Matrix metalloproteinases in oral cancer: A catabolic activity on extracellular matrix components

Vidya G Doddawad; S Shivananda; HL Kalabharathi; Aditya Shetty; S Sowmya; HK Sowmya

doi:10.4103/bbrj.bbrj_10_23

REVIEW ARTICLE

Year : 2023 | Volume : 7 | Issue : 1 | Page : 17-23

Matrix metalloproteinases in oral cancer: A catabolic activity on extracellular matrix components

Vidya G Doddawad¹, S Shivananda², HL Kalabharathi³, Aditya Shetty⁴, S Sowmya⁵, HK Sowmya⁶
¹ Department of Oral Pathology and Microbiology, JSS Dental College and Hospital, JSS Academy of Higher Education and Research, Mysore, Karnataka, India
² Department of Oral and Maxillofacial Surgery, JSS Dental College and Hospital, JSS Academy of Higher Education and Research, Mysore, Karnataka, India
³ Department of Pharmacology, JSS Medical College, JSS Academy of Higher Education and Research, Mysore
⁴ Department of Conservative and Endodontics, AB Shetty Institute of Dental Science, NITTE Deemed to be University, Deralakatte, Mangalore, Karnataka, India
⁵ Department of Prosthodontics, JSS Dental College and Hospital, JSS Academy of Higher Education and Research, Mysore, Karnataka, India
⁶ Department of Conservative Dentistry and Endodontics, JSS Dental College and Hospital, JSS Academy of Higher Education and Research, Mysore, Karnataka, India

Date of Submission	02-Nov-2022
Date of Decision	25-Jan-2023
Date of Acceptance	04-Feb-2023
Date of Web Publication	14-Mar-2023

Correspondence Address:
Vidya G Doddawad
Department of Oral Pathology and Microbiology, JSS Dental College and Hospital, JSS Academy of Higher Education and Research, Mysore - 570 015, Karnataka
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/bbrj.bbrj_10_23

Abstract

Zinc-dependent proteolytic enzymes known as matrix metalloproteinases (MMPs) are a class of structurally related enzymes that are known to be crucial in the catabolic turnover of extracellular matrix (ECM) components. MMPs are thought to control the activity of a number of non-ECM bioactive substrates, such as growth factors, cytokines, chemokines, and cell receptors, which control the tissue microenvironment. The interaction between cells and ECM plays a key role in normal development and differentiation of organism and many pathological states as well. The primary class of controlling proteases in the ECM is known as MMPs. Aspects of normal physiology and pathology depend on the ability of MMPs to change the structural integrity of tissues. Uncontrolled ECM turnover, tissue remodeling, inflammatory response, cell proliferation, and migration are pathogenic alterations that can result from an imbalance between the concentration of active metalloproteinases and their inhibitors (tissue inhibitors of metalloproteinases [TIMPs]). This detailed review provides some information on the function of MMPs in inflammatory, caries and periapical, cancer, and other oral diseases. Blood and saliva are the two biological fluids that are most frequently used to diagnose oral disorders. Most of the ECM components in patients undergo digestion to lower molecular weight forms, resulting in much higher amounts of MMPs in their saliva/blood than in healthy individuals. Conventional treatment successfully reduces the levels of MMPs which inhibits the progressive breakdown of collagens in ECM components.

Keywords: Caries, matrix metalloproteinases, oncogenesis, oral cancer, oral disease

How to cite this article:
Doddawad VG, Shivananda S, Kalabharathi H L, Shetty A, Sowmya S, Sowmya H K. Matrix metalloproteinases in oral cancer: A catabolic activity on extracellular matrix components. Biomed Biotechnol Res J 2023;7:17-23

How to cite this URL:
Doddawad VG, Shivananda S, Kalabharathi H L, Shetty A, Sowmya S, Sowmya H K. Matrix metalloproteinases in oral cancer: A catabolic activity on extracellular matrix components. Biomed Biotechnol Res J [serial online] 2023 [cited 2023 Jun 10];7:17-23. Available from: https://www.bmbtrj.org/text.asp?2023/7/1/17/371685

Introduction

Matrix metalloproteinases (MMPs) belong to a family of structurally related zinc-dependent endopeptidases, which are proteolytic enzymes and play a key role in the regulation of extracellular matrix (ECM) and non-ECM protein components.^[1],[2],[3] The non-ECM protein component are growth factors, cytokines, chemokines, and cell receptors, which determine the tissue microenvironment.^[2]

