Angiopoietin-2 Promotes Disease Progression of Neuroendocrine Tumors
Angiopoietin-2 Promotes Disease Progression of Neuroendocrine Tumors
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DOI：
10.1158/1078-0432.ccr-09-1924
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发表时间：
2010-01-15
影响因子：
11.5
通讯作者：
Scholz, Arne
中科院分区：
文献类型：
--
作者：
Detjen, Katharina M.;Rieke, Svenja;Scholz, Arne
目的：抑制血管生成是治疗神经内分泌肿瘤的一个有前途的策略。血管生成素-2（Angiopoietin-2，Ang-2）是内皮酪氨酸激酶Tie-2的配体，是肿瘤血管生成过程中血管重塑的关键调节因子。因此，我们解决了人类neuroendocrine tumors.Experimental设计的表达和生物学意义的Ang-2：手术标本和血清从神经内分泌肿瘤患者被用来确定Ang-2的表达，通过原位杂交或ELISA（循环Ang-2）。在稳定转染BON人胰腺神经内分泌肿瘤细胞后评价Ang-2的生物学效应。将BON克隆作为原位异种移植物在裸鼠中生长以确定肿瘤生长和腹部转移扩散。进一步分析包括微血管密度，淋巴管密度，和nodal invasion.Results：标本胰腺神经内分泌肿瘤和非转化胰腺组织显示血管紧张素-2 mRNA的表达在内皮细胞的均匀。与此相反，上皮表达的血管紧张素-2 mRNA只发生在神经内分泌肿瘤。尽管血清水平升高证实了Ang-2的成功诱导，但BON原位异种移植物中Ang-2的过表达并不影响原发性肿瘤的生长。然而，增加微血管密度和增强淋巴转移是明显的，在血管紧张素-2表达肿瘤，表明血管紧张素-2在实验性神经内分泌肿瘤的功能作用。与这一观点相一致，与健康对照组相比，神经内分泌肿瘤患者的循环Ang-2显著升高。此外，循环Ang-2与转移性与局限性疾病相关。结论：神经内分泌肿瘤中Ang-2的诱导表达是疾病进展的一个临床相关病理机制，是一个不良预后指标。Clin Cancer Res; 16（2）; 420-9.（C）2010年AACR。
Purpose: Inhibition of angiogenesis represents a promising therapeutic strategy in neuroendocrine tumors. Angiopoietin-2 (Ang-2), a ligand of the endothelial tyrosine kinase Tie-2, is emerging as a key regulator of vascular remodeling during tumorangiogenesis. We therefore addressed the expression and biological significance of Ang-2 in human neuroendocrine tumors.Experimental Design: Surgical specimens and serum from neuroendocrine tumor patients were used to determine Ang-2 expression by in situ hybridization or ELISA (circulating Ang-2). Ang-2 biological effects were evaluated following stable transfection into BON human pancreatic neuroendocrine tumor cells. BON clones were grown as orthotopic xenografts in nude mice to determine tumor growth and abdominal metastatic spread. Further analyses included microvessel density, lymphatic vessel density, and nodal invasion.Results: Specimens from pancreatic neuroendocrine tumors and nontransformed pancreatic tissue revealed uniform expression of Ang-2 mRNA in endothelial cells. In contrast, epithelial expression of Ang-2 mRNA occurred exclusively in neuroendocrine tumors. Overexpression of Ang-2 in BON orthotopic xenografts did not affect primary tumor growth, although successful Ang-2 induction was confirmed from elevated serum levels. However, increased microvessel density and enhanced lymphatic metastasis were evident in Ang-2-expressing tumors, indicating a functional role of Ang-2 in experimental neuroendocrine tumors. Consistent with this notion, circulating Ang-2 was significantly elevated in neuroendocrine tumor patients compared with healthy controls. Circulating Ang-2 furthermore correlated with metastatic versus localized disease. The highest Ang-2 concentrations occurred in patients with liver metastasis, and concentrations >= 75th percentile predicted shorter survival (P = 0.0003).Conclusion: Induction of Ang-2 in neuroendocrine tumors represents a clinically relevant pathomechanism of disease progression and constitutes an adverse prognostic marker. Clin Cancer Res; 16(2); 420-9. (C)2010 AACR.