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

J Immunol. 2001 Jun 1;166(11):6483-90. doi: 10.4049/jimmunol.166.11.6483.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 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
  • Monocytes / immunology*
  • Monocytes / pathology
  • Neoplasm Transplantation
  • Neovascularization, Pathologic / immunology
  • Tumor Cells, Cultured / transplantation
  • Tumor Necrosis Factor-alpha / biosynthesis

Substances

  • Chemokine CCL2
  • Tumor Necrosis Factor-alpha