Key Matrix Remodeling Enzymes: Functions and Targeting in Cancer

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2021 Apr 3

PMID 33809973

Citations 36

Authors

Zoi Piperigkou

Konstantina Kyriakopoulou

Christos Koutsakis

Stylianos Mastronikolis

Nikos K Karamanos

Affiliations

Soon will be listed here.

Abstract

Tissue functionality and integrity demand continuous changes in distribution of major components in the extracellular matrices (ECMs) under normal conditions aiming tissue homeostasis. Major matrix degrading proteolytic enzymes are matrix metalloproteinases (MMPs), plasminogen activators, atypical proteases such as intracellular cathepsins and glycolytic enzymes including heparanase and hyaluronidases. Matrix proteases evoke epithelial-to-mesenchymal transition (EMT) and regulate ECM turnover under normal procedures as well as cancer cell phenotype, motility, invasion, autophagy, angiogenesis and exosome formation through vital signaling cascades. ECM remodeling is also achieved by glycolytic enzymes that are essential for cancer cell survival, proliferation and tumor progression. In this article, the types of major matrix remodeling enzymes, their effects in cancer initiation, propagation and progression as well as their pharmacological targeting and ongoing clinical trials are presented and critically discussed.

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References

Zhu L, Kate P, Torchilin V . Matrix metalloprotease 2-responsive multifunctional liposomal nanocarrier for enhanced tumor targeting. ACS Nano. 2012; 6(4):3491-8. PMC: 3337349. DOI: 10.1021/nn300524f. View

Karamanos N, Theocharis A, Neill T, Iozzo R . Matrix modeling and remodeling: A biological interplay regulating tissue homeostasis and diseases. Matrix Biol. 2018; 75-76:1-11. PMC: 6377817. DOI: 10.1016/j.matbio.2018.08.007. View

Jaiswal R, Varshney A, Yadava P . Diversity and functional evolution of the plasminogen activator system. Biomed Pharmacother. 2018; 98:886-898. DOI: 10.1016/j.biopha.2018.01.029. View

Waster P, Orfanidis K, Eriksson I, Rosdahl I, Seifert O, Ollinger K . UV radiation promotes melanoma dissemination mediated by the sequential reaction axis of cathepsins-TGF-β1-FAP-α. Br J Cancer. 2017; 117(4):535-544. PMC: 5558678. DOI: 10.1038/bjc.2017.182. View

Hudson N . Biophysical Mechanisms Mediating Fibrin Fiber Lysis. Biomed Res Int. 2017; 2017:2748340. PMC: 5467299. DOI: 10.1155/2017/2748340. View

Jenkins G, Seiffert D, Parmer R, Miles L . Regulation of plasminogen gene expression by interleukin-6. Blood. 1997; 89(7):2394-403. View

Dai X, Yan J, Fu X, Pan Q, Sun D, Xu Y . Aspirin Inhibits Cancer Metastasis and Angiogenesis via Targeting Heparanase. Clin Cancer Res. 2017; 23(20):6267-6278. DOI: 10.1158/1078-0432.CCR-17-0242. View

Ahn S, Mohamedali A, Pascovici D, Adhikari S, Sharma S, Nice E . Proteomics Reveals Cell-Surface Urokinase Plasminogen Activator Receptor Expression Impacts Most Hallmarks of Cancer. Proteomics. 2019; 19(21-22):e1900026. DOI: 10.1002/pmic.201900026. View

OReilly E, Roach J, Miller P, Yu K, Tjan C, Rosano M . Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of Necuparanib Combined with Nab-Paclitaxel and Gemcitabine in Patients with Metastatic Pancreatic Cancer: Phase I Results. Oncologist. 2017; 22(12):1429-e139. PMC: 5728039. DOI: 10.1634/theoncologist.2017-0472. View

10.

Thompson C, Purushothaman A, Ramani V, Vlodavsky I, Sanderson R . Heparanase regulates secretion, composition, and function of tumor cell-derived exosomes. J Biol Chem. 2013; 288(14):10093-10099. PMC: 3617250. DOI: 10.1074/jbc.C112.444562. View

11.

Farina A, Mackay A . Gelatinase B/MMP-9 in Tumour Pathogenesis and Progression. Cancers (Basel). 2014; 6(1):240-96. PMC: 3980597. DOI: 10.3390/cancers6010240. View

12.

Piperigkou Z, Karamanou K, Afratis N, Bouris P, Gialeli C, Belmiro C . Biochemical and toxicological evaluation of nano-heparins in cell functional properties, proteasome activation and expression of key matrix molecules. Toxicol Lett. 2015; 240(1):32-42. DOI: 10.1016/j.toxlet.2015.10.005. View

13.

Boyd D, Kim S, Wang H, Jones T, Gallick G . A urokinase-derived peptide (A6) increases survival of mice bearing orthotopically grown prostate cancer and reduces lymph node metastasis. Am J Pathol. 2003; 162(2):619-26. PMC: 1851141. DOI: 10.1016/S0002-9440(10)63855-2. View

14.

Li Y, He J, Wang F, Wang X, Yang F, Zhao C . Role of MMP-9 in epithelial-mesenchymal transition of thyroid cancer. World J Surg Oncol. 2020; 18(1):181. PMC: 7376963. DOI: 10.1186/s12957-020-01958-w. View

15.

Ramani V, Vlodavsky I, Ng M, Zhang Y, Barbieri P, Noseda A . Chemotherapy induces expression and release of heparanase leading to changes associated with an aggressive tumor phenotype. Matrix Biol. 2016; 55:22-34. PMC: 5033659. DOI: 10.1016/j.matbio.2016.03.006. View

16.

Csoka A, Frost G, Stern R . The six hyaluronidase-like genes in the human and mouse genomes. Matrix Biol. 2001; 20(8):499-508. DOI: 10.1016/s0945-053x(01)00172-x. View

17.

Quiros R, Rao G, Plate J, Harris J, Brunn G, Platt J . Elevated serum heparanase-1 levels in patients with pancreatic carcinoma are associated with poor survival. Cancer. 2006; 106(3):532-40. DOI: 10.1002/cncr.21648. View

18.

Lokeshwar V, Cerwinka W, Isoyama T, Lokeshwar B . HYAL1 hyaluronidase in prostate cancer: a tumor promoter and suppressor. Cancer Res. 2005; 65(17):7782-9. DOI: 10.1158/0008-5472.CAN-05-1022. View

19.

Theodoro T, Matos L, Cavalheiro R, Justo G, Nader H, Pinhal M . Crosstalk between tumor cells and lymphocytes modulates heparanase expression. J Transl Med. 2019; 17(1):103. PMC: 6439996. DOI: 10.1186/s12967-019-1853-z. View

20.

Stern R, Jedrzejas M . Hyaluronidases: their genomics, structures, and mechanisms of action. Chem Rev. 2006; 106(3):818-39. PMC: 2547145. DOI: 10.1021/cr050247k. View