Defective expression of the monocyte chemotactic protein-1 receptor CCR2 in macrophages associated with human ovarian carcinoma

Monocyte chemotactic protein-1 (MCP-1, CCL2) is an important determinant of macrophage infiltration in tumors, ovarian carcinoma in particular. MCP-1 binds the chemokine receptor CCR2. Recent results indicate that proinflamma tory and antiinflammatory signals regulate chemokine receptor expression in monocytes, The present study was designed to investigate the expression of CCR2 in tumor-associated macrophages (TAM) from ovarian cancer patients. T AM isolated from ascitic or solid ovarian carcinoma displayed defective CCR 2 mRNA (Northern blot and PCR) and surface expression and did not migrate i n response to MCP-1, The defect was selective for CCR2 in that CCR1 and CCR 5 were expressed normally in TAM, CCR2 gene expression and chemotactic resp onse to MCP-1 were decreased to a lesser extent in blood monocytes from can cer patients. CCR2 mRNA levels and the chemotactic response to MCP-1 were d rastically reduced in fresh monocytes cultured in the presence of tumor asc ites from cancer patients. Ab against TNF-alpha restored the CCR2 mRNA leve l in monocytes cultured in the presence of ascitic fluid, The finding of de fective CCR2 expression in TAM, largely dependent on local TNF production, is consistent with previous in vitro data on down-regulation of chemokine r eceptors by proinflammatory molecules, Receptor inhibition may serve as a m echanism to arrest and retain recruited macrophages and to prevent chemokin e scavenging by mononuclear phagocytes at sites of inflammation and tumor g rowth. In the presence of advanced tumors or chronic inflammation, systemic down-regulation of receptor expression by proinflammatory molecules leakin g in the systemic circulation may account for defective chemotaxis and a de fective capacity to mount inflammatory responses associated with advanced n eoplasia.