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

白细胞介素-1 β（IL-1β）是一种多功能的促炎细胞因子，几乎影响所有细胞类型。本研究构建了信号肽与人IL-1β基因杂交的逆转录病毒表达载体。用IL-1β基因转导小鼠刘易斯肺癌（LLC）细胞（LLC/IL-1β）。LLC/IL-1β促进小鼠肿瘤生长，但对肿瘤生长特性无明显影响。LLC/IL-1β肿瘤中CD 31的免疫组化显示过度新生血管形成。LLC/IL-1β细胞分泌大量VEGF和MIP-2，其主要功能之一是血管生成。此外，LLC/IL-1β肿瘤含有超过4倍浓度的肝细胞生长因子（HGF），尽管LLC/IL-1β细胞本身在体外不分泌HGF。原位杂交结果显示，间质成纤维细胞高表达HGF mRNA，抗血管生成剂TNP-470可抑制LLC/IL-1β细胞的肿瘤生长。这些结果表明，分泌IL-1β到肿瘤环境中诱导来自癌症和基质细胞的几种血管生成因子，从而通过新血管形成促进肿瘤生长。

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.