Expression of complement protein C5a in a murine mammary cancer model: tumor regression by interference with the cell cycle
Expression of complement protein C5a in a murine mammary cancer model: tumor regression by interference with the cell cycle
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DOI：
10.1007/s00262-005-0672-7
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发表时间：
2005-10-01
影响因子：
5.8
通讯作者：
Martin, BK
中科院分区：
文献类型：
--
作者：
Kim, DY;Martin, CB;Martin, BK
C5a过敏毒素蛋白在与补体激活相关的炎症中起着核心作用。这种蛋白通常被认为是最有效的炎症反应诱导剂之一，C5a肽激动剂被用作分子佐剂。然而，全长C5a蛋白尚未被测试为一种潜在的肿瘤治疗方法。在这份报告中，我们描述了一种微型基因结构的创建，它将C5a的表达导向任何感兴趣的细胞。在小鼠乳腺肉瘤EMT6中有功能表达。当表达C5a的细胞被注射到同基因小鼠中时，大多数表达C5a的克隆都显著地抑制了肿瘤的生长。对一个表达低水平C5a的克隆的进一步鉴定表明，注射该品系的小鼠中有三分之一的肿瘤完全消退。肿瘤消退的小鼠对未经修饰的EMT6细胞随后的攻击具有免疫力，这表明天然免疫反应的一个组成部分可以用于增强获得性免疫。细胞分析表明，早在第10天就可以检测到实际肿瘤细胞数量的显著差异。在所有时间点，细胞周期进程都明显受阻，并在退化事件的早期观察到高水平的凋亡。这些数据表明，补体蛋白C5a在肿瘤免疫中可以起到显著的保护作用。
The C5a anaphylatoxin protein plays a central role in inflammation associated with complement activation. This protein is commonly regarded as one of the most potent inducers of the inflammatory response and a C5a peptide agonist was used as a molecular adjuvant. However, the full length C5a protein has not been tested as a potential tumor therapy. In this report, we describe the creation of a mini-gene construct that directs C5a expression to any cell of interest. Functional expression could be demonstrated in the murine mammary sarcoma, EMT6. When C5a expressing cells were injected into syngeneic mice, most C5a-expressing clones had significantly reduced tumor growth. Further characterization of a clone expressing low levels of C5a demonstrated that one-third of mice injected with this line had complete tumor regression. The mice whose tumors regressed were immune to subsequent challenge with unmodified EMT6 cells, suggesting that a component of the innate immune response can be used to augment adaptive immunity. Cellular analyses demonstrated that a significant difference in actual tumor cell number could be detected as early as day 10. A block in cell cycle progression was evident at all time points and high levels of apoptosis were observed early in the regression event. These data demonstrate that the complement protein C5a can play a significant protective role in tumor immunity.