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 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.
Nesbit
M
M
The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.
Schaider
H
H
Miller
T H
TH
Herlyn
M
M
D000818:Animals; D002455:Cell Division / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000502:physiology*; D018920:Coculture Techniques; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008546:Melanoma, Experimental / Q000098:blood supply / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D009000:Monocytes / Q000276:immunology* / Q000473:pathology; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000276:immunology; D014407:Tumor Cells, Cultured / Q000637:transplantation; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D018932:Chemokine CCL2; D014409:Tumor Necrosis Factor-alpha