Proinflammatory cytokine IL-1β promotes tumor growth of Lewis lung carcinoma by induction of angiogenic factors:: In vivo analysis of tumor-stromal interaction
Proinflammatory cytokine IL-1β promotes tumor growth of Lewis lung carcinoma by induction of angiogenic factors:: In vivo analysis of tumor-stromal interaction
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DOI：
10.4049/jimmunol.169.1.469
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发表时间：
2002-07-01
影响因子：
4.4
通讯作者：
Nukiwa, T
中科院分区：
文献类型：
--
作者：
Saijo, Y;Tanaka, M;Nukiwa, T
炎症与肿瘤的发展有关。IL-1 β是一种多功能促炎细胞因子，影响几乎所有类型的细胞。为了研究IL-1 β在体内肿瘤生长中的作用，我们将编码人IL-1 β基因的逆转录病毒载体转导到小鼠刘易斯肺癌（LLC）细胞中，随后将LLC/IL-1 β接种到同基因C57 BL/6小鼠。来源于LLC/IL-1 β的肿瘤生长更快（240%，第18天，相对于空载体对照LLC/neo; p < 0.01），并显示出更丰富的脉管系统（250%，相对于LLC/neo; p < 0.05），而LLC/IL-1 β细胞、LLC/neo细胞和野生型LLC细胞在体外生长速率方面没有显示出任何显著差异。与LLC/neo细胞相比，LLC/IL-1 β细胞分泌的血管内皮生长因子的量是LLC/neo细胞的2倍，巨噬细胞炎性蛋白2（CXCL 2）的量是LLC/neo细胞的10倍以上，CXCL 2的主要功能之一是血管生成。虽然LLC/IL-1 β本身不分泌肝细胞生长因子（HGF），但LLC/IL-1 β细胞衍生的肿瘤也含有浓度高出4倍的另一种血管生成因子HGF。LLC/IL-1 β肿瘤切片中HGF mRNA的原位杂交显示间质成纤维细胞和浸润细胞过度表达HGF mRNA。此外，当在体外培养的HGF的存在下，LLC/IL-1 β细胞分泌更大量的血管内皮生长因子和巨噬细胞炎症蛋白-2。抗血管生成剂TNP-470和抗CXCR 2抗体在体内抑制LLC/IL-1 β细胞的肿瘤生长。这些结果表明，分泌IL-1 β到肿瘤环境中诱导肿瘤和基质细胞的几种血管生成因子，从而通过过度新生血管促进肿瘤生长。
Inflammatory conditions are associated with tumor development. IL-1beta is a multifunctional and proinflammatory cytokine that affects nearly all types of cells. To investigate the role of IL-1beta in tumor growth in vivo, we transduced the retroviral vector coding human IL-1beta gene into mouse Lewis lung carcinoma (LLC) cells and subsequently inoculated the transformant (LLC/IL-1beta) to syngeneic C57BL/6 mice. Tumors derived from LLC/IL-1beta grew faster (240 %, day 18, vs null-vector control LLC/neo; p < 0.01) and showed more abundant vasculature (250%, vs LLC/neo; p < 0.05), whereas LLC/IL-1beta cells, LLC/neo cells, and wild-type LLC cells did not show any significant difference in the growth rate in vitro. As compared with LLC/neo cells, LLC/IL-1beta cells secreted 2-fold the amount of vascular endothelial growth factor and > 10-fold the amount of macrophage-inflammatory protein-2 (CXCL2), one of whose main functions is angiogenesis. Although LLC/IL-1beta itself did not secrete hepatocyte growth factor (HGF), the tumor derived from LLC/IL-1beta cells also contained a >4-fold higher concentration of HGF, another angiogenic factor. In situ hybridization of HGF mRNA in LLC/IL-1beta tumor sections demonstrated that stromal fibroblasts and infiltrating cells overexpressed HGF mRNA. Moreover, when cultured in the presence of HGF in vitro, LLC/IL-1beta cells secreted even larger amounts of vascular endothelial growth factor and macrophage-inflammatory protein-2. The antiangiogenic agent TNP-470 and anti-CXCR2 Ab inhibited the tumor growth of LLC/IL-1beta cells in vivo. These results indicated that secreting IL-1beta into the tumor milieu induces several angiogenic factors from tumor and stromal cells and thus promotes tumor growth through hyperneovascularization.