Immunology Group, Lund University, Lund, Sweden.
PLoS One. 2012;7(3):e34207. doi: 10.1371/journal.pone.0034207. Epub 2012 Mar 28.
By breeding TRAMP mice with S100A9 knock-out (S100A9(-/-)) animals and scoring the appearance of palpable tumors we observed a delayed tumor growth in animals devoid of S100A9 expression. CD11b(+) S100A9 expressing cells were not observed in normal prostate tissue from control C57BL/6 mice but were readily detected in TRAMP prostate tumors. Also, S100A9 expression was observed in association with CD68(+) macrophages in biopsies from human prostate tumors. Delayed growth of TRAMP tumors was also observed in mice lacking the S100A9 ligand TLR4. In the EL-4 lymphoma model tumor growth inhibition was observed in S100A9(-/-) and TLR4(-/-), but not in RAGE(-/-) animals lacking an alternative S100A9 receptor. When expression of immune-regulating genes was analyzed using RT-PCR the only common change observed in mice lacking S100A9 and TLR4 was a down-regulation of TGFβ expression in splenic CD11b(+) cells. Lastly, treatment of mice with a small molecule (ABR-215050) that inhibits S100A9 binding to TLR4 inhibited EL4 tumor growth. Thus, S100A9 and TLR4 appear to be involved in promoting tumor growth in two different tumor models and pharmacological inhibition of S100A9-TLR4 interactions is a novel and promising target for anti-tumor therapies.
通过将 TRAMP 小鼠与 S100A9 敲除（S100A9(-/-)）动物杂交，并对可触及肿瘤的出现进行评分，我们观察到缺乏 S100A9 表达的动物肿瘤生长延迟。在对照 C57BL/6 小鼠的正常前列腺组织中未观察到 CD11b(+) S100A9 表达细胞，但在 TRAMP 前列腺肿瘤中很容易检测到。此外，在人类前列腺肿瘤活检中观察到 S100A9 表达与 CD68(+)巨噬细胞相关。在缺乏 S100A9 配体 TLR4 的小鼠中，TRAMP 肿瘤的生长也延迟。在 S100A9(-/-)和 TLR4(-/-)小鼠中观察到 EL-4 淋巴瘤模型中的肿瘤生长抑制，但在缺乏替代 S100A9 受体 RAGE(-/-)的动物中没有观察到。当使用 RT-PCR 分析免疫调节基因的表达时，在缺乏 S100A9 和 TLR4 的小鼠中观察到的唯一共同变化是脾 CD11b(+)细胞中 TGFβ表达下调。最后，用一种小分子（ABR-215050）治疗小鼠，该小分子抑制 S100A9 与 TLR4 的结合，抑制 EL4 肿瘤生长。因此，S100A9 和 TLR4 似乎参与促进两种不同肿瘤模型中的肿瘤生长，抑制 S100A9-TLR4 相互作用的药理学抑制是一种新的有前途的抗肿瘤治疗靶点。
