MMPs: The Master Regulators of Cancer Invasion and Metastasis

Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, are capable of degrading almost all protein components of the extracellular matrix (ECM). MMPs play dual roles in both maintaining normal physiological functions and contributing to diseases. They are essential for tissue remodeling, wound healing, and ECM integrity in healthy conditions, but their dysregulation can lead to tissue damage and disease progression, such as MMP-2 and MMP-9 in cancer metastasis and MMP-3 in arthritis (1–3). MMPs have garnered attention as potential therapeutic targets for conditions like cancer, cardiovascular diseases, and inflammatory disorders (3–5). Researchers are exploring the application of MMPs in addressing health issues, including their benefits for diagnosis, prognosis, or treatment of various diseases. Although there is currently no FDA-approved specific drug for MMPs, ongoing preclinical and clinical studies seek to harness their promising therapeutic potential, with a focus on MMP-2 and MMP-9 inhibitors, offering hope for cancer patients with metastatic malignancies and arthritis treatments4, (6-11). Sino Biological is actively contributing to MMP research by providing a comprehensive range of recombinant MMP proteins and associated antibodies, including MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, MMP-10, MMP-12, MMP-19, and MMP-26. These products are invaluable in understanding MMPs' intricate roles in human health, advancing drug development, and improving disease treatment strategies.

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Physiological and Pathological Roles

MMPs serve dual roles in maintaining normal physiological functions and contributing to pathological conditions. In healthy conditions, MMPs are essential for tissue remodeling and growth, trauma repair, immune response, and maintaining the integrity of the ECM (3,9). However, in pathological settings, dysregulation of MMPs can lead to tissue damage and disease progression (2,12). In general, MMPs, especially MMP-2 and MMP-9, play a crucial role in tumor invasion and the building of metastatic formations because of their ability to degrade extracellular matrix proteins, highlighting their pivotal role in cancer disease progression6. Overexpression of different types of MMPs has been demonstrated in various cancers, such as breast, lung, and liver cancers (Table 1), and the overexpression degree of some MMPs has been noted to correlate with the stage of disease and prognosis (3,14,15). Similarly, other MMPs like MMP-1, MMP-3, and MMP-13 are linked to cartilage degradation in arthritis, underlining their significance in inflammatory conditions (4,13). In addition, MMPs are involved in atherosclerosis and plaque rupture and are associated with the progression of cardiovascular diseases such as myocardial infarction and heart failure (3).

From Bench to Bedside

MMPs have garnered significant attention as potential therapeutic targets for a range of diseases. MMP-2 and MMP-9, for instance, are well-known participants in the progression of cancer, specifically in facilitating metastasis and invasion (6,16,17). These proteases have been identified as key factors in the ECM degradation associated with various malignancies, making them promising targets for anti-cancer drug development (17,18). Additionally, MMPs are implicated in cardiovascular diseases, with research focusing on interventions to modulate their activity to prevent or treat conditions like atherosclerosis and aneurysms (2,16). Inflammatory disorders, such as rheumatoid arthritis, are also under the MMP research, as these enzymes play a critical role in tissue destruction and inflammation (4,15,19).

Despite the potential therapeutic promise of targeting MMPs, there’s currently no FDA-approved drug to specifically target MMPs. The journey from bench to bedside is ongoing, with promising research exploring the therapeutic potential of MMPs. MMP inhibitors targeting various diseases are advancing rapidly. MMP-2 and MMP-9, in particular, are the most extensively researched MMPs of ongoing clinical trials aimed at treating cancer, offering hope for patients with metastatic malignancies (5,17,20). Furthermore, research into MMP-3 is paving the way for potential treatments for arthritis and joint-related disorders (13), while other MMPs are also under investigation for their roles in inflammatory conditions and cancer development (14). Clinical trials targeting almost all MMPs are related to cancer treatment. Additionally, targeting MMP-1, MMP-3, MMP-8, and MMP-12 is prominently focused on addressing autoimmune diseases. MMP-2, MMP-9, MMP-12, and MMP-13 have been closely associated with clinical trials concentrated on cardiovascular conditions. Targeting MMP-7, MMP-9, and MMP-12 has spurred the initiation of numerous clinical inquiries related to fibrosis and asthma (Table 2).

Application in Research

Extensive research has explored MMPs' role in various human health problems, including cancer, arthritis, and cardiovascular disease. For instance, Trang et al. developed a generalizable method for masking antibody binding domains using a heterodimeric coiled-coil domain, which is selectively activated by tumor-associated proteases MMP-2 and MMP-9. They confirmed that cleaving the mask restored antibody binding for CC2B-hBU12 when incubated with human MMP-2 (Cat#: 10082-HNAH, Sino Biological), enhancing the specificity and efficacy of cancer therapy with the minimal cytokine release and improved antibody circulation (21). Using gelatin zymography, Li et al. observed that the MMP-9 (Cat#: 10327-HNAH, Sino Biological) activity in cerebral arteries was induced by treatment with feces from unruptured intracranial aneurysm (UIA) patients compared with treatment with control feces, which is related to inflammatory process in cerebral arteries (22). Lei et al. introduced a new FRET-peptide microarray method to profile MMP activities in clinical thyroid tissue samples from PTC and TN patients. They found that the relative fluorescence recoveries were directly related to the logarithm of MMP-2 (Cat#: 10082-HNAH, Sino Biological), MMP-3 (Cat#: 10467-HNAE, Sino Biological), and MMP-9 (Cat#: 10327-HNAH, Sino Biological) concentrations (23). By using purified recombinant human MMP-8 (Cat#: 10254-HNAH, Sino Biological) as positive control, Lee et al. established diagnosis models for periodontitis using protein biomarkers (19). Saddiqi et al. demonstrated that recombinant MMP-9 (Cat#: 80049-R08H, Sino Biological) inhibits SDF-1/CXCR4 signaling in diabetic nephropathy, reinforcing the idea that MMP-9 plays a significant role in this condition (24).