The effects of MMPs are connected to numerous crucial physiopathological processes. MMPs have an important role in physiological processes such as tissue differentiation, wound healing, and embryonic development.^{[1],[4],[5],[6]} However, tumor invasion, metastasis, dysregulated angiogenesis, inflammation, and even cell death are influenced by the overexpression of many MMPs.^[7],[8],[9]

Matrix Metalloproteinase Classification

In 1962, the first metalloproteinase was found while investigating the ECM breakdown that causes tadpole tail resorption. Since then, there are now at least 26 members of the MMP family in humans and 24 in mice. Some of these are still being explored in detail.^{[1],[2],[3],[10],[11]}

The multigene metzincin family, which includes transmembrane and secreted proteins called a disintegrin and metalloproteinases (ADAMs), a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs), bone morphogenetic protein-1/Tolloid-like metalloproteinases (BMPI/TLLs), and meprins, is thought to include MMPs.^{[12],[13],[14],[15]}

A significant and rapidly growing group of enzymes are metal-binding proteinases. According to similarities in protein fold, experts have suggested categorizing this class of MMPs into clans and families (based on evolutionary relationships).^{[16],[17],[18],[19],[20],[21]} The MMP class currently consists of 8 clans and about 40 families. The MMP family is an ever-expanding group that already includes more than 20 enzymes.^{[1],[12],[22],[23],[24]} The MMPs are divided into two categories: the capability to define the entire collection of MMPs produced by human cells has been made possible by the availability of the complete human genome sequence.^{[1],[4],[24],[25]} Thus, the MMP family is encoded by 24 different genes, according to recent genomic studies.^[6],[26] A new classification system based on MMP structures rather than their substrate specificities has been developed as a result of an analysis of the structural design of these enzymes [Figure 1].^[27]

Figure 1: Basic structure of matrix metalloproteinase

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To date, at least 26 human MMPs are known. Based on substrate specificity and homology, MMPs can be divided into six groups [Table 1].^[27],[28]

Table 1: Matrix metalloproteinases can be classified based on substrate specificity and homology

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Collagenases
Gelatinases
Stromelysins
Matrilysins
Membrane-type MMPs that additionally contain a transmembrane and intracellular domain, a membrane linker domain, or are membrane associated
Others: MMPs.

Interstitial collagens I, II, and III are predominantly broken down by collagenases. Additionally required for the cleavage of noncollagen and non-ECM components are their catalytic domains. Gelatinases break down lamins, fibronectin, and other gelatins. Despite having a structure resembling that of collagenases, the third class of MMPs, stromelysins, does not break interstitial collagen. The hemopexin domain is absent from matrilysins. MT-MMPs are made up of two glycosylphosphatidylinositol-anchored members and four transmembrane members (MT1-MMP, MT2-MMP, MT3-MMP, and MT5-MMP) (MT4-MMP and MT6-MMP).^{[1],[12],[25]} The pericellular proteolysis and consequent cell motility are crucial processes mediated by MT-MMPs.^[2]

The Structure of Matrix Metalloproteinases

The MMPs are characterized by a prodomain, catalytic domain, hemopexin like domain, and cytoplasmic domain:^{[28],[29],[30],[31]}

Signal peptide which directs MMPs to the secretory or plasma membrane insertion pathway
Prodomain that confers latency to the enzymes by occupying the active site zinc, making the catalytic enzyme inaccessible to substrates
Zinc-containing catalytic domain
Hemopexin domain which mediates interactions with substrates and confers specificity of the enzymes
At the end, a transmembrane domain and cytoplasmic domain.

The cysteine residue in the propeptide's 80–90 amino acid composition interacts with the catalytic zinc atom through its side chain thiol group. The propeptide has a sequence that is extremely conserved.^[32] Proteolytic removal of the propeptide causes zymogen activation since all MMP family members are generated in a latent phase.

Two zinc ions and at least one calcium ion are covalently attached to different residues in the catalytic domain. The MMPs' catalytic reactions include one of the two zinc ions, which are located in the active site. The calcium ion and the second zinc ion, also referred to as structural zinc, are situated in the catalytic domain around 12 apart from the catalytic zinc. All MMPs share the three histidine residues that coordinate with the catalytic zinc ion, which is necessary for the proteolytic action of MMPs. The second zinc ion and the calcium ion's functions in the catalytic domain are not well understood; however, the MMPs have been demonstrated to have strong affinity for structural zinc and calcium^{[1],[12],[20],[33],[34]}
MMPs have a highly conserved hemopexin-like domain that shares a sequence resemblance with the plasma protein hemopexin. A functional involvement for the hemopexin-like domain in substrate binding and/or interactions with the tissue inhibitors of metalloproteinases (TIMPs), a subfamily of MMPIs, has been demonstrated. The family of MMPs evolved into many subgroups by adding and/or removing structural and functional domains in addition to these fundamental characteristics.^{[1],[3],[4],[27]} The catalytic domain and the next hemopexin domain are connected by a proline-rich hinge region. Additional protein–protein interactions are made possible by the hemopexin domain with substrates and naturally occurring inhibitors
After the hemopexin domain, a transmembrane domain, glycosylphosphatidylinositol anchor, or cytoplasmic tail may be positioned.^[2]

