hTERT-promoter-based tumor-specific expression of MCP-1 effectively sensitizes cervical cancer cells to a low dose of cisplatin

摘要

Cervical cancers at advanced stages or with recurrent status are mainly treated by platinum-based chemotherapy, such as cisplatin. However, a novel strategy to reduce the minimally effective dose is required to prevent severe adverse effects that limit the effectiveness of the treatment. Monocyte chemoattractant protein-1 (MCP-1) is a subtype of chemokines that can promote monocyte/macrophage infiltration and enhance their phagocytosis at not only sites of inflammatory lesions but also of tumors. The present study applies MCP-1-based gene therapy to treat cervical cancers. To achieve tumor-specific expression of MCP-1, retroviral expression vector was constructed using the human telomerase reverse transcriptase gene (hTERT) promoter. Retroviral expression of MCP-1 into cervical cancer ME180 cells did not affect their proliferation either in vitro or in vivo. However, when combined with a suboptimal low dose of cisplatin, tumor formation was obviously reduced in clones transduced with MCP-1, but not in control clones. Histological examination revealed that a substantial number of macrophages infiltrated the tumor sites of MCP-1-transduced cells, but not of controls. These findings suggest that MCP-1 expression sensitizes cervical cancer cells to an otherwise ineffective low dose of cisplatin, possibly by inducing the migration of macrophages to eradicate tumor cells. This system may be a novel strategy for chemotherapy combined with immunogene therapy against otherwise intractable cervical cancers.