Low-Level Monocyte Chemoattractant Protein-1 Stimulation of Monocytes Leads to Tumor Formation in Nontumorigenic Melanoma Cells

• Published in: The Journal of immunology (1950) 2001-06, Vol.166 (11), p.6483-6490
• Main Authors: Nesbit, Mark, Schaider, Helmut, Miller, Thomas H, Herlyn, Meenhard
• Format: Article
• Language: English
• Subjects: Animals; Cell Division - immunology; Cell Movement - immunology; Cell Survival - immunology; Cells, Cultured; Chemokine CCL2 - biosynthesis; Chemokine CCL2 - physiology; Coculture Techniques; Dose-Response Relationship, Immunologic; Humans; Macrophages - immunology; Macrophages - pathology; Melanoma, Experimental - blood supply; Melanoma, Experimental - immunology; Melanoma, Experimental - pathology; Mice; Mice, SCID; monocyte chemoattractant protein 1; Monocytes - immunology; Monocytes - pathology; Neoplasm Transplantation; Neovascularization, Pathologic - immunology; Tumor Cells, Cultured - transplantation; Tumor Necrosis Factor-alpha - biosynthesis
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.166.11.6483

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