Abstract FR:

We tested the effect of fractalkine gene transfer on the development of liver metastasis of colon cancer in mice. Our strategy has consisted in inducing the expression of fractalkine by mouse colon adenocarcinoma cells and then in evaluating the tumorigenicity of these cells after injection under the liver capsule. The development of fractalkine expressing tumors is delayed when compared to parental tumors. This delay is suppressed when cd4+ or cd8+ t lymphocytes are depleted, and remains unchanged when natural killer cells are eliminated. These results suggest that the antitumor effect of fractalkine results from the induction of a specific immune response. We were able to observe a reduction in both the production and activation of mmp2 and mmp9 in fractalkine expressing tumors. The negative regulation of mmps activity could represent an antitumor mechanism adding on to the immune response. In parallel, we studied the signaling pathways involved in the recruitment of leukocytes to the inflammatory, infectious and tumor sites in response to chemokines. We demonstrated that fractalkine prevents the migration of monocytes induced by an other chemokine, namely mcp-1. This effect seems to result from the inhibition of several proteins involved in the transduction of the promigratory signal of mcp-1, among which pyk2 and p38, and from a reduction in mmp2 activation. However, fractalkine stimulates the migration of natural killer cells through a mechanism which requires p38 activation.