(See article on pages 1189–1197.)
Despite intensive interest in the genetic abnormalities of cancer cells, changes in gene expression that accompany later stages of tumorigenesis have attracted relatively little attention. Ito et al. have previously used subtractive libraries to clone genes that are differentially expressed between two mouse melanoma cell lines, one of which, BL6, can metastasize efficiently to the lungs when implanted subcutaneously, while the other subline, F10, cannot. Because both sublines metastasize when injected intravenously, their primary phenotypic difference probably relates to an early event in metastasis, such as detachment or intravasation. Now the authors show that the connexin gene CX26 is specifically expressed in BL6 cells but that expression of exogenous Cx26 allows F10 cells to metastasize. Conversely, point mutants in CX26 diminish the metastatic potential of BL6 cells and block their ability to transfer dye to endothelial cells in a coculture assay for gap junction activity. Although gap junctions typically form between cells bearing the same connexin proteins, Cx26 does not form gap junctions between BL6 cells. Furthermore, this connexin is not found in the endothelial cells that interact with BL6 cells. Ito and colleagues suggest that another endothelial connexin, possibly Cx43, forms heterotypic gap junctions with Cx26. The nature of the intercellular communication between the cell types and its relevance to metastasis remain to be explored.