title: Monocyte chemotactic cytokine gene transfer modulates macrophage infiltration, growth, and susceptibility to IL-2 therapy of a murine melanoma.
abstract: Tumor-derived chemotactic factors have been identified and suggested to play a role in the regulation of macrophage infiltration in neoplastic tissues. The present study was designed to assess the in vivo relevance of a tumor-derived chemotactic factor molecularly identified as monocyte chemotactic protein (MCP; alternative designations are JE and MCAF) by gene transfer in a murine melanoma. After gene transfer, MCP-producing melanoma clones showed a marked (twofold) increase in the percentage of tumor-associated macrophages compared with control clones and with the parent line: for instance, the percentage of tumor-associated macrophages was 20.9 +/- 1.5, 29.4 +/- 2.3, and 47.6 +/- 2.5 for the parent line, the control V14 clone, and the MCP-producing L12 clone, respectively. MCP-producing cells were tumorigenic but exhibited a slower growth rate in vivo (e.g., doubling time of 2.9 and 6.6 days for the control V14 and the MCP-producing L12 clone, respectively) with a prolongation of survival time. The in vitro growth rate of melanoma clones was unaffected by MCP gene transfer. The same difference between MCP-producing and control cells, in terms of macrophage infiltration and growth rate, was detected after implantation in athymic mice. Whereas the in vivo growth rate of MCP-expressing tumors was slower, after i.m. inoculation of small cell numbers (10(2) cells) MCP-producing cells were slightly, but significantly, more tumorigenic. Local administration of IL-2 had modest, but definite, antitumor activity in this model; MCP-producing cells were less susceptible to local IL-2 immunotherapy. These results demonstrate that a tumor-derived chemotactic cytokine can indeed play a role in the regulation of mononuclear phagocyte recruitment in neoplastic tissues and emphasize how tumor-associated macrophages can exert a dual influence in tumor-host interactions.
authors.affiliation: Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Bottazzi
authors.forename: S
authors.initials: S
authors.lastname: Walter
authors.forename: D
authors.initials: D
authors.lastname: Govoni
authors.forename: F
authors.initials: F
authors.lastname: Colotta
authors.forename: A
authors.initials: A
authors.lastname: Mantovani
mesh_terms: D000818:Animals; D018932:Chemokine CCL2; D002630:Chemotactic Factors / Q000235:genetics* / Q000502:physiology; D007376:Interleukin-2 / Q000627:therapeutic use*; D008264:Macrophages / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D051379:Mice; D014162:Transfection
chemical_list: D018932:Chemokine CCL2; D002630:Chemotactic Factors; D007376:Interleukin-2