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REVIEW ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 1  |  Page : 28-35

Seesaw of matrix metalloproteinases (MMPs)


1 Department of Oral Pathology and Microbiology, Bhojia Dental College, Baddi, Solan, India
2 Department of Prosthodontics and Implantology, Himachal Dental College, Sundernagar, Mandi, H.P, India
3 Department of Oral Pathology and Microbiology, Subharti Dental College, Meerut, U.P, India
4 Department of Oral Pathology and Microbiology, Manav Rachna Dental College, Faridabad, Haryana, India
5 Paradise Diagnostics, Delhi, India

Date of Web Publication13-Apr-2016

Correspondence Address:
Charu Kapoor
Department of Oral Pathology and Microbiology, Bhojia Dental College, Budd, Baddi, Solan, Himachal Pradesh - 176 001
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.157337

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 > Abstract 

The family of human matrix metalloproteinases (MMPs) comprises several tightly regulated classes of proteases. These enzymes and their specific inhibitors play important roles in tumor progression and the metastatic process by facilitating extracellular matrix (ECM) degradation. As scientific understanding of the MMPs has advanced, therapeutic strategies focusing on blocking these enzymes by MMP inhibitors (MMPIs) have rapidly developed. This paper reviews MMPs in detail. Their perspectives in therapeutic intervention in cancer are also mentioned.

Keywords: Disease, inflammation, matrix metalloproteinase inhibitors, tissue remodeling, wound healing


How to cite this article:
Kapoor C, Vaidya S, Wadhwan V, Hitesh, Kaur G, Pathak A. Seesaw of matrix metalloproteinases (MMPs). J Can Res Ther 2016;12:28-35

How to cite this URL:
Kapoor C, Vaidya S, Wadhwan V, Hitesh, Kaur G, Pathak A. Seesaw of matrix metalloproteinases (MMPs). J Can Res Ther [serial online] 2016 [cited 2019 Nov 22];12:28-35. Available from: http://www.cancerjournal.net/text.asp?2016/12/1/28/157337




 > Introduction Top


The ability of cancer cells to invade other tissues and spread to distant organs is an often-fatal characteristic of malignant tumors. Proteolytic enzymes play a fundamental role in cancer progression providing an access for tumor cells to the vascular and lymphatic systems, which support tumor growth and constitute an escape route for further dissemination.[1],[2] The complexity of proteolytic systems operating in human tissues is impressive, as assessed by the finding that more than 500 genes encoding proteases or protease-like proteins are present in the human genome. However, among all the proteolytic enzymes potentially associated with tumor invasion, the members of the matrix metalloproteinase (MMP) family have reached an outstanding importance due to their ability to cleave virtually any component of the extracellular matrix (ECM) and basement membranes, thereby allowing cancer cells to penetrate and infiltrate the subjacent stromal matrix.[3],[4],[5],[6] MMPs are a major group of enzymes that regulate cell–matrix composition. The MMPs are zinc-dependent endopeptidases known for their ability to cleave one or several ECM constituents, as well as nonmatrix proteins. They comprise a large family of proteases that share common structural and functional elements and are products of different genes. Ample evidence exists on the role of MMPs in normal and pathological processes, including embryogenesis, wound healing, inflammation, arthritis, and cancer. The association of MMPs with cancer metastasis has raised considerable interest because they represent an attractive target for development of novel antimetastatic drugs aimed at inhibiting MMP activity. Therefore, understanding the structure and function of these key enzymes has significant implications for cancer therapeutics.[7],[8],[9] This paper aims to briefly summarize current knowledge about the structure, classification, and physiopathological role of MMPs in select nontumorous lesions, tumor invasion, and metastasis. The perspectives in therapeutic intervention in cancer are also mentioned.


