Matrix metalloproteinases: molecular aspects of their roles in tumour invasion and metastasis
Introduction
The MMPs are a family of highly conserved metal atom-dependent endopeptidases, which, collectively, are capable of degradation of most, if not all components of the basement membrane and extracellular matrix. In particular, the MMPs include the only enzymes known to be capable of degrading fibrillar collagen. Fibrillar collagen refers to the polymeric structure adopted by collagens I, II, III, V and XI. Type I collagen is the most abundant collagen in humans, and comprises the principal collagen found in skin and bones.
There are currently at least 20 known human MMPs, with new members still being discovered (Table 1) 1, 2. Using many different methodologies, including gel zymography, immunohistochemistry and PCR-based techniques, the presence of individual members of the MMP family has been studied in most tumour types. Overexpression of MMPs is now known to be a characteristic of most malignant tumours, and, in the case of some carcinomas, the presence of specific MMPs has been shown to be of prognostic significance 3, 4, 5, 6, 7, 8, 9, 10, 11, 12. This review focuses on the role of MMPs in tumour invasion and metastasis, with emphasis on recent findings regarding the regulation of MMPs, and their interactions with cell adhesion molecules.
Tumour cell invasion and metastasis are now regarded as multi-step phenomena, involving proteolytic degradation of basement membranes and extracellular matrix (ECM), altered cell adhesion and physical movement of tumour cells. Angiogenesis, the formation of new blood vessels, is essential both for tumour growth and for successful tumour invasion and metastasis. Angiogenesis is complex and dynamic, and requires proliferation of endothelial cells from pre-existing blood vessels, breakdown of extracellular matrix (ECM) and migration of endothelial cells. Thus, growth and development of blood vessels within tumours requires the same factors that are crucial to tumour cell invasion and the MMPs play a central role in all of these processes. Individual MMPs may have different, possibly contradictory, roles in angiogenesis. Proteolysis of the ECM is a prerequisite for angiogenesis, and activated MMPs (specifically, MMP-2) are present in endothelial cells of blood vessels at sites of angiogenesis. However, several MMPs (MMP-2, MMP-7, MMP-9 and MMP-3) have recently been shown to be capable of proteolytic cleavage of plasminogen to form angiostatin, an endogenous angiogenesis inhibitor, which specifically inhibits proliferation of endothelial cells 13, 14, 15. However, the role of MMPs in angiogenesis is a large topic, which will not be dealt with in detail in this review.
The MMPs are responsible for degradation of the constituents of basement membranes and the ECM. Through interactions with an array of cell adhesion molecules, MMPs are implicated in altered adhesion between the tumour cell and its environment, and recently have been shown to play a role in the movement of cells through the ECM.
In addition to their function in the breakdown of the ECM, MMPs also have growth regulatory effects on both primary and secondary tumours. In vitro studies have demonstrated degradation of insulin-like growth factor receptor binding proteins (IGFBP-3 and -5) by MMPs; this may contribute to the observed growth-regulatory functions of the MMPs [16].
There is also experimental evidence that MMPs are involved in the early stages of tumour growth and development. Goss and co-workers observed a 48% decrease in the number of adenomas in Min mice following administration of the synthetic MMP inhibitor Batimastat [17].
We have recently reviewed the literature on the presence of MMPs and their major physiological inhibitors, the tissue inhibitors of metalloproteinases (TIMPs) in tumours [18]. In this review, we focus on the molecular mechanisms by which MMPs participate in tumour invasion and metastasis, with emphasis on emerging patterns of interaction with cell adhesion molecules, and examine recent research regarding the control of MMP expression. Lastly, we outline some studies of MMP inhibitors, which are being evaluated as anticancer agents.
Section snippets
Regulation of MMPs
The constitutive level of expression of MMP genes is normally low, the enzymes being induced under various physiological circumstances when ECM remodelling is required, for example during embryogenesis, wound repair and bone remodelling. Increased expression or activation of MMPs is observed in many disease states, in particular, arthritis and neoplasia. As befits a group of enzymes with such potentially devastating effects, MMP expression appears to be tightly regulated and to occur at a
Functions of MMPs: interactions with cell adhesion molecules
Both altered matrix degradation and cell adhesion are vital factors in promoting tumour invasion. Recent studies reveal mechanistic links between these two processes, and provide evidence that MMPs participate in both these processes, via multiple interactions with constituents of the cell adhesion apparatus. It is becoming apparent that complex, co-ordinated interactions between MMPs and cell adhesion molecules take place in order to facilitate the movement of cells through the ECM. There is
Therapeutic inhibition of MMPs
As the role of MMPs in tumour development and progression became apparent, many potential inhibitors of these enzymes (matrix metalloproteinase inhibitors, MMPIs) were assessed for anticancer properties. MMPIs can belong to a number of different chemical classes.
Conclusions
Considerable information is now available about the role of MMPs and their inhibitors in tumour progression and metastasis; however, the challenge remains to apply this knowledge in a clinically useful fashion. To date, individual MMPs have been shown to be of prognostic significance in several types of tumours (often in small series). Precise information about which MMPs are critical to tumour invasion and/or metastasis in various types of tumours may enable the rational development of drugs
Acknowledgements
Research in the authors' laboratory is supported in part by an Aberdeen Colorectal Cancer Initiative Grant from the University of Aberdeen Development Trust.
