THE EFFECT OF THE JE (MCP-1) GENE, WHICH ENCODES MONOCYTE CHEMOATTRACTANT PROTEIN-1, ON THE GROWTH OF HELA-CELLS AND DERIVED SOMATIC-CELL HYBRIDS IN NUDE-MICE

To investigate the effect of tumor-associated macrophages on the in vi vo growth properties of cervical carcinoma cells, tumorigenic human pa pilloma virus (HPV) 18-positive HeLa cells were transfected with an ex pression vector harboring the cDNA for the macrophage chemoattractant protein-1 JE (MCP-1). Although the endogenous gene is present and not structurally rearranged, its expression seems to be negatively affecte d by a still unknown mechanism. Inoculation of JE (MCP-1)-negative HeL a cells into nude mice led to rapidly growing tumors, where macrophage infiltration into the inner tumor mass was not detectable immunohisto chemically. The activity that attracted mononuclear cells under both i n vitro and in vivo conditions was reconstituted in HeLa cells after t ransfection with the JE (MCP-1) expression vector. Heterotransplantati on of those cells into immunocompromised animals resulted in significa nt growth retardation that was accompanied by a strong infiltration of macrophages. On the other hand, in vivo selection of nonmalignant hyb rids made between wild-type HeLa cells and normal human fibroblasts in nude mice resulted in tumorigenic segregants 4 mo after inoculation i nto the animals. Monitoring JE (MCP-1) expression directly within thos e nodules, we found that transcription was either absent or only weakl y detectable. Recultivation of JE (MCP-1)-positive tissue grafts under in vitro conditions revealed that the gene was only marginally induci ble by tumor necrosis factor-alpha, a cytokine that normally induces a very strong activation of transcription in nontumorigenic cells. Thes e findings suggest that functional JE (MCP-1) expression and in turn a ctivated macrophages may play a pivotal role in controlling the prolif eration rate of HPV-positive cells in vivo. (C) 1995 Wiley-Liss, Inc.