Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Campus Virchow-Klinikum, Charité-Universitätsmedizin, Berlin, Germany.
Clin Cancer Res. 2010 Jan 15;16(2):420-9. doi: 10.1158/1078-0432.CCR-09-1924. Epub 2010 Jan 12.
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 tumor angiogenesis. We therefore addressed the expression and biological significance of Ang-2 in human neuroendocrine tumors.
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.
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 >or=75th percentile predicted shorter survival (P = 0.0003).
Induction of Ang-2 in neuroendocrine tumors represents a clinically relevant pathomechanism of disease progression and constitutes an adverse prognostic marker.
血管生成抑制代表了神经内分泌肿瘤有前途的治疗策略。血管生成素-2（Ang-2）是内皮酪氨酸激酶 Tie-2 的配体，它作为肿瘤血管生成过程中血管重塑的关键调节因子而出现。因此，我们研究了 Ang-2 在人类神经内分泌肿瘤中的表达和生物学意义。
使用手术标本和神经内分泌肿瘤患者的血清，通过原位杂交或 ELISA（循环 Ang-2）来确定 Ang-2 的表达。通过稳定转染 BON 人胰腺神经内分泌肿瘤细胞来评估 Ang-2 的生物学效应。BON 克隆作为原位异种移植在裸鼠中生长，以确定肿瘤生长和腹部转移扩散。进一步的分析包括微血管密度、淋巴管密度和淋巴结侵犯。
胰腺神经内分泌肿瘤和非转化胰腺组织的标本显示内皮细胞中 Ang-2 mRNA 的均匀表达。相比之下，上皮细胞中的 Ang-2 mRNA 仅在神经内分泌肿瘤中表达。在 BON 原位异种移植中过表达 Ang-2 不会影响原发性肿瘤的生长，尽管从升高的血清水平证实了成功的 Ang-2 诱导。然而，在表达 Ang-2 的肿瘤中观察到微血管密度增加和淋巴管转移增强，表明 Ang-2 在实验性神经内分泌肿瘤中具有功能作用。与这一观点一致的是，与健康对照组相比，神经内分泌肿瘤患者的循环 Ang-2 明显升高。循环 Ang-2 还与转移性与局限性疾病相关。在有肝转移的患者中，Ang-2 浓度最高，浓度>或=75 百分位数预测生存率较短（P = 0.0003）。
在神经内分泌肿瘤中诱导 Ang-2 是疾病进展的一种具有临床相关性的发病机制，并构成不良预后标志物。
