Elsevier

European Journal of Cancer

Volume 36, Issue 13, August 2000, Pages 1621-1630
European Journal of Cancer

Matrix metalloproteinases: molecular aspects of their roles in tumour invasion and metastasis

https://doi.org/10.1016/S0959-8049(00)00156-8Get rights and content

Abstract

The matrix metalloproteinases (MMPs) are a family of proteolytic enzymes, whose physiological functions include tissue remodelling and embryogenesis. The importance of this group of proteins in the processes of tumour invasion and metastasis is now widely acknowledged, and has led to the search for MMP inhibitors for use as anticancer treatments in a clinical setting. This review aims to bring the reader up-to-date with current research relating to MMPs, with particular emphasis on emerging mechanisms of regulation of these enzymes, and their interaction with cell adhesion molecules. The therapeutic inhibition of MMPs will also be discussed.

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.

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