Low-level monocyte chemoattractant protein-1 stimulation of monocytes leads to tumor formation in nontumorigenic melanoma cells

Tumors commonly produce chemokines for recruitment of host cells, but the b iological significance of tumor-infiltrating inflammatory cells, such as mo nocytes/macrophages, for disease outcome is not clear. Here, we show that a ll of 30 melanoma cell lines secreted monocyte chemoattractant protein-1 (M CP-1), whereas normal melanocytes did not. When low MCP-1-producing melanom a cells from a biologically early, nontumorigenic stage were transduced to overexpress the MCP-1 gene, tumor formation depended on the level of chemok ine secretion and monocyte infiltration; low-level MCP-1 secretion with mod est monocyte infiltration resulted in tumor formation, whereas high secreti on was associated with massive monocyte/macrophage infiltration into the tu mor mass, leading to its destruction within a few days after injection into mice. Tumor growth stimulated by monocytes/macrophages was due to increase d angiogenesis. Vessel formation in vitro was inhibited with mAbs against T NF-alpha, which, when secreted by cocultures of melanoma cells with human m onocytes, induced endothelial cells under collagen gels to form branching, tubular structures. These studies demonstrate that the biological effects o f tumor-derived MCP-1 are biphasic, depending on the level of secretion. Th is correlates with the degree of monocytic cell infiltration, which results in increased tumor vascularization and TNF-alpha production.