References

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2. Wang, X. & Khalil, R. A. Matrix Metalloproteinases, Vascular Remodeling, and Vascular Disease. in Advances in Pharmacology vol. 81 241–330 (Academic Press Inc., 2018).

3. Mustafa, S., Koran, S. & AlOmair, L. Insights Into the Role of Matrix Metalloproteinases in Cancer and its Various Therapeutic Aspects: A Review. Frontiers in Molecular Biosciences vol. 9 Preprint at https://doi.org/10.3389/fmolb.2022.896099 (2022).

4. Li, R. L. et al. Targeting matrix metalloproteases: A promising strategy for herbal medicines to treat rheumatoid arthritis. Frontiers in Immunology vol. 13 Preprint at https://doi.org/10.3389/fimmu.2022.1046810 (2022).

5. Tseng, Y. T., Chen, M., John, J. S. & Ekberg, J. Targeting Matrix Metalloproteinases: A Potential Strategy for Improving Cell Transplantation for Nervous System Repair. Cell Transplantation vol. 30 Preprint at https://doi.org/10.1177/09636897211012909 (2021).

6. Jiang, H. & Li, H. Prognostic values of tumoral MMP2 and MMP9 overexpression in breast cancer: a systematic review and meta-analysis. BMC Cancer 21, (2021).

7. Shay, G., Lynch, C. C. & Fingleton, B. Moving targets: Emerging roles for MMPs in cancer progression and metastasis. Matrix Biology vols 44–46 200–206 Preprint at https://doi.org/10.1016/j.matbio.2015.01.019 (2015).

8. K?hrmann, A., Kammerer, U., Kapp, M., Dietl, J. & Anacker, J. Expression of matrix metalloproteinases (MMPs) in primary human breast cancer and breast cancer cell lines: New findings and review of the literature. BMC Cancer 9, (2009).

9. de Almeida, L. G. N. et al. Matrix Metalloproteinases: From Molecular Mechanisms to Physiology, Pathophysiology, and PharmacologyS. Pharmacological Reviews vol. 74 712–768 Preprint at https://doi.org/10.1124/pharmrev.121.000349 (2022).

10. Cabral-Pacheco, G. A. et al. The roles of matrix metalloproteinases and their inhibitors in human diseases. International journal of molecular sciences, 21, 9739 (2020).

11. Garza-Veloz, I., Cabral-Pacheco, G. A. & Martinez-Fierro, M. L. Matrix Metalloproteinases and Their Inhibitors Subjects: Biochemistry & Molecular Biology.

12. Niland, S., Riscanevo, A. X. & Eble, J. A. Matrix metalloproteinases shape the tumor microenvironment in cancer progression. International Journal of Molecular Sciences vol. 23 Preprint at https://doi.org/10.3390/ijms23010146 (2022).

13. Shi, B., Guo, X., Iv, A., Zhang, Z. & Shi, X. Polymorphism of MMP-3 gene and imbalance expression of MMP-3 / TIMP-1 in articular cartilage are associated with an endemic osteochondropathy, Kashin- Beck disease. BMC Musculoskelet Disord 23, (2022).

14. Xiao, Y. et al. Matrix metalloproteinase 7 contributes to intestinal barrier dysfunction by degrading tight junction protein Claudin-7. Front Immunol 13, (2022).

15. He, L. et al. The immunomodulatory role of matrix metalloproteinases in colitis-associated cancer. Frontiers in Immunology vol. 13 Preprint at https://doi.org/10.3389/fimmu.2022.1093990 (2023).

16. Bharadwaj, S., Sahoo, A. K. & Yadava, U. Editorial: Advances in the therapeutic targeting of human matrix metalloproteinases in health and disease. Frontiers in Molecular Biosciences vol. 10 Preprint at https://doi.org/10.3389/fmolb.2023.1150474 (2023).

17. Levin, M., Udi, Y., Solomonov, I. & Sagi, I. Next generation matrix metalloproteinase inhibitors — Novel strategies bring new prospects. Biochimica et Biophysica Acta - Molecular Cell Research vol. 1864 1927–1939 Preprint at https://doi.org/10.1016/j.bbamcr.2017.06.009 (2017).

18. Winer, A., Adams, S. & Mignatti, P. Matrix metalloproteinase inhibitors in cancer therapy: Turning past failures into future successes. Molecular Cancer Therapeutics vol. 17 1147–1155 Preprint at https://doi.org/10.1158/1535-7163.MCT-17-0646 (2018).

19. Lee, J. et al. Diagnostic models for screening of periodontitis with inflammatory mediators and microbial profiles in Saliva. Diagnostics 10, (2020).

20. Liu, M. et al. Identification of the MMP family as therapeutic targets and prognostic biomarkers in the microenvironment of head and neck squamous cell carcinoma. J Transl Med 21, (2023).

21. Trang, V. H. et al. A coiled-coil masking domain for selective activation of therapeutic antibodies. Nat Biotechnol 37, 761–765 (2019).

22. Li, H. et al. Alterations of gut microbiota contribute to the progression of unruptured intracranial aneurysms. Nat Commun 11, 3218 (2020).

23. Lei, Z., Zhang, H., Wang, Y., Meng, X., & Wang, Z. Peptide microarray-based metal enhanced fluorescence assay for multiple profiling of matrix metalloproteinases activities. Analytical Chemistry, 89, 6749-6757 (2017).

24. Siddiqi, F. S. et al. CXCR4 promotes renal tubular cell survival in male diabetic rats: Implications for ligand inactivation in the human kidney. Endocrinology (United States) 156, 1121–1132 (2015).