Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany.
Institute of Pathology, Heidelberg University, Heidelberg, Germany.
EMBO Mol Med. 2017 Jun;9(6):741-749. doi: 10.15252/emmm.201607222.
Hepatocellular carcinoma (HCC) is among the most common and deadliest cancers worldwide. A major contributor to HCC progression is the cross talk between tumor cells and the surrounding stroma including activated hepatic stellate cells (HSC). Activation of HSC during liver damage leads to upregulation of the orphan receptor endosialin (CD248), which contributes to regulating the balance of liver regeneration and fibrosis. Based on the established role of endosialin in regulating HSC/hepatocyte cross talk, we hypothesized that HSC-expressed endosialin might similarly affect cell proliferation during hepatocarcinogenesis. Indeed, the histological analysis of human HCC samples revealed an inverse correlation between tumor cell proliferation and stromal endosialin expression. Correspondingly, global genetic inactivation of endosialin resulted in accelerated tumor growth in an inducible mouse HCC model. A candidate-based screen of tumor lysates and differential protein arrays of cultured HSC identified several established hepatotropic cytokines, including IGF2, RBP4, DKK1, and CCL5 as being negatively regulated by endosialin. Taken together, the experiments identify endosialin-expressing HSC as a negative regulator of HCC progression.
肝细胞癌（HCC）是全球最常见和致命的癌症之一。肿瘤细胞与周围基质之间的串扰是 HCC 进展的主要原因之一，包括激活的肝星状细胞（HSC）。肝损伤期间 HSC 的激活导致孤儿受体内皮细胞唾液酸糖蛋白 1（endosialin，CD248）的上调，这有助于调节肝再生和纤维化的平衡。基于 endosialin 在调节 HSC/肝细胞串扰中的既定作用，我们假设 HSC 表达的 endosialin 可能同样会影响肝癌发生过程中的细胞增殖。事实上，对人类 HCC 样本的组织学分析显示，肿瘤细胞增殖与基质 endosialin 表达呈负相关。相应地，在诱导型小鼠 HCC 模型中，endosialin 的全局遗传失活导致肿瘤生长加速。对肿瘤裂解物的基于候选的筛选和培养的 HSC 的差异蛋白阵列分析鉴定出几种已建立的嗜肝细胞细胞因子，包括 IGF2、RBP4、DKK1 和 CCL5，它们受 endosialin 负调控。总之，这些实验确定表达 endosialin 的 HSC 是 HCC 进展的负调节剂。
