Regulation of accumulation and function of myeloid derived suppressor cells in different murine models of hepatocellular carcinoma.
Regulation of accumulation and function of myeloid derived suppressor cells in different murine models of hepatocellular carcinoma.
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DOI：
10.1016/j.jhep.2013.06.010
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发表时间：
2013-11
影响因子：
25.7
通讯作者：
Greten, Tim F.
中科院分区：
文献类型：
--
作者：
Kapanadze, Tamar;Gamrekelashvili, Jaba;Ma, Chi;Chan, Carmen;Zhao, Fei;Hewitt, Stephen;Zender, Lars;Kapoor, Veena;Felsher, Dean W.;Manns, Michael P.;Korangy, Firouzeh;Greten, Tim F.
髓源性抑制细胞（MDSC）是具有免疫抑制活性的未成熟髓细胞。它们在患有不同类型癌症的荷瘤小鼠和人类中积累，包括肝细胞癌（HCC）。本研究的目的是在小鼠肝癌模型中检查MDSC的生物学，并鉴定一种模拟人类疾病的模型。在不同年龄的小鼠中进行MDSC的比较分析，这些小鼠具有可移植的、二乙基亚硝胺（DEN）诱导的和表达MYC的HCC。在HCC小鼠中发现MDSC蓄积，与测试的模型无关。与缓慢生长的DEN诱导或MYC表达的HCC相反，可移植肿瘤快速诱导MDSC的全身募集，其中MDSC数量仅在患有晚期肿瘤的小鼠中肝内增加。来自皮下肿瘤小鼠的MDSC比来自DEN诱导的HCC小鼠的MDSC更具抑制性。在皮下肿瘤小鼠中观察到与MDSC生成（GM-CSF、VEGF、IL-6、IL-1β）和迁移（MCP-1、KC、S100 A8、S100 A9）相关的基因表达增强。相反，在DEN诱导的HCC小鼠中，只有KC水平增加。KC和GM-CSF过表达或抗KC和抗GM-CSF治疗控制了HCC小鼠中MDSC的频率。最后，成功使用索拉非尼进行抗肿瘤治疗后，MDSC的频率降低。我们的数据表明，MDSC的积累是一个晚期事件在肝癌的发生和显着不同的肿瘤模型的研究。
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. The comparative analysis of MDSC was performed in mice, bearing transplantable, diethylnitrosoamine (DEN)-induced and MYC-expressing HCC at different ages. An accumulation of MDSC was found in mice with HCC irrespectively 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, IL-6, IL-1β) 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 over-expression 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. Our data indicate that MDSC accumulation is a late event during hepatocarcinogenesis and differs significantly depending on the tumor model studied.
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