Induction of chemokine secretion and enhancement of contact-dependent macrophage cytotoxicity by engineered expression of granulocyte-macrophage colony-stimulating factor in human colon cancer cells.
We investigated the role of tumor cell-derived GM-CSF in recruitment and tumoricidal activation of tissue macrophages. Transfection of the murine GM-CSF gene into KM12SM human colon cancer cells decreased the tumorigenicity of transfected cells and nontransfected bystander colon cancer cells in nude mice. Sequential tissue sections from sites injected with high GM-CSF-producing tumor cells (but not from nontransfected or low GM-CSF-producing cells) demonstrated a dense infiltration of polymorphonuclear cells (PMN), followed by infiltration of macrophages, which correlated with expression of the macrophage-inflammatory protein-1alpha and the monocyte chemoattractant protein-1 (MCP-1) in mouse PMN and macrophages. GM-CSF-producing KM12SM cells were highly sensitive to lysis by mouse macrophages and also increased macrophage-mediated lysis of bystander nontransfected KM12SM cells. The incubation of macrophages with GM-CSF induced expression of the CD11b surface adhesion molecule, which was associated with increased attachment to tumor cells. All KM12SM cells were sensitive to macrophage-mediated lysis in the presence of rGM-CSF and recombinant MCP-1. Collectively, the results demonstrate that tumor cell-derived GM-CSF stimulates PMN and macrophages to secrete macrophage-inflammatory protein-1alpha and MCP-1, which triggers recruitment of mononuclear cells, induces expression of adhesion molecules on macrophages, and enhances contact-dependent cytolysis of tumor cells.
Shinohara
H
H
Department of Cancer Biology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Yano
S
S
Bucana
C D
CD
Fidler
I J
IJ
D000818:Animals; D002450:Cell Communication / Q000235:genetics / Q000276:immunology*; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D054407:Chemokine CCL4; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D018920:Coculture Techniques; D003110:Colonic Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000517:prevention & control; D003602:Cytotoxicity, Immunologic / Q000235:genetics / Q000276:immunology*; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D019073:HT29 Cells; D006801:Humans; D007279:Injections, Subcutaneous; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis / Q000235:genetics; D016177:Macrophage-1 Antigen / Q000096:biosynthesis; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009504:Neutrophils / Q000276:immunology; D015202:Protein Engineering; D011994:Recombinant Proteins; D014162:Transfection; D014407:Tumor Cells, Cultured
D018932:Chemokine CCL2; D054407:Chemokine CCL4; D018925:Chemokines; D019402:Macrophage Inflammatory Proteins; D016177:Macrophage-1 Antigen; D011994:Recombinant Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor