochimica et biophysica acta 2012; 1824 (1): 68–88. https://doi.org/10.1016/j.bbapap.2011.10.002.
Novinec M, Lenarčič B, Turk B. Cysteine cathepsin activity regulation by glycosaminoglycans. Biomed Res Int 2014; 2014: 309718. https://doi.org/10.1155/2014/309718.
Fonović M, Turk B. Cysteine cathepsins and extracellular matrix degradation. Biochim Biophys Acta 2014; 1840 (8): 2560–70. https://doi.org/10.1016/j.bbagen.2014.03.017.
Gao H, Zhang Z, Deng J, Song Y. Cathepsin S: molecular mechanisms in inflammatory and immunological processes. Front Immunol 2025; 16: 1600206. https://doi.org/10.3389/fimmu.2025.1600206.
Lalmanach G, Saidi A, Bigot P, et al. Regulation of the proteolytic activity of cysteine cathepsins by oxidants. Int J Mol Sci 2020; 21 (6): 1944. https://doi.org/10.3390/ijms21061944.
Gondi CS, Rao JS. Cathepsin B as a cancer target. Expert Opin Ther Targets 2013, 17 (3): 281–291. https://doi.org/10.1517/14728222.2013.740461.
Tan GJ, Peng ZK, Lu JP, Tang FQ. Cathepsins mediate tumor metastasis. World J Biol Chem 2013; 4 (4): 91–101. https://doi.org/10.4331/wjbc.v4.i4.91.
Stoka V, Vasiljeva O, Nakanishi H, Turk V. The role of cysteine protease cathepsins B, H, C, and X/Z in neurodegenerative diseases and cancer. Int J Mol Sci 2023; 24 (21): 15613. https://doi.org/10.3390/ijms242115613.
Vidak E, Javoršek U, Vizovišek M, Turk B. Cysteine cathepsins and their extracellular roles: shaping the microenvironment. Cells 2019; 8 (3): 264. https://doi.org/10.3390/cells8030264.
Rot AE, Hrovatin M, Bokalj B, et al. Cysteine cathepsins: from diagnosis to targeted therapy of cancer. Biochimie 2024; 226: 10–28. https://doi.org/10.1016/j.biochi.2024.09.001.
Chen S, Dong H, Yang S, Guo H. Cathepsins in digestive cancers. Oncotarget 2017; 8 (25): 41690–700. https://doi.org/10.18632/oncotarget.16677.
Sudhan DR, Siemann DW. Cathepsin L inhibition by the small molecule KGP94 suppresses tumor microenvironment enhanced metastasis associated cell functions of prostate and breast cancer cells. Clin Exp Metastasis 2013, 30 (7): 891–902. https://doi.org/10.1007/s10585-013-9590-9.
Sui H, Shi C, Yan Z, Wu M. Overexpression of Cathepsin L is associated with chemoresistance and invasion of epithelial ovarian cancer. Oncotarget 2016; 7 (29): 45995–6001. https://doi.org/10.18632/oncotarget.10276.
Peng P, Chen JY, Zheng K, et al. Favorable prognostic impact of cathepsin H (CTSH) high expression in thyroid carcinoma. Int J Gen Med 2021; 14: 5287–99. https://doi.org/10.2147/IJGM.S327689.
Broder C, Becker-Pauly C. The metalloproteases meprin α and meprin β: unique enzymes in inflammation, neurodegeneration, cancer and fibrosis. Biochem J 2013; 450 (2): 253–64. https://doi.org/10.1042/BJ20121751.
Salo AM, Cox H, Farndon P, et al. A connective tissue disorder caused by mutations of the lysyl hydroxylase 3 gene. Am J Hum Genet. 2008; 83 (4): 495–503. https://doi.org/10.1016/j.ajhg.2008.09.004.