 > Structure of MMP Top


MMPs are a large family of calcium-dependent zinc-containing endopeptidases, which are responsible for the tissue remodeling and degradation of the ECM, including collagens, elastins, gelatin, matrix glycoproteins, and proteoglycan. MMPs are usually minimally expressed in normal physiological conditions, and thus homeostasis is maintained. However, MMPs are regulated by hormones, growth factors, and cytokines, and are involved in ovarian functions. Endogenous MMP inhibitors (MMPIs) and tissue inhibitors of MMPs (TIMPs) strictly control these enzymes. Overexpression of MMPs results in an imbalance between the activity of MMPs and TIMPs that can lead to a variety of pathological disorders. The earliest descriptions of MMPs were in 1949 as depolymerizing enzymes which, it was proposed, could facilitate tumor growth by making connective tissue stroma, including that of small blood vessels, more fluid. About after 13 years, the first vertebrate MMP, collagenase, was isolated and characterized as the enzyme responsible for the resorption by tadpole tail. During the next 20 years, several mammalian enzymes were partially purified, but it was not until 1985 that the field really developed when structural homologies became apparent, allowing many new members to be identified through the techniques of molecular biology.[2],[3],[4],[5]

Most members of the MMP family are organized into three basic, distinctive, and well-conserved domains based on structural considerations [Figure 1]:[10]
Figure 1: (a) Basic domain structures of MMPs. The images for the propeptide region and the catalytic and hemopexin-like domains shown here are from crystallographic sources. The propeptide region is shown by the green ribbon, catalytic domain as a surface in pink, hinge region as a surface in white, and the hemopexin-like domain is represented by the ribbon drawn in yellow. (b) General Structure of MMP. MMP = Matrix metalloproteinase

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  • Catalytic domain (which incorporates II)
  • Amino terminal propeptide - necessary to maintain enzyme latency
  • Signal peptide - directs the secretion from the cell
  • Hemopexin-like domain at the carboxyl terminal - contributes to substrate substrate specificity and its interaction with endogenous inhibitors [Figure 2].[11]
Figure 2: Propeptide interaction with the catalytic domain through a conserved cysteine residue (c) and the Zn2+ ion in the catalytic pocket (the so-called cysteine switch)

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Structure

  • The propeptide consists of approximately 80–90 amino acids containing a cysteine residue, which interacts with the catalytic zinc atom via its side chain thiol group. A highly conserved sequence (.PRCGXPD.) is present in the propeptide. Removal of the propeptide by proteolysis results in zymogen activation, as all members of the MMP family are produced in a latent form
  • The catalytic domain contains two zinc ions and at least one calcium ion coordinated to various residues. One of the two zinc ions is present in the active site and is involved in the catalytic processes of the MMPs. The second zinc ion (also known as structural zinc) and the calcium ion are present in the catalytic domain approximately 12 Å away from the catalytic zinc. The catalytic zinc ion is essential for the proteolytic activity of MMPs; the three histidine residues that coordinate with the catalytic zinc are conserved among all the MMPs. Little is known about the roles of the second zinc ion and the calcium ion within the catalytic domain, but the MMPs are shown to possess high affinities for structural zinc and calcium ions [6],[7]
  • The hemopexin-like domain of MMPs is highly conserved and shows sequence similarity to the plasma protein, hemopexin. The hemopexin-like domain has been shown to play a functional role in substrate binding and/or in interactions with the TIMPs, a family of specific MMPIs.[8],[9] In addition to these basic domains, the family of MMPs evolved into different subgroups by incorporating and/or deleting structural and functional domains [Figure 3].[10],[11],[12]
Figure 3: Schematics of the domain structures of the 23 representative MMPs. Catalytic domain (represented by green) has an insertion of gelatin-binding domain in MMP-2 and 9. In all other MMPs, the catalytic domain is a continuous entity

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The catalytic activity of the MMPs is regulated at multiple levels including transcription, secretion, activation, and inhibition. The last is accomplished by members of the TIMP family, which presently includes four proteins: TIMP-1, 2, 3, and 4.[8],[13] Binding of the TIMPs to the catalytic domain results in efficient inhibition of enzymatic activity of MMPs.[10],[11]

The propeptide of the MMPs contains a “cysteine switch” motif, PRCGXPD, in which the cysteine residue interacts with the catalytic zinc domain to maintain inactivity by preventing a water molecule, essential for catalysis, from binding to the zinc atom until the propeptide has been removed by proteolysis.[14]

[TAG:2]Classification of MMPS [14],[15],[16],[17],[18][/TAG:2]

