EXPRESSION OF THE JE MCP-1 GENE SUPPRESSES METASTATIC POTENTIAL IN MURINE COLON-CARCINOMA CELLS/

The purpose of this study was to determine whether the expression of t he JE/MCP-1 gene encoding for the monocyte chemottractant protein, MCP -1 (also known as monocyte chemotactic and activating factor MCAF TDCF and SMC-CF) can influence the metastatic properties of tumor cells. T he highly metastatic murine colon carcinoma CT-26 cells, syngeneic to BALB/c mice that do not produce endogenous JE/MCP-1 protein, were tran sfected with a BCMGS-Neo expression vector (control) or a vector conta ining full-length JE cDNA. CT-26 parental cells, CT-26 Neo, and CT-26 JE/MCP-1-positive cells were injected into syngeneic or nude mice. The CT-26 JE/MCP-positive cells produced significantly fewer lung metasta ses. The decrease in incidence of metastasis was not due to the inabil ity of the transfected cells to arrest in the lung vasculature or to d ifferences in cell cycle time. CT-26 cells producing JE/MCP-1 were hig hly susceptible to lysis by syngeneic macrophages treated with subthre shold concentrations of lipopolysaccharide. In addition, culture super natants of JE/MCP-1-expressing cells plus lipopolysaccharide synergist ically activated tumoricidal properties in syngeneic macrophages. This activity was blocked by anti-JE/MCP-1 antibodies, indicating the invo lvement of the JE/MCP-1 molecule in this process. Moreover, purified J E/MCP-1 added to lipopolysaccharide-containing medium resulted in sign ificant activation of macrophages against parental CT-26 cells. These data suggest that, in addition to its chemotactic properties, JE/MCP-1 can synergize with bacterial endotoxins to activate macrophages to be come tumoricidal and, hence, could suppress metastasis.