Cox TR, Bird D, Baker AM, et al. LOX-mediated collagen crosslinking is responsible for fibrosis-enhanced metastasis. Cancer Res 2013; 73 (6): 1721–32. https://doi.org/10.1158/0008-5472.CAN-12-2233.
Arnold P, Otte A, Becker-Pauly C. Meprin metalloproteases: Molecular regulation and function in inflammation and fibrosis. Biochim Biophys Acta - Mol Cell Res 2017; 1864 (11 Pt B): 2096–104. https://doi.org/10.1016/j.bbamcr.2017.05.011.
Bayly-Jones C, Lupton CJ, Fritz C, et al. Helical ultrastructure of the metalloprotease meprin α in complex with a small molecule inhibitor. Nat Commun 2022; 13 (1): 6178. https://doi.org/10.1038/s41467-022-33893-7.
Bond JS, Rojas K, Overhauser J, et al. The structural genes, MEP1A and MEP1B, for the alpha and beta subunits of the metalloendopeptidase meprin map to human chromosomes 6p and 18q, respectively. Genomics 1995; 25 (1): 300–3. https://doi.org/10.1016/0888-7543(95)80142-9.
Werny L, Colmorgen C, Becker-Pauly C. Regulation of meprin metalloproteases in mucosal homeostasis. Biochimica et biophysica acta. Mol Cell Res 2022, 1869 (1): 119158. https://doi.org/10.1016/j.bbamcr.2021.119158.
Rösmann S, Hahn D, Lottaz D, et al. Activation of human meprin-alpha in a cell culture model of colorectal cancer is triggered by the plasminogen-activating system. J Biol Chem 2002, 277 (43): 40650–8. https://doi.org/10.1074/jbc.M206203200.
Ohler A, Debela M, Wagner S, et al. Analyzing the protease web in skin: meprin metalloproteases are activated specifically by KLK4, 5 and 8 vice versa leading to processing of proKLK7 thereby triggering its activation. Biol Chem 2010; 391 (4): 455–60. https://doi.org/10.1515/BC.2010.023.
Jäckle F, Schmidt F, Wichert R, et al. Metalloprotease meprin β is activated by transmembrane serine protease matriptase-2 at the cell surface thereby enhancing APP shedding. Biochem J 2015; 470 (1): 91–103. https://doi.org/10.1042/BJ20141417.
Breig O, Yates M, Neaud V, et al. Metalloproteinase meprin α regulates migration and invasion of human hepatocarcinoma cells and is a mediator of the oncoprotein Reptin. Oncotarget 2017; 8 (5): 7839–51. https://doi.org/10.18632/oncotarget.13975.
Bedau T, Peters F, Prox J, et al. Ectodomain shedding of CD99 within highly conserved regions is mediated by the metalloprotease meprin β and promotes transendothelial cell migration. FASEB J 2017; 31 (3): 1226–37. https://doi.org/10.1096/fj.201601113R.
Minder P, Bayha E, Becker-Pauly C, Sterchi EE. Meprinα transactivates the epidermal growth factor receptor (EGFR) via ligand shedding, thereby enhancing colorectal cancer cell proliferation and migration. J Biol Chem 2012, 287 (42): 35201–11. https://doi.org/10.1074/jbc.M112.368910.
Schütte A, Hedrich J, Stöcker W, Becker-Pauly C. Let it flow: Morpholino knockdown in zebrafish embryos reveals a pro-angiogenic effect of the metalloprotease meprin alpha2. PloS One 2010; 5 (1): e8835. https://doi.org/10.1371/journal.pone.0008835.
Nasevicius A, Larson J, Ekker SC. Distinct requirements for zebrafish angiogenesis revealed by a VEGF-A morphant. Yeast (Chichester, England) 2020; 17 (4): 294–301. https://doi.org/10.1002/1097-0061(200012)17:4<294::AID-YEA54>3.0.CO;2-5.
Paolillo M, Schinelli S. Extracellular matrix alterations in metastatic processes. Int J Mol Sci