Multiple mechanisms, including transcription, secretion, activation, and inhibition, control the MMPs' catalytic activity. Members of the TIMP family, which currently consists of four proteins (TIMP-1, TIMP-2, TIMP-3, and TIMP-4), carry out the last task. MMPs' enzymatic activity is effectively inhibited when TIMPs bind to their catalytic domain. The “cysteine switch” motif found in the propeptide of the MMPs, PRCGXPD, interacts with the catalytic zinc domain to maintain inactivity by preventing a water molecule necessary for catalysis from attaching to the zinc atom until the propeptide has been digested by proteolysis.^{[27],[35],[36]}

The Regulation of Matrix Metalloproteinases

The majority of MMPs are formed and secreted in a dormant, inactive state before being activated in an extracellular or intercellular setting. The majority of MMPs are produced and released as inactive proenzymes or zymogens (pro-MMP), which can be secreted or attached to membranes. Processing and activation of these pro-MMPs causes their substrates to partial breakdown. Several proteinases, including trypsin, plasmin, kallikrein, mast cell tryptase, and other MMPs, can activate pro-MMPs. Nonspecific protease inhibitors such as 1-antiprotease and 2-macroglobulin and specific inhibitors such as TIMPs control the activity of MMPs. In the tissues, MMP expression regulation must be tightly regulated.^{[1],[37],[38],[39]}

This occurs on a few levels:

On the level of altering gene expression in patients with a genetic predisposition
On the level of transcription by cytokines (interleukin-1 [IL-1] and tumor necrosis factor), hormones (parathormone, PTH), and bacteria products (LPS)
On the level of enzyme sequestration to intracellular bubbles
On the level proenzyme activation (metal ions, oxidative stress, detergents, other proteolytic enzymes, and plasmin)
On the level of substrate specificity − through the pH of the environment
Through TIMPs and serine protease inhibitors (serpins).

MMP interactions with other metalloproteinases, proteoglycan core proteins, and/or their glycosaminoglycan chains regulate MMP localization, activation, and activity. Numerous other factors, such as cell transformation, hormones (depending on the type of cell), some cytokines (such as IL-1 or IL-6), or growth factors (such as epidermal growth factor [EGF] or transforming growth factor-beta [TGF-β]), can also affect the expression of MMPs. A-macroglobulin, a plasma protein that serves as a general proteinase inhibitor, and TIMPs are examples of natural inhibitor proteins that are inhibited in order to precisely control the proteolytic activities of MMPs (TIMPs).^{[3],[20],[25],[40]}

All four proteins in the TIMP family (TIMPs 1 through 4) are characterized by a largely similar structure. It is worth noticing that TIMPs were initially characterized as inhibitors of MMPs, but later research has shown that they have a wider range of activities; it is now known now that they also inhibit some of the disintegrin-metalloproteinases, ADAMs, and ADAMTSs.^{[3],[12],[41]} TIMPs inhibit MMP activity in a 1:1 molar proportion through a structure that consists of an N-domain responsible for MMP inhibition and a C-subdomain that mediates interaction with pro-MMPs.^[42],[43] TIMPs do not form covalent bonds with MMPs, nor are they cleaved by these enzymes, but they form tight complexes inhibiting the proteolytic activity of MMPs.^[1],[2]

Uncontrolled ECM turnover, tissue remodeling, inflammatory response, cell proliferation, and migration are pathogenic alterations that can result from an imbalance between the concentration of active metalloproteinases and their inhibitors. Additionally, because TIMPs have the power to regulate how cells interact with one another via adhesion and signaling molecules like growth factors, their influence on the ECM's stability is crucial. TIMPs' importance as signaling molecules is only now being recognized.^{[2],[44],[45]}

