Consistent with this data, we found a significant association between high ezrin expression and poor outcome in pediatric osteosarcoma patients.Ezrins linkage of the cell membrane to the actin cytoskeleton allows the cell to interact directly with its microenvironment, and provides an intracellular scaffolding that Fenoprofen calcium hydrate facilitates signal transduction through a number of growth factor receptors and adhesion molecules.superfamily of proteins, ezrin is the bestcharacterized ERM protein.Ezrins role in the process of metastasis has not been previously defined and is not understood.Ezrin is expressed in a variety of cancers, some of which are associated with poor outcome.To study the role of ezrin in metastasis, we suppressed ezrin protein expression or disrupted ezrin phosphorylation in highly metastatic, wildtype KM mouse osteosarcoma cells. The Cefuroxime sodium suppression of ezrin protein, accomplished by stable transfection of fulllength antisense ezrin, significantly diminished both experimental and spontaneous metastases in mice. In this model, experimental pulmonary metastases result from intravenous injection of tumor cells, whereas spontaneous pulmonary metastases develop from a primary orthotopic appendicular tumor.The suppression of ezrin did not influence invitro proliferation of cells or primary tumor development in vivo. EzrinTA cannot be phosphorylated, and therefore acts as a dominantnegative inhibitor of ezrin.Experimental metastases were completely inhibited in cells expressing ezrinTA, whereas metastases continued to develop in cells expressing the empty vector developed metastasis in, and mice, respectively.Mice receiving TAGFP clones did not have gross or microscopic metastasis at the conclusion of d experiments.Collectively, these invivo experiments using ezrinAS and ezrinTA suggest that ezrin protein and function are necessary for metastasis in this model.This finding was notable given the redundancy and overlapping activities of ERM family members, and the multiplicity and redundancy of proteins involved in metastasis. Western blot analysis of cells expressing ezrinAS detected other ERM proteins in all cells, but the levels of these proteins were not influenced by ezrin suppression. These data suggest that in cancer metastasis, unlike in most normal tissues, ezrin has a crucial and unique role that is not redundant with, and cannot be replaced by, other ERM family proteins.Representative fields from lung are shown at magnification.White arrows indicate examples of fluorescent tumor cells in lung.Significant, ezrindependent decrease in number of tumor cells detected in lung at and hafter tailvein of injection of cells was found reveals significantly fewer KMAS clones with marked suppression of ezrin, as compared to KMWT cells, at, and hafter tailvein injection of tumor cells.The number and localization of cells arresting within the lung was defined by simultaneous imaging of green tumor cells and red vessels.The localization of metastasizing cells was similar for all cells and included small pulmonary arterioles, where cells had presumably been trapped in vessels based on size restriction, and largediameter arterioles, where cells may have undergone receptormediated adhesion to vessel walls. After hof delivery of tumor cells to the lung, a decrease in the number of metastatic cells was seen for all tumor cells.This initial drop in metastatic cells was expected, and has been referred to as metastatic inefficiency. At hafter tumor cell injection, the number of cells with wildtype levels of ezrin was largely unchanged.

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