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*
Istituto di Ricerche Farmacologiche "Mario Negri," Milan, Italy;
Department of Obstetrics and Gynecology, S. Gerardo Hospital, Monza, Italy;
Department of Biotechnology, University of Brescia, Brescia, Italy;
Receptor Pharmacology, Leukosite, Inc., Cambridge, MA; and
¶
Biological Therapy Laboratory, Imperial Cancer Research Fund, London, United Kingdom
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 proinflammatory and anti-inflammatory 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. TAM isolated from
ascitic or solid ovarian carcinoma displayed defective CCR2 mRNA
(Northern blot and PCR) and surface expression and did not migrate in
response to MCP-1. The defect was selective for CCR2 in that CCR1 and
CCR5 were expressed normally in TAM. CCR2 gene
expression and chemotactic response to MCP-1 were decreased to a lesser
extent in blood monocytes from cancer patients. CCR2
mRNA levels and the chemotactic response to MCP-1 were drastically
reduced in fresh monocytes cultured in the presence of tumor ascites
from cancer patients. Ab against TNF-
restored the
CCR2 mRNA level in monocytes cultured in the presence of
ascitic fluid. The finding of defective CCR2 expression
in TAM, largely dependent on local TNF production, is consistent with
previous in vitro data on down-regulation of chemokine receptors
by proinflammatory molecules. Receptor inhibition may serve as a
mechanism to arrest and retain recruited macrophages and to prevent
chemokine scavenging by mononuclear phagocytes at sites of inflammation
and tumor growth. In the presence of advanced tumors or chronic
inflammation, systemic down-regulation of receptor expression by
proinflammatory molecules leaking in the systemic circulation may
account for defective chemotaxis and a defective capacity to mount
inflammatory responses associated with advanced
neoplasia.
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