Metal-binding proteinases represent a relatively large and evergrowing group of enzymes.[5],[10],[15] authors have proposed dividing this class of MMPs into clans (based on similarity of protein fold) and families (based on evolutionary relationships).(10) Currently, the MMP class comprises eight clans and some 40 families. The MMP family is a continually growing group, now comprising more than 20 enzymes.[1],[10],[15],[16] There are two classification systems of the MMPs:

The availability of the complete human genome sequence has allowed defining the complete set of MMPs produced by human cells. Thus, recent genomic studies have revealed that there are 24 distinct genes encoding members of the MMP family (Puente et al., 2003). Analysis of the structural design of these enzymes has led to a new classification system based on MMP structures rather than on their substrate specificities [Figure 3].

  1. To date, at least 26 human MMPs are known. On the basis of substrate specificity and homology, MMPs can be divided into six groups [Table 1]:
    Table 1: Classification of MMPs based on structure of enzyme

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    1. Collagenases
    2. Gelatinases
    3. Stromelysins
    4. Matrilysins
    5. Membrane-type MMPs (MT-MMPs), that additionally contain a transmembrane and intracellular domain, a membrane linker domain, or are membrane associated
    6. Others: MMPs.[12],[13],[14],[15]


  2. The availability of the complete human genome sequence has allowed defining the complete set of MMPs produced by human cells. Thus, recent genomic studies have revealed that there are 24 distinct genes encoding members of the MMP family. Analysis of the structural design of these enzymes has led to a new classification system based on MMP structures rather than on their substrate specificities. It includes [Figure 4]:[19],[20],[21],[22],[23],[24]
    Figure 4: Diversity of human MMPs. Structural classification of human MMPs based on their domain organization

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    1. Archetypal MMP: Composed of the three human collagenases (MMP-1, 8, and 13), the two stromelysins (MMP-3 and 10), and four additional MMPs with unique structural characteristics (MMP-12, 19, 20, and 27)
    2. Matrilysins (MMP-7and 26): Lacks the hemopexin domain
    3. Gelatinases (MMP-2 and 9) incorporate three fibronectin type II modules that provide a compact collagen binding domain
    4. MT-MMPs: Localized at the cell surface through a C-terminal transmembrane domain (MT1-, MT2-, MT3-, and MT5-MMP) or by a glycosylphosphatidylinositol anchor (MT4- and MT6-MMP). The MT-MMPs also have an additional insertion of basic residues between the propeptide and the catalytic domain, which is cleaved by furin-like serine proteases leading to the intracellular activation of the proenzymes
    5. Furin-like cleavage site: It is also present in three secreted MMPs (MMP-11, 21, and 28) that do not fit to any of the previous subgroups and in two unusual transmembrane MMPs (MMP-23A and 23B), which are anchored through an N-terminal segment and show identical amino acid sequence, despite being encoded by two distinct human genes.




[TAG:2]Seesaw of Mmps [13],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26][/TAG:2]

There is growing evidence, however, that the MMPs have a more expansive role, as they influence many biological pathways during developmental and physiological processes,[6],[10] are important for the creation and maintenance of a microenvironment facilitating growth and spreading of neoplasms.[5],[6],[9],[11],[12],[14] as well as contributing to nontumorous diseases such as cardiovascular disease. MMPs are produced by a variety of cell types, including epithelial cells, fibroblasts, and inflammatory cells.[3] The normal and pathological processes in which MMPs are implicated are listed in [Table 2].
Table 2: Normal and pathological processes in which MMPs are implicated (modified according to Parks and Mechan): Role in diseases

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MMPs in inflammation, immune response, and healing

MMPs are shown to act as regulatory enzymes in both anti- and proinflammatory pathways. MMPs are involved during immune responses activation such mitogen activated protein kinase (MAPK) signaling and nuclear factor-KB (NF-KB)signaling activation [Figure 5].
Figure 5: MMPs as modulators of inflammation and innate immunity

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MMPs and angiogenesis

Angiogenesis is a complex process by which new blood vessels are formed from existing vessels; it involves multiple interactions between endothelial cells, surrounding pericytes, smooth muscle cells, ECM, and angiogenic cytokines/growth factors.

