Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs

Figures & data

Figure 1. Typical MMP structure.

Table 1. Classification of the main members of MMP family with their biological effect, chromosomal location and the group of substrates6,11,12.

Traditional classification (common name)	Numerical classification	Biological effect	Chromosomal location	Group of substrates for enzymes
MMP classification
Collagenases
Collagenase-1	MMP-1	The migration of keratinocytes, reepithelialization, cell migration, platelet aggregation, increase in the bioavailability of IGF-1, cell proliferation, pro-inflammatory effect, and PARP1 activation; in cancer progression – proteolytic activity, degrade physical barriers	11q22-q23	Collagen (I, II, III, VII, VIII, X), casein, entactin, laminin, pro-MMP-1, -2, -9, and serpins
Collagenase-2	MMP-8	The activation of osteoclasts, the enhancement of collagen affinity, β-FGF release, anti-inflammatory activity; in cancer progression – cleavage of α- and β-chemokines and regulation of their mobilization	11q21-q22	Collagen (I–III, V, VII, VIII, X), gelatin, aggrecan, fibronectin
Collagenase-3	MMP-13	In cancer progression- induction of EMT; cell migration	11q22.3
Gelatinases
Gelatinase A	MMP-2	The growth of axons, cell migration, the differentiation of mesenchymal cell with inflammation phenotype, enhancement of collagen affinity, cell proliferation, migration of epithelial cells, anti-inflammatory, an increase in the bioavailability of TGF-β, neuronal apoptosis leading to neurodegeneration; in cancer progression – cleavage of IGF-1 binding proteins, proliferation	16q13	Gelatin, collagen (IV–VI, X), elastin, fibronectin
Gelatinase B	MMP-9	Collagen affinity enhancing, pro-inflammatory and anti-inflammatory activity, tumor cell resistance, IL-2 response reduction, hypertrophic chondrocyte apoptosis and the subsequent incorporation of new units of functional osteoblasts; in cancer progression–activation of TGF-β	20q11.2-q13.1	Gelatin, collagens (IV, V, VII, X, XIV), elastin, fibrillin, osteonectin
Stromelysins
Stromelysin-1	MMP-3	Migration of cells, epithelial cells apoptosis, the formation of epithelial bubbles, epithelial–mesenchymal conversion, angiostatin-like elements generation, the collagen affinity enhancement, release of bFGF, increase in the bioavailability of IGF-1, cell proliferation, pro-inflammatory and anti-inflammatory activity, increase the bioavailability of TGF-β, disorder in cells aggregation, increase in cell invasiveness; in cancer progression–degradation of COL-IV, perlecan; release of VEGF and bFGF, upregulation of angiogenesis	11q23	Laminin, aggregan, gelatin, fibronectin
Stromelysin-2	MMP-10	In cancer progression–degradation of COL-IV, COL-XVIII, perlecan; generation of tumstatin, endostatin, angiostatin, and endorepellin	11q22.3-q23	Collagens (III–V), gelatin, casein, aggregan, elastin, MMP-1,8
Stromelysin-3	MMP-11	In cancer progression – release of α1-proteinase inhibitor, decrease cancer cell sensitivity to NK cells	22q11.2	Fibronectin, laminin, aggregan, gelatin
Matrilysin	MMP-7	Adipocyte differentiation, collagen affinity enhancement, an increase in the bioavailability of IGF 1 and TGF-β, cell differentiation, abnormal cell aggregation and increase in cells invasiveness, apoptosis induced by Fas receptor activation, the effect of pro-inflammatory activation of osteoclasts, vasoconstriction and cell growth	11q21-q22	Collagen (IV–X), fibronectin, laminin, gelatin, aggregan, pro-MMP-9
Metalloelastase	MMP-12		11q22.2-q22.3	Elastin, gelatin, collagen I, IV, fibronectin, laminin, vitronectin, proteoglycan
Matrilysin-2	MMP-26		11p15	Gelatin, collagen IV, pro-MMP-9
Membrane-type MMPs (MT-MMP)
MT-MMP-1	MMP-14	Anti-inflammatory, cell migration, the formation of renal tubules, epithelial cell migration, adhesion reduction, flattening of the cells reduction, trailers embryo to the uterine epithelium	14q11-q12	Collagen (I, II, III), gelatin, fibronectin, laminin aggrecan, tenascin
MT-MMP-2	MMP-15	Adhesion and cell flattering reduction	15q13-q21	Fibronectin, laminin, aggrecan, perlecan
MT-MMP-3	MMP-16	Adhesion and cell flattering reduction	8q21	Collagen III, gelatin, casein
MT-MMP-4	MMP-17		12q24.3	Fibrinogen, TNF precursor
MT-MMP-5	MMP-24		20q11.2	Proteoglycans

Figure 2. Chemical structure of Batimastat (A) [according to⁴⁵], Marimastat (B) [according to⁴⁵], Prinomastat (C) [according to⁴⁶], Tanomastat (D) [according to⁴⁷], MMI 270B (E) [according to⁴⁸], Metastat (F) [according to⁴⁸], Minocycline (G) [according to⁴⁸], Doxycycline (H) [according to⁴⁸].

Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 2006;69:562–73.

 PubMed Web of Science ®Google Scholar

Gialeli C, Theocharis AD, Karamanos NK. Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. FEBS J 2011;278:16–27.

 PubMed Web of Science ®Google Scholar

Rogowicz A, Zozulińska D, Wierusz-Wysocka B. The role of matrix metalloproteinases in the development of vascular complications of diabetes mellitus–clinical implications. Pol Arch Med Wewn 2007;117:43–8.

 PubMedGoogle Scholar

Rasmussen HS, McCann PP. Matrix metalloproteinase inhibition as a novel anticancer strategy: a review with special focus on Batimastat and Marimastat. Pharmacol Ther 1997;75:69–75.

 PubMed Web of Science ®Google Scholar

Wang A, Stout D, Zhang Q, Johnson EF. Contributions of ionic interactions and protein dynamics to cytochrome P450 2D6 (CYP2D6) substrate and inhibitor binding. J Biol Chem 2015;290:5092–104.

 PubMed Web of Science ®Google Scholar

Fisher JF, Mobashery S. Recent advances in MMP inhibitor design. Cancer Metastasis Rev 2006;25:115–36.

 PubMed Web of Science ®Google Scholar

Vandenbroucke RE, Libert C. Is there new hope for therapeutic matrix metalloproteinase inhibition? Nat Rev Drug Discov 2014;13:904–27.

 PubMed Web of Science ®Google Scholar