Role of integrin αvβ3 in the early phase of liver metastasis: PET and IVM analyses

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Abstract
To clarify the function of integrin αvβ3 in the early stage of liver metastasis, we investigated the interactions of metastatic cells with their target organ under the actual blood flow by using positron emission tomography (PET). The cells used were CHO-K1 cells and their transfectants bearing human integrin αvβ3 cDNA (αvβ3-CHO-K1 cells). The liver accumulation of αvβ3-CHO-K1 cells was significantly higher than that of CHO-K1 cells after injection via the portal vein, whereas no significant difference was observed in the lung accumulation after tail vein injection, suggesting a specific interaction of αvβ3-CHO-K1 cells with the hepatic sinusoids. Furthermore, to clarify the precise location of each cell in the liver, i.e., to determine whether individual cells were intravascularly localized or had extravasated, we performed intravital fluorescence microscopy (IVM) on the liver by using stable transfectants bearing the green fluorescent protein (GFP) gene, namely, GFP-CHO-K1 and GFP-αvβ3-CHO-K1 cells. Both types of cells remained in the hepatic blood vessels 1 h after injection via the portal vein. On the other hand, expression of integrin αvβ3 promoted the cells to reach the extravascular region after 24 h. These results suggest the possibility that the specific accumulation of αvβ3-CHO-K1 cells in the liver is followed by migration of the cells into the extravascular region. Interestingly, the adhesion of the two types of cells to hepatic sinusoidal endothelial cells in vitro did not correspond to in vivo accumulation of these cells. Therefore, integrin αvβ3 may function to promote extravasation of integrin αvβ3-expressing tumor cells in liver through a process possibly mediated by vitronectin produced by this organ.