References (69)
- et al.
Regulation of angiostatin production by matrix metalloproteinase-2 in a model of concomitant resistance
J. Biol. Chem.
(1999) - et al.
Angiostatin-converting enzyme activities of human matrilysin (MMP-7) and gelatinase B/type IV collagenase (MMP-9)
J. Biol. Chem.
(1997) - et al.
Matrix metalloproteinases as insulin-like growth factor binding protein-degrading proteinases
Prog. Growth Factor Res.
(1995) - et al.
The AP-1 site and MMP gene regulationwhat is all the fuss about?
Matrix Biol.
(1997) - et al.
Nuclear targets for transcription regulation by oncogenes
Trends Genet.
(1991) - et al.
p53 down-regulates human matrix metalloproteinase-1 (collagenase-1) gene expression
J. Biol. Chem.
(1999) - et al.
Inhibition of matrix metalloproteinase maturation and HT1080 invasiveness by a synthetic furin inhibitor
FEBS Lett.
(1998) - et al.
Proteolytic activation of the precursor of membrane type 1 matrix metalloproteinase by human plasmin. A possible cell surface activator
FEBS Lett.
(1997) - et al.
Activation of matrix metalloproteinase-9 (MMP-9) via a converging Plasmin/Stromelysin-1 cascade enhances tumor cell invasion
J. Biol. Chem.
(1999) - et al.
Beta-catenin regulates the expression of the matrix metalloproteinase-7 in human colorectal cancer
Am. J. Pathol.
(1999)
TCF/LEF factor earn their wings
Trend Genet.
Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin alpha v beta 3
Cell
Integrin-mediated signalling of gelatinase B secretion in colon cancer cells
Biochem. Biophys. Res. Commun.
Interleukin-6 regulation of matrix metalloproteinase (MMP-2 and MMP-9) and tissue inhibitor of metalloproteinase (TIMP-1) expression in malignant non-Hodgkin's lymphomas
Blood
A pilot study of the safety and effects of the matrix metalloproteinase inhibitor Marimastat in gastric cancer
Eur. J. Cancer
Chemically modified tetracyclines inhibit inducible nitric oxide synthase expression and nitric oxide production in cultured rat mesangial cells
Biochem. Biophys. Res. Commun.
Identification and characterization of human MT5-MMP, a new membrane-bound activator of progelatinase A overexpressed in brain tumours
Cancer Res.
Cloning and characterization of human MMP-23, a new matrix metalloproteinase predominantly expressed in reproductive tissues and lacking conserved domains in other family members
J. Biol. Chem.
Matrix metalloproteinase-1 is associated with poor prognosis in oesophageal cancer
J. Pathol.
Tissue levels of matrix metalloproteinases MMP-2 and MMP-9 are related to the overall survival of patients with gastric carcinoma
Br. J. Cancer
Matrix metalloproteinases and their inhibitors in gastric cancer
Gut
Matrix metalloproteinase-1 is associated with poor prognosis in colorectal cancer
Nature Med.
Matrix metalloprotease 2 (MMP-2) and matrix metalloprotease 9 (MMP-9) type IV collagenases in colorectal cancer
Cancer Res.
Stromelysin-3an independent prognostic factor for relapse-free survival in node-positive breast cancer and demonstration of novel breast carcinoma cell expression
Am. J. Pathol.
Enhanced expression of tissue inhibitors of metalloproteinases in human colorectal tumors
Jap. J. Clin. Oncol.
Matrix metalloproteinase-2 immunoreactive proteina marker of aggressiveness in breast carcinoma
Cancer
High levels of messenger RNAs for tissue inhibitors of metalloproteinase (TIMP-1 and TIMP-2) in primary breast carcinomas are associated with development of distant metastases
Clin. Cancer Res.
TIMP-1 and adverse prognosis in non-small cell lung cancer
Clin. Cancer Res.
Generation of an angiostatin-like fragment from plasminogen by stromelysin-1 (MMP-3)
Biochemistry
Differing effects of endogenous and synthetic inhibitors of metalloproteinases on intestinal tumorigenesis
Int. J. Cancer
Matrix metalloproteinases in tumour invasion and metastasis
J. Pathol.
Regulating expression of the gene for matrix metalloproteinase-1 (collagenase)mechanisms that control enzyme activity, transcription, and mRNA stability
Crit. Rev. Eukaryot. Gene. Express.
Mechanisms controlling the transcription of matrix metalloproteinase genes in normal and neoplastic cells
Enzyme Protein
Methylation-associated silencing of the tissue inhibitor of metalloproteinase-3 gene suggests a suppressor role in kidney, brain and other human cancers
Cancer Res.
Cited by (531)
In vitro antimetastatic potential of pseudolaric acid B in HSC-3 human tongue squamous carcinoma cell line
2024, Archives of Oral BiologyHarnessing the supremacy of MEG3 LncRNA to defeat gastrointestinal malignancies
2024, Pathology Research and PracticeEffect of Piper cubeba total extract and isolated lignans on head and neck cancer cell lines and normal fibroblasts
2022, Journal of Pharmacological SciencesLuteolin inhibits the proliferation, adhesion, migration and invasion of choroidal melanoma cells in vitro
2021, Experimental Eye Research