Methods of Detection of Matrix Metalloproteinases

Numerous assay systems, such as bioassay, zymography assay, immunoassay, fluorimetric assay, radioisotopic assay, phage-displayed assay, multiple-enzyme/multiple-reagent assay, and activity-based profiling assay, have been developed as a result of the numerous studies that have concentrated on the role of MMPs in biological processes and their involvement in diseases.^[46],[47]

Matrix Metalloproteinases in Oral Health and Diseases

The extracellular matrix (ECM) is composed of various components including collagen, elastin, gelatin, matrix glycoproteins, and proteoglycans. MMPs (matrix metalloproteinases) are zinc-containing endopeptidases that are calcium-dependent and responsible for the degradation of the ECM. Hormones, growth factors, and cytokines control MMPs. TIMPs and endogenous MMP inhibitors (MMPIs) tightly regulate these enzymes.^[48],[49] A range of pathologic features can develop as a result of an imbalance between the activity of MMPs and TIMPs caused by excessive MMP expression. There is a lot of evidence for the involvement of MMPs in both pathological and normal processes, including embryogenesis, inflammation, caries, periodontitis, periapical disorders, and oral cancer.^[23] Understanding the physiopathological role of MMPs in oral health and in a few common oral lesions is understandable by this paper.^[27]

These MMPs are expressed at extremely low levels, if at all, under normal circumstances because the synthesis and breakdown of ECM components are balanced. They are produced and activated in considerably higher amounts whenever active tissue remodeling is necessary.^[38]

Matrix Metalloproteinases in Inflammation, Immune Response, and Healing

There is evidence that MMPs function as regulatory enzymes in both pro- and anti-inflammatory pathways. MMPs play a role in immune response activation, including nuclear factor-κB and mitogen-activated protein kinase signaling.^[50]

Matrix Metalloproteinases in Caries, Periodontitis, and Periapical Lesion

It is crucial to discuss the development of human dentinal caries lesions in order to better understand the function of MMP activity in the oral environment. MMPs have been isolated from pulp tissue, odontoblasts, and dentin, where they play a critical role in the creation of the dentin matrix and regulate the development of secondary dentin and caries.^[38]

The presence of MMP-8, MMP-2, and MMP-9 in human oral carious lesions in both pre- and active stages is a strong indicator of their involvement in the carious process.^[23],[51] During dentinogenesis, MMPs are essential in matrix remodeling. In pulp, odontoblasts, and predentin/dentin, the primary MMPs that have been found include MMP-8, MMP-2, MMP-9, MMP-3, MMP-2, MMP-14, and MMP-20.^[2],[12] While MMP-13 was not found to have been expressed in coronal dentin, it was discovered to be present in radicular dentin, which was expressed differentially as caries advanced. MMP activity has been found to decrease with age in both active and chronic carious lesions.^[38]

MMPs and tissue inhibitors of MMPs help to partially control the inflammatory-induced loss of pulp tissue that is seen in both irreversible and reversible pulpitis (TIMPs). It has been discovered that the concentration of MMP-3 in acute pulpitis is substantially higher than that in normal pulp tissue.^[38],[52]

Saliva is commonly used for the diagnosis of periodontal diseases. The serum and salivary molecules contain immunoglobulins, enzymes, bacteria or bacterial products, volatile compounds, and phenotypic markers. The prevalent MMPs (MMP-2, MMP-8, MMP-9, and MMP-13) are produced by polymorphonuclear leukocytes or osteoclasts, and interfere in local bone metabolism, as well as being involved in the destruction of connective tissues.^[53],[54] Periodontitis patients have significantly higher levels of these enzymes than healthy people.^[2]

When it comes to apical periodontitis, persistent microorganisms after root canal therapy have been linked to significant tissue disorganization and elevated MMP levels in the periapical region. One of the crucial enzymes in the beginning of the bone resorption of the periapical lesion has been identified as interstitial collagenase (MMP-1). The other MMPs that have been identified in periapical lesions include MMP-2, MMP-3, MMP-8, MMP-9, and MMP-13.^{[38],[55],[56]}

Matrix Metalloproteinases in Oral Mucosal Lesions

MMPs have been studied in relation to several autoimmune diseases, including psoriasis, pemphigus, pemphigoid, lichen planus, and discoid lupus erythematosus, which can also affect the mucosal surfaces. MMPs mediate the inflammatory response and cause skin damage, according to numerous studies [Table 2].^[27]

Table 2: Effect of matrix metalloproteinase in various oral lesions available in the literature

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Matrix Metalloproteinases in Oral Cancer

Malignant tumors frequently result in death due to the capacity of cancer cells to spread to distant organs and infect other tissues. 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. The members of the MMP family, however, have reached an outstanding importance among all the proteolytic enzymes potentially linked to tumor invasion because of their capacity to cleave almost any ECM and basement membrane, allowing cancer cells to penetrate and infiltrate the stromal matrix. Due to their potential as a target to produce novel antimetastatic medicines that impede MMP activity, MMPs and cancer metastasis have attracted a lot of attention.^[57],[58] Understanding these essential enzymes' structure and activity will therefore have a big impact on cancer therapies.

