Tumor cell-derived prostaglandin E2 inhibits monocyte function by interfering with CCR5 and Mac-1

The cyclooxygenases (COX)-1 and COX-2 are key enzymes in the conversion of arachidonic acid to prostaglandins and other eicosanoids. 'Whereas COX-1 is expressed ubiquitously, COX-2 is an immediate-early gene often associated with malignant transformation, and a role for the COX enzymes in tumor init iation and promotion is discussed. Nonsteroidal anti-inflammatory drugs (NS AIDs) like aspirin and indomethacin that block COX-1 and -2 have been shown to have beneficial effects for tumor patients. Therefore, these compounds have gained interest also among oncologists. However, the molecular mechani sm by which NSAIDs inhibit carcinogenesis is not clearly understood. The pr ostaglandin-dependent and -independent effect may both account for their an tineoplastic action. We show here that tumor cells derived from different t umors regularly produce prostaglandin E-2 (PGE,) interfering with the funct ion of monocytes. in particular, PGE, inhibits the potential of monocytes t o migrate in the direction of a chemotactic stimulus and to adhere to endot helial cell. This inhibition is most probably due to a modulation of the ch emokine receptor CCR5 and the beta 2-integrin Mac-1. Both down-regulation o f CCR5 and reduced expression of Mac-1 may diminish the potential of periph eral blood monocytes to leave blood vessels and invade target tissues. Sinc e both dysfunctions can be restored with NSAIDs, our findings help to expla in the molecular chemopreventive action of NSAIDs on tumor formation and pr ogession.- Zeidler, R., Csanady, M., Gires, O., Lang, S., Schmitt, B., Woll enberg, B. Tumor cell-derived prostaglandin E2 inhibits monocyte function b y interfering with CCR5 and Mac-1.