Hepatic stellate cell and monocyte interaction contributes to poor prognosis in hepatocellular carcinoma.
Hepatic stellate cell and monocyte interaction contributes to poor prognosis in hepatocellular carcinoma.
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DOI：
10.1002/hep.27822
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发表时间：
2015-08
期刊：
影响因子：
--
通讯作者：
Wang XW
中科院分区：
文献类型：
--
作者：
Ji J;Eggert T;Budhu A;Forgues M;Takai A;Dang H;Ye Q;Lee JS;Kim JH;Greten TF;Wang XW
肝细胞癌（HCC）患者生存率低，术后复发率高。肝微环境在HCC的发生、发展和复发中起重要作用；然而，这些现象的因果机制尚不清楚。鉴于肝脏的主要潜在纤维化和肝硬化状况，容易发生HCC及其复发，炎症环境成分的改变被认为是促进HCC发展的因素。特别是，活化的肝星状细胞（a - hsc）在肝纤维化和肝硬化中起关键作用，已被认为是hcc易发微环境的贡献者。在这里，我们在319例HCC患者的非肿瘤组织中鉴定并验证了a - hsc特异性基因表达特征，该特征与HCC复发和生存显著且独立相关。肿瘤周围，而不是肿瘤组织相关的a - hsc特异性基因表达与复发和生存率低相关。对另外143例HCC患者的a - hsc特异性基因特征的分析和进一步的免疫组织化学验证表明，a - hsc优先影响单核细胞群，将其基因表达从炎症特征转变为免疫抑制特征。此外，a - hsc与单核细胞的相互作用通过促进细胞增殖、迁移和肿瘤球的形成，诱导HCC细胞的成瘤性和进行性特征。我们的研究结果表明，a - hsc通过与肝脏微环境中单核细胞活性的相互作用和改变，在促进HCC进展中起着重要作用。因此，破坏炎症环境和微环境成分之间的相互作用和信号事件可能是预防HCC肿瘤复发的有用治疗策略。
Hepatocellular carcinoma (HCC) patients suffer from a poor survival rate and high incidence of post-operative recurrence. The hepatic microenvironment plays a significant role in the initiation, progression and recurrence of HCC; however the causal mechanisms of these phenomena are unclear. Given the predominant underlying fibrotic and cirrhotic conditions of the liver prone to HCC and its recurrence, alterations of components of the inflammatory milieu have been suggested as factors that promote HCC development. In particular, activated hepatic stellate cells (A-HSC) that play a key role in liver fibrosis and cirrhosis, have been suggested as contributors to the HCC-prone microenvironment. Here, we have identified and validated an A-HSC-specific gene expression signature among non-tumor tissues of 319 HCC patients that is significantly and independently associated with HCC recurrence and survival. Peritumoral, rather than tumor tissue-related A-HSC-specific gene expression is associated with recurrence and poor survival. Analyses of A-HSC-specific gene signatures and further immunohistochemical validation in an additional 143 HCC patients have revealed that A-HSCs preferentially affect monocyte populations, shifting their gene expression from an inflammatory to an immunosuppressive signature. In addition, the interaction between A-HSCs and monocytes induces protumorigenic and progressive features of HCC cells by enhancing cell proliferation, migration and tumor sphere formation. Our results show that A-HSCs play a significant role in promoting HCC progression via interaction with and alteration of monocyte activities within the liver microenvironment. Thus, disrupting the interactions and signaling events between the inflammatory milieu and components of the microenvironment may be useful therapeutic strategies for preventing HCC tumor relapse.