Jurianz K, Ziegler S, Garcia-Schüler H, Kraus S, Bohana-Kashtan O, Fishelson Z, Kirschfink M
Institute of Immunology, University of Heidelberg, Germany.
Mol Immunol. 1999 Sep-Oct;36(13-14):929-39. doi: 10.1016/s0161-5890(99)00115-7.
Clinical and experimental studies have suggested that complement may play a role in tumor cytotoxicity. However, the efficiency of complement-mediated tumor cell lysis is hampered by various protective mechanisms, which may be divided into two categories: basal and induced mechanisms. The basal mechanisms are spontaneously expressed in cells without a need for prior activation, whereas the induced mechanisms develop in cells subjected to stimulation with cytokines, hormones, drugs or with sublytic doses of complement and other pore-formers. Membrane-associated complement regulatory proteins, such as CD55 (DAF, Decay-Accelerating Factor), CD46 (MCP, Membrane Cofactor Protein), CD35 (CR1, Complement Receptor type 1) and CD59, which serve as an important mechanism of self protection and render autologous cells insensitive to the action of complement. appear to be over-expressed on certain tumors. Furthermore, tumor cells secrete several soluble complement inhibitors. Tumor cells may also express proteases that degrade complement proteins, such as C3, or ecto-protein kinases which can phosphorylate complement components, such as C9. Besides this basal resistance, nucleated cells resist, to some extent, complement damage by removing the membrane attack complexes (MAC) from their surface. Several biochemical pathways, including protein phosphorylation, activation of G-proteins and turnover of phosphoinositides have been implicated in resistance to complement. Calcium ion influx and activation of protein kinase C (PKC) and of mitogen-activated protein kinase (MAPK) have also been demonstrated to be associated with the complement-induced enhanced resistance to lysis. The complete elucidation of the molecular mechanisms involved in basal and induced tumor cell resistance will enable the development of strategies for interfering with these evasion mechanisms and the use of the cytotoxic complement system against tumor cells.
临床和实验研究表明，补体可能在肿瘤细胞毒性中发挥作用。然而，补体介导的肿瘤细胞裂解效率受到多种保护机制的阻碍，这些机制可分为两类：基础机制和诱导机制。基础机制在细胞中自发表达，无需预先激活，而诱导机制则在受到细胞因子、激素、药物或亚溶细胞剂量的补体及其他成孔剂刺激的细胞中产生。膜相关补体调节蛋白，如CD55（衰变加速因子，DAF）、CD46（膜辅因子蛋白，MCP）、CD35（补体受体1型，CR1）和CD59，作为自我保护的重要机制，使自体细胞对补体作用不敏感，似乎在某些肿瘤上过度表达。此外，肿瘤细胞分泌几种可溶性补体抑制剂。肿瘤细胞还可能表达降解补体蛋白（如C3）的蛋白酶，或可使补体成分（如C9）磷酸化的胞外蛋白激酶。除了这种基础抗性外，有核细胞通过从其表面去除膜攻击复合物（MAC）在一定程度上抵抗补体损伤。包括蛋白质磷酸化、G蛋白激活和磷酸肌醇周转在内的几种生化途径与补体抗性有关。钙离子内流以及蛋白激酶C（PKC）和丝裂原活化蛋白激酶（MAPK）的激活也已被证明与补体诱导的增强裂解抗性有关。全面阐明基础和诱导性肿瘤细胞抗性所涉及的分子机制，将有助于制定干扰这些逃避机制的策略，并利用细胞毒性补体系统对抗肿瘤细胞。
