The E-cadherin–catenin complex in tumour metastasis: structure, function and regulation
Introduction
Since it was first recognised that tumours had the ability to invade adjacent tissues and spread to distant organs, extensive research has been performed, expanding the body of knowledge on this basic hallmark of malignancy. In recent years, with the advent of molecular techniques, crucial insights into the interplay of various factors at a molecular and genetic level have been gained. The resultant model shows metastasis to be a co-ordinated multi-step process encompassing the detachment of cells from the primary tumour to the development of a tumorigenic lesion at a distant site 1, 2.
The process of metastasis appears to be regulated by a variety of gene products. These include cell–cell and cell–extracellular matrix receptors 3, 4; proteolytic enzymes that facilitate breakdown and invasion of the basement membrane, vascular channels and organs 5, 6, 7; motility factors which allow migration through tissues 8, 9; receptors mediating organ-specific invasion [10]; growth factors necessary for the maintenance of the tumour microcolonies in the secondary organ [11]; and angiogenic factors that result in neovascularisation of the metastasis, allowing the supply of nutrients, removal of metabolites and haematogenous spread of metastatic cells 12, 13. Weakening of cell–cell adhesion is obviously imperative for tumour cells to metastasise. In recent years, several families of biochemically and genetically distinct cell adhesion molecules have been described. These include the cadherins, integrins, adhesion molecules belonging to the immunoglobulin superfamily, selectins and cell-determinant CD44.
The role of E-cadherin in metastasis has become topical in the past few years due to its apparent promise as a prognostic indicator, with loss or reduction of expression correlating with enhanced aggressiveness and dedifferentiation of many carcinomas 14, 15, 16, 17, 18, 19. Some tumours also display the ability to regulate E-cadherin expression during the process of metastasis, which raises questions about the role of the tumour microenvironment [20]. It has recently been hypothesised that hypoxia within tumours, resulting in tumour necrosis, causes downregulation of E-cadherin, and ultimately sets the metastatic cascade in motion [21]. In this paper, the interactions of the E-cadherin–catenin complex with various regulating factors, the consequences of the interactions on cell signalling pathways, and the relationship with the metastatic potential of tumours will be reviewed.
Section snippets
The E-cadherin–catenin complex
The cadherin family consists of transmembrane glycoproteins responsible for calcium-dependent cell adhesion. The family is widespread in normal tissues but the individual members display pronounced tissue specificity. E-cadherin is one of the members of the family and is present within epithelial cells, where it tends to localise to specialised junctions of the zonula adherens type 22, 23.
The human E-cadherin gene (CDH1) is situated on chromosome 16q22.1, within a large conserved-linkage group
Regulation of E-cadherin by interactions with the E-cadherin–catenin complex in non-transformed cells
Regulation of E-cadherin expression can occur in both physiological and pathological settings. Variations in E-cadherin expression have been noted during specific events in embryonic morphogenesis 64, 65. An example of such a process is during the development of the murine cochlea, where E-cadherin is downregulated on the lateral membranes of the reticular lamina, allowing the process of fluid space opening in the organ of Corti [66]. Embryonic processes have become important in providing
Regulation of E-cadherin in malignant cells
The E-cadherin–catenin complex, that mediates cell adhesion, is dependent on numerous interactions that have been highlighted above. Thus, it should be obvious that cell adhesion is not solely dependent on the structural and functional integrity of the E-cadherin molecule but also that of the associated catenins and other molecules that mediate its binding to the cytoskeleton. Reduction in cell adhesion is of major importance in tumour metastasis and appears to be achieved by a variety of
The role of hypoxia in E-cadherin regulation and metastasis
It is clear that factors external to the cell have a major influence on cell adhesion. The milieu in which the transformed cells of malignant tumours exist is bound to be very different from that found in normal tissues. By their very nature, malignant tumours act to create an environment that aids their transformation and progression. Growth by cellular proliferation is the main function of malignant tumours and it occurs at the expense of all other cellular activities. The disorganised
Conclusion
It has been demonstrated that the control of E-cadherin-mediated cell adhesion in benign and malignant epithelial cells is complex and relies on interactions between various external factors and intracellular signalling pathways. The loss or downregulation of E-cadherin is a key event in the process of tumour invasion and metastasis. As understanding of the interactions involving components of the E-cadherin system increases, hopefully so will the ability to predict and combat these events,
The outstanding questions
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What is the true role of p120ctn in cell adhesion?
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What is the pathway through which E-cadherin stimulates contact adhesion and does it have a role in tumour progression?
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Does EGFR stimulation have an effect on the small GTPases, possibly through an interaction with GAP?
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Can E-cadherin downregulation be blocked?
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Does hypoxia initiate the metastatic cascade?
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Does tirapazamine have a role to play in the prevention of metastasis?
Acknowledgements
The author thanks Professor K.S.O. Beavon for critical reading of this manuscript and Mrs V. Wiseman for the preparation of the illustrations.
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