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Ezrin, a key component in tumor metastasis

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Abstract

Identification of the key regulatory molecules in metastasis is crucial for understanding tumor dissemination and for the development of novel interventions. The recent identification of ezrin as a necessary component in the metastasis of osteosarcoma and rhabdomyosarcoma is, therefore, an important advance. Ezrin has been implicated in many roles, for example, as a conduit for signals between metastasis-associated cell-surface molecules and signal transduction components. This suggests that ezrin and, potentially, other members of the ERM (ezrin–radixin–moesin) family have key roles in the coordination of signals and cellular complexes that are required for the successful metastasis of these and other malignancies.

Section snippets

Ezrin interactions with cell-surface receptors

Examination of the cellular structures and processes with which ezrin is involved reveals interactions with several previously identified metastasis-associated molecules 7, 9, 10. Therefore, rather than influencing only a single event, as do many other metastasis-associated molecules, ezrin overexpression might participate in many of the challenges that a proto-metastatic cell must overcome (Box 1). This suggests that ezrin and, by implication, other ERM proteins represent a crucial crossroad

Ezrin and cell-adhesion functions

In addition to coordinating and integrating important metastasis-associated membrane-tyrosine-kinase-mediated signaling events, ezrin has an important role in cell adhesion and cell–cell communications. One of the functions of ezrin is to participate in the formation of cell-surface complexes that mediate cell–cell [9] and cell–extracellular matrix [15] attachments. Among the components of these adhesion complexes are E-cadherin and integrins.

E-cadherin is an adhesion molecule that is known to

Ezrin interaction with signal transduction mechanisms

Ezrin functions as a conduit and a linker connecting the metastasis-associated cell-surface proteins in osteosarcoma and rhabdomyosarcoma to other molecules in the interior of the cell. ERM activity is regulated by a combination of phosphorylation and phospholipid binding, thought to be events that are mediated by Rho [4]. Interestingly, it has also been suggested that ERM proteins positively regulate Rho function in a Rho autoregulatory feedback loop [4]. ERM proteins have been shown to bind

Upstream regulation of ezrin expression

Although the requirement for ezrin in these tumors to enable successful metastasis seems clear, the mechanism underlying the upregulation of its expression is not obvious. Understanding the upstream changes that result in ezrin overexpression might be crucial in eventually controlling or eradicating pediatric metastases. The relevant pathways and molecules that are affected by ezrin could provide novel intervention targets, potentially better than those offered by ezrin or the molecules with

Ezrin and ERMs in other malignancies

The question remains as to whether the importance of ezrin in metastasis is limited to this member of the ERM family and to osteosarcoma and rhabdomyosarcoma. ERM proteins are thought to have redundant functions but potentially unique expression patterns [6]. If ezrin is a crucial element in the metastasis of pediatric cancers, a similar function might be expected from other members of the ERM family, but evidence of this for radixin and moesin has not been established. However, loss of merlin,

Concluding remarks

Whether ezrin truly functions as a central organizer for tumor dissemination in pediatric cancers is unresolved. However, the importance of ezrin in the metastatic cascade in osteosarcoma and rhabdomyosarcoma is clear (Figure 1). More importantly, evidence from both canine models and prospective human studies demonstrate correlations between ezrin expression levels and poor outcome [3], consistent with a crucial role for ezrin in tumor dissemination. This implies that the experimental models

Acknowledgements

I thank Dr Danny Welch for critical reading of this manuscript and the reviewers for their constructive comments. I also apologize to the many investigators whose important studies could not be referenced here owing to space limitations.

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