Tumor-Associated Macrophages as Targets for Cancer Therapy

Extract

Tumor-associated macrophages (TAMs) originate in the circulation and are recruited to the tumor site by specific tumor-derived attractants such as monocyte chemotactic protein-1 ( 1 , 2 ). By use of several mechanisms, TAMs bind to the tumor cells via glycoproteins, sugars, and phospholipids and become localized at the tumor-host tissue interface ( 2 , 3 ). Unlike macrophages that are involved in inflammation, TAMs proliferate at the tumor site. Although macrophages have the potential to mediate tumor cytotoxicity and to stimulate antitumor lymphocytes, the tumor cells can not only block the host's defense program but also can benefit from the activities of the TAMs. In some cases, tumor-derived molecules actually redirect TAM activities to promote tumor survival and growth. Many tumor-derived factors— including interleukin (IL)-4, -6, and -10; transforming growth factor-β1 (TGF-β1); prostaglandin E2; and macrophage colony-stimulating factor—reduce the cytotoxic activity of the TAMs 4 , 5 ). TGF-β1 has also been shown to increase urokinase expression in TAMs ( 6 ). The strategic location of the TAMs also allows them to have a number of important additional effects on tumor cells. TAMs produce growth factors, including IL-1 and platelet-derived growth factor, which may directly promote tumor growth ( 1 ). Proteases secreted by TAMs degrade the surrounding tissue and could facilitate tumor cell expansion and invasion. Last, TAMs secrete factors that promote angiogenesis, including vascular endothelial growth factor, a protein that further supports the growth and spread of tumors. Thus, TAMs can either directly or indirectly contribute to tumor survival, growth, and metastasis and these cells could be a potential target for antitumor therapy. Possible strategies that involve TAMs include reducing the number of host macrophages and/or increasing the cells' tumoricidal activity.