Tumor Cell-Derived Angiopoietin-2 Promotes Metastasis in Melanoma.
Tumor Cell-Derived Angiopoietin-2 Promotes Metastasis in Melanoma.
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DOI：
10.1158/0008-5472.can-19-2660
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发表时间：
2020-06-15
期刊：
影响因子：
11.2
通讯作者：
Felcht M
中科院分区：
文献类型：
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作者：
Abdul Pari AA;Singhal M;Hübers C;Mogler C;Schieb B;Gampp A;Gengenbacher N;Reynolds LE;Terhardt D;Géraud C;Utikal J;Thomas M;Goerdt S;Hodivala-Dilke KM;Augustin HG;Felcht M
血管生成素(Angpt)-TIE信号通路控制血管成熟并维持静息脉管系统的静止表型。上下文激动和拮抗Tie2配体ANGPT2被认为完全由内皮细胞产生，在炎症和癌症等病理疾病中破坏构成性ANGPT1-TIE2信号，破坏微血管的稳定。然而，零星的报道也将肿瘤细胞描述为ANGPT2的来源。采用基于原位杂交的ANGPT2检测，我们在黑色素瘤患者的一个亚群中发现了ANGPT2的强肿瘤细胞表达。活检的比较分析显示，在转移部位表达angpt2的肿瘤细胞比例高于原发部位。肿瘤细胞表达的Angpt2对于原发肿瘤的生长是必不可少的，然而对原发肿瘤的深入分析显示，在没有明显的免疫和血管改变的情况下，沉默肿瘤细胞Angpt2表达会增强肿瘤内坏死。缺乏angpt2的肿瘤细胞的全球转录谱鉴定了氧化还原稳态的扰动和对细胞氧化应激的增加反应。超微结构分析表明，在angpt2沉默的肿瘤细胞中，功能失调的线粒体显著增加，从而导致ROS产生和下游MAPK应激信号的增强。在功能上，angpt2沉默的肿瘤细胞中ROS的增强降低了体外和体内的定植潜力。综上所述，这些发现揭示了迄今为止未被认识到的肿瘤细胞表达的ANGPT2作为转移定殖的自分泌阳性调节因子的作用，并验证了ANGPT2作为一个明确定义的黑色素瘤患者亚群的治疗靶点。
The Angiopoietin (Angpt)-TIE signaling pathway controls vascular maturation and maintains the quiescent phenotype of resting vasculature. The contextual agonistic and antagonistic Tie2 ligand ANGPT2 is believed to be exclusively produced by endothelial cells, disrupting constitutive ANGPT1-TIE2 signaling to destabilize the microvasculature during pathological disorders like inflammation and cancer. However, scattered reports have also portrayed tumor cells as a source of ANGPT2. Employing in situ hybridization-based detection of ANGPT2, we found strong tumor cell expression of ANGPT2 in a subset of melanoma patients. Comparative analysis of biopsies revealed a higher fraction of ANGPT2-expressing tumor cells in metastatic versus primary sites. Tumor cell-expressed Angpt2 was dispensable for primary tumor growth, yet in-depth analysis of primary tumors revealed enhanced intratumoral necrosis upon silencing of tumor cell Angpt2 expression in the absence of significant immune and vascular alterations. Global transcriptional profiling of Angpt2-deficient tumor cells identified perturbations in redox homeostasis and an increased response to cellular oxidative stress. Ultrastructural analyses illustrated a significant increase of dysfunctional mitochondria in Angpt2-silenced tumor cells, thereby resulting in enhanced ROS production and downstream MAPK stress signaling. Functionally, enhanced ROS in Angpt2-silenced tumor cells reduced colonization potential in vitro and in vivo. Taken together, these findings uncover the hitherto unappreciated role of tumor cell-expressed ANGPT2 as an autocrine positive regulator of metastatic colonization and validate ANGPT2 as a therapeutic target for a well-defined subset of melanoma patients.