Almost all types of human cancer have increased MMP expression and activity, which is associated with advanced tumor stage, increased invasion and metastasis, and worse survival. Early MMP production by tumor cells or the stromal cells around them promotes ECM remodeling and the release of ECM and/or membrane-bound growth factors, creating an ideal milieu for the development of the primary tumor.^[59],[60]

Additionally, substantial evidence points to the possibility that MMPs control tumor growth by encouraging the release of substances that promote cell proliferation, such as insulin-like growth factor, which binds to binding proteins. MMP activities have also historically been linked to various evasion strategies that cancer cells create to evade host immune response. MMPs break down ECM components, promoting tumor cell invasion, angiogenesis, and metastasis. By cleaving E-cadherin and processing integrins, MMPs modify connections between tumor cells and the ECM, which increases the invasiveness of tumor cells.^[13],[40] Growth factors and cytokines are among the signaling molecules that MMPs also process and activate. They increase the accessibility of these molecules to target cells by either releasing them from inhibitory complexes and the ECM (e.g. TGF) or by shedding them from the cell surface (e.g. heparin-binding EGF).^[27]

The Future of Research into Matrix Metalloproteinases and Their Inhibitors

Oral diseases are only a significant proportion of the MMP family's tale. In order to identify the macromolecular interactions of enzymes with compartments in the extracellular or intracellular environments, or with the cell surface, researchers are concentrating on the posttranslational regulation of MMP activity. This is because they are aware of how basic MMP functions in the pathology of diseases.^[12],[23]

These interactions may cause the enzymes to concentrate near or on the target substrates, which may activate dormant proenzymes and lead to abnormalities associated with the lesions. The inhibition or blockage of the processing of a particular substrate needs to be used to control the activity of enzymes. This research may offer hints as to how precise new MMP-inhibition targets might be synthesized for innovative oral disease treatments, perhaps with fewer adverse effects than inhibitors. Researchers may find sophisticated chairside testing or mouthrinse screening tests for monitoring caries, periodontitis, peri-implantitis, and oral cancer with further improvement of diagnostic procedures. Clinical trials can identify oral pathogenic abnormalities in salivary proteins that are connected to increased MMP production using saliva as a basic biological fluid in diagnosis. MMP inhibitors are a concern even though there is a lot of documentation linking different MMPs to oral disorders, including malignancies.^[61],[62] To determine a suitable balance of MMP inhibitors or their activators, further research on the involvement of MMPs in oral malignancies is still required. Because of limited efficacy and undesirable side effects, many clinical tests have failed. In some disease models, different MMPs can have opposite effects, with some causing disease symptoms while others producing beneficial effects. As a result, blocking both MMPs can result in a complex range of effects, highlighting the need for a better understanding of the specific role of each MMP in different diseases. However, it is evident that the potential of a patient's recovery will increase as medical research into the complexity of oral diseases continues.

There has been a lot of focus on creating clinically viable MMP antagonists because of the crucial roles that this enzyme family plays in tumor development, metastasis, and the dysregulated angiogenesis that fuels them. Several MMPIs are now being tested on various human subjects. The potential of this therapeutic strategy is yet unfulfilled, and discussions about the possible causes of the therapeutic failure in cancer therapy continue in the academic, pharmaceutical, and biotechnology sectors. Some therapeutic trials have yielded promising results, albeit they are by no means the majority. For the diagnosis and treatment of MMP-related oral disorders, measuring MMP activity is important.^[2]

Conclusion

Due to their ability to speed up the breakdown of ECM, these enzymes and their inhibitors play significant roles in the development of tumors and the spread of cancer. Unquestionably, the pathologist plays a crucial role in determining whether tumors alone express MMPs or TIMPs. With the advancement of scientific knowledge about the expression and pathophysiology of MMPs and their inhibitors (MMPIs), therapeutic strategies are being developed to specifically target these enzymes in oral diseases. This focus on more targeted intervention is expected to improve treatment outcomes.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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