A role for ezrin in a neglected metastatic tumor function

Abstract

In the previous issue of Trends in Molecular Medicine, Kent Hunter discussed the potential effects of ezrin in tumormetastasis [1]. In his article, two recent papers were described, which identified ezrin as a key component in the metastasis of pediatric tumors [2,3]. The speculation concerning the role of ezrin in tumor metastasis was based on both the best-known ezrin functions and the ability of ezrin to confer metastatic capabilities to lowmetastatic tumors in experimental models. However, the most recognized ezrin function is to connect membrane proteins to the actin cytoskeleton [4–6], whereas the tumor functions that are directly related to metastatic behaviour are the capacity of tumor cells to migrate within tissues, transmigrate through vessels and to adhere to the metastatic organs. Therefore, the linkage between ezrin and metastatic behaviour is through the adhesion molecules that are known to depend on the ezrin-mediated linkage to actin, such as CD44, and are directly related to the invasion and metastasis of tumors [7]. However, in a recent paper, another ezrin-mediated function that might influence metastatic behaviour, which is related to a neglected tumor activity, has been proposed [8]. The phagocyte-like behavior of tumor cells was first observed a century ago [9,10]. Numerous studies have since described the phagocytic activity of various murine and human tumor cells against dead cells and undefined particles [11,12]. However, oncologists have generally considered the finding of phagocytosed nuclei, cell debris and matrix components within tumor cells a curiosity and the result of an aberrant or an inefficient activity within themalignant cell. Using several quantitativemeasures of phagocytic activity in tumor cell lines that were derived from either metastatic lesions or primary tumors, it was reported that cell lines derived exclusively frommetastatic tumors showed strong phagocytic activity. On the basis of previous evidence on the essential role of ezrin in the phagocytic process ofmacrophages [13], the role of ezrin on the phagocytic activity of human tumor cells was examined. This data showed that ezrin is localized within the phagocytic vacuoles (Figure 1), together with lysosomal antigens [8]. Furthermore, by using oligo-antisense inhibition to block the synthesis of ezrin, the phagocytic activity of metastatic tumor cells was abrogated. However, the ezrin levels were comparable in both metastatic and non-metastatic tumors, suggesting that the overexpression of ezrin was not the sole cause of this phenomenon. In fact, contrasting results on the level of ezrin in adult tumors have been reported [14,15]. Therefore, it appears that a mechanism that is involved in ezrin activation and phosphorylation becomes deregulated in tumor cells, particularly in adult tumors. Rho-GTPases, which are known to be involved in ezrin–radixin–moesin (ERM) activation, are good candidates for the aberrant isoforms that are overexpressed in tumor metastasis [16], and Rho activation might induce aberrant phagocytic activity in non-professional phagocytes [17]. The role of phagocytic activity of tumors in metastasis needs to be clarified. Two major hypotheses can be proposed: (i) the ability of tumors to phagocytose might contribute to tumor escape from immune surveillance through the subtraction of antigenic material that is required for the processing activity of professional antigen-presenting cells, or (ii) a more complex hypothesis, in which the phagocytic activity allows tumors to survive in adverse environments, such as those that occur during hypoxic conditions because of the low blood supply during tumor growth or in metastatic organs, by ‘feeding’ on apoptotic cells and/or extracellular matrix components.