在不同的肝癌小鼠模型中髓源性抑制细胞的积累和功能调节。
Regulation of accumulation and function of myeloid derived suppressor cells in different murine models of hepatocellular carcinoma.
机构信息
Gastrointestinal Malignancy Section, Medical Oncology Branch, National Cancer Institute, Bethesda, USA; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
出版信息
J Hepatol. 2013 Nov;59(5):1007-13. doi: 10.1016/j.jhep.2013.06.010. Epub 2013 Jun 22.
BACKGROUND & AIMS: Myeloid derived suppressor cells (MDSC) are immature myeloid cells with immunosuppressive activity. They accumulate in tumor-bearing mice and humans with different types of cancer, including hepatocellular carcinoma (HCC). The aim of this study was to examine the biology of MDSC in murine HCC models and to identify a model, which mimics the human disease.
METHODS
The comparative analysis of MDSC was performed in mice, bearing transplantable, diethylnitrosoamine (DEN)-induced and MYC-expressing HCC at different ages.
RESULTS
An accumulation of MDSC was found in mice with HCC irrespective of the model tested. Transplantable tumors rapidly induced systemic recruitment of MDSC, in contrast to slow-growing DEN-induced or MYC-expressing HCC, where MDSC numbers only increased intra-hepatically in mice with advanced tumors. MDSC derived from mice with subcutaneous tumors were more suppressive than those from mice with DEN-induced HCC. Enhanced expression of genes associated with MDSC generation (GM-CSF, VEGF, IL6, IL1β) and migration (MCP-1, KC, S100A8, S100A9) was observed in mice with subcutaneous tumors. In contrast, only KC levels increased in mice with DEN-induced HCC. Both KC and GM-CSF overexpression or anti-KC and anti-GM-CSF treatment controlled MDSC frequency in mice with HCC. Finally, the frequency of MDSC decreased upon successful anti-tumor treatment with sorafenib.
CONCLUSIONS
Our data indicate that MDSC accumulation is a late event during hepatocarcinogenesis and differs significantly depending on the tumor model studied.
背景与目的
髓系来源抑制细胞（MDSC）是具有免疫抑制活性的未成熟髓系细胞。它们在荷瘤小鼠和不同类型癌症的患者中积累，包括肝细胞癌（HCC）。本研究旨在研究小鼠 HCC 模型中 MDSC 的生物学特性，并鉴定一种模拟人类疾病的模型。
方法
对携带可移植、二乙基亚硝胺（DEN）诱导和 MYC 表达 HCC 的不同年龄小鼠进行 MDSC 的比较分析。
结果
无论所测试的模型如何，在患有 HCC 的小鼠中均发现 MDSC 积累。移植瘤迅速诱导 MDSC 的全身募集，与缓慢生长的 DEN 诱导或 MYC 表达 HCC 相反，在肿瘤进展的小鼠中，MDSC 数量仅在肝内增加。源自皮下肿瘤小鼠的 MDSC 比源自 DEN 诱导 HCC 小鼠的 MDSC 更具抑制作用。在患有皮下肿瘤的小鼠中观察到与 MDSC 生成（GM-CSF、VEGF、IL6、IL1β）和迁移（MCP-1、KC、S100A8、S100A9）相关的基因表达增强。相比之下，仅在 DEN 诱导 HCC 小鼠中 KC 水平增加。KC 和 GM-CSF 的过表达或抗 KC 和抗 GM-CSF 治疗均可控制 HCC 小鼠中 MDSC 的频率。最后，sorafenib 成功抗肿瘤治疗后，MDSC 的频率降低。
结论
我们的数据表明，MDSC 积累是肝癌发生过程中的晚期事件，并且根据所研究的肿瘤模型而有很大差异。
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