MMPs contribute to angiogenesis not only by degrading basement membrane and other ECM components, allowing endothelial cells to detach and migrate into new tissue, but also by releasing ECM-bound proangiogenic factors (basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and transforming growth factor (TGF)). In addition, MMP degradation of ECM components generates fragments with now-accessible integrin binding sites, triggering integrin intracellular signaling [Figure 6].
Figure 6: Role of MMPs in angiogenesis: Angiogenic factors such as VEGF and bFGF (colored triangles) secreted by inflammatory or tumor cells bind to their respective receptors (Y-shaped receptors) on the surface of endothelial cells. This activates the endothelial cells to secrete MMPs, to change their expression of integrins (T-shaped receptors), and to undergo proliferation. bFGF = Basic fibroblast growth factor (bFGF) and VEGF = Vascular endothelial growth factor

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MMPs and cancer

The expression and activity of MMPs are increased in almost every type of human cancer; and this correlates with advanced tumor stage, increased invasion and metastasis, and shortened survival. Early expression of MMPs, either by the tumor cells themselves or by surrounding stromal cells, helps to remodel the ECM and release ECM and/or membrane-bound growth factors, which provides a favorable microenvironment for the establishment of the primary tumor [Figure 7].
Figure 7: Role of MMPs in cancer. MMPs contribute to the establishment of a conducive microenvironment for primary tumor growth, in tumor angiogenesis, and in the ability of tumor cells to migrate and invade into the surrounding stroma; in the breakdown of blood vessel basement membranes, which allows tumor cells entry into the circulation (intravasation) and exit from the circulation (extravasation); and in the modification of the distant site microenvironment, which allows growth of tumor cells by facilitating angiogenesis to the metastatic site

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Also there are increasing evidence suggesting that MMPs regulate tumor growth by favoring the release of cell proliferating factors such as insulin-like growth factor (IGF) which binds to specific-binding protein. MMPs activities have also been traditionally associated with variety of escaping mechanism that cancer cell develop to avoid host immune response. MMPs degrade components of ECM, facilitating angiogenesis, tumor cell invasion, and metastasis. MMPs modulate the interactions between tumor cells by cleaving E-cadherin, and between tumor cells and ECM by processing integrins, which also enhances the invasiveness of tumor cells. MMPs also process and activate signaling molecules, including growth factors and cytokines, making these factors more accessible to target cells by either liberating them from the ECM (e. g., VEGF and bFGF) and inhibitory complexes (e. g. TGF), or by shedding them from cell surface (e. g., heparin-binding epidermal growth factor) [Figure 8] and [Table 3].
Figure 8: Role of MMPs in regulation of cell adhesion and migration

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Table 3: Role of MMPs in cancer: Dysplasia, cancer and metastasis

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MMPs in oral mucosal lesions

The role of MMPs has been investigated in a number of skin conditions that can also involve the mucosal surfaces like: Lichen planus (LP), discoid lupus erythematosus (DLE), psoriasis, pemphigus, and phemgoid. Various studies have shown that MMPs mediate the inflammatory response and induce dermal destruction [Table 4].
Table 4: Role of MMPs in mucocutaneous lesions

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[TAG:2]MMPS as Therapeutic Targets [18],[19],[20],[21],[22],[23][/TAG:2]

Given the important roles that MMPs play in tumor growth, metastasis, and the dysregulated angiogenesis that drives them; there has been significant attention paid to the development of clinically useful antagonists of this enzyme family. There are a number of MMPIs that are currently being tested against a variety of human.

The promise of this therapeutic approach has yet to be realized and the academic, pharmaceutical, and biotechnology arenas continue to debate the potential issues underlying the lack of therapeutic success in cancer treatment. Although certainly not in the majority, there have been some promising results from some clinical trials.


 > Conclusion Top


MMPs are also considered to be promising targets for cancer therapy due to their strong involvement in malignant pathologies. On this point, the role of the pathologist in evaluation of the expression of MMPs and TIMPs within tumors alone is indisputable. A better understanding of the expression and pathobiology of MMPs and their inhibitors in individual malignant tumors may help to change current cancer therapy towards more specific and patient-friendly approaches.

 
 > References Top

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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