Tumor promotion effect by IL-1β gene transfer : Analysis of cancer-stromal interaction.

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Interleukin-1β (IL-1β) is a multifunctional and proinflamatory cytokine and affects nearly all cell type. In this study, we have constructed the retroviral vector expressing a hybrid gene of signal sequence and human IL-1β gene. Mouse Lewis lung carcinoma (LLC) cells were transduced with IL=1β gene (LLC/IL-1β). LLC/IL-1β accelerated tumor growth in mice despite of no change of growth property in vitro. Immunohistochemistry of CD31 in LLC/IL-1β tumor revealed hyper-neovascularization. LLC/IL-1β cells secreted larger amount of VEGF and MIP-2 whose one of main function is angigenesis. Moreover, LLC/IL-1β tumor contained over 4 times higher concentration of hepatocyte growth factor (HGF), although LLC/IL-1β cells itself did not secreted HGF in vitro. In situ hybridization of HGF mRNA demonstrated that stromal fibroblasts overexpressed HGF mRNA.An anti-angiogenic agent TNP-470 inhibited tumor growth of LLC/IL-1β cells. These results demonstrated that secreting IL-1β into tumor milieu induces several angiogenic factors from cancer and stromal cells and thus promotes tumor growth through neovascularization.