Durkin Alan J, Bloomston Mark, Yeatman Timothy J, Gilbert-Barness Enid, Cojita Diane, Rosemurgy Alexander S, Zervos Emmanuel E
Department of Surgery, University of South Florida College of Medicine and Tampa General Hospital, Digestive Disorders Center, Tampa, FL, USA.
J Am Coll Surg. 2004 Nov;199(5):724-31. doi: 10.1016/j.jamcollsurg.2004.07.021.
Derangements in the balance of the Tie-2 receptor ligands, angiopoietin-1 and angiopoietin-2 (Ang-1 and Ang-2), have been implicated in the growth and differentiation of several human tumors. To assess the potential role of angiogenesis factors in pancreatic tumorigenesis, we confirmed previously observed oligonucleotide-based microarray data by analyzing their expression in pancreatic tumors using semiquantitative reverse transcription polymerase chain reaction and immunohistochemistry.
RNA harvested from tissue samples obtained from patients with normal pancreata, adenocarcinoma of the pancreas, and neuroendocrine tumors of the pancreas (nine each) was grouped by tissue type, pooled, and hybridized to a cDNA microarray and global gene expression patterns were determined. Semiquantitative reverse transcription polymerase chain reaction was applied to individual pool components to specifically determine expression of Tie-2, Ang-1, and Ang-2. A separate set of tumors and matched normal pancreas were then stained for expression of Ang-2 protein using immunohistochemistry.
Microarray data showed that Ang-2 was upregulated in neuroendocrine tumors ( approximately 8 times more than normal) and adenocarcinoma of the pancreas ( approximately 5 times more than normal) although Ang-1 and Tie-2 were not differentially expressed. Reverse transcription polymerase chain reaction confirmed these findings showing strong Ang-2 expression in nine of nine neuroendocrine tumors, eight of nine adenocarcinoma of the pancreas, and weak expression in two of nine normal pancreata. Immunohistochemistry showed tumor-specific staining of Ang-2 in 10 of 15 matched adenocarcinoma of the pancreas (67%) and 6 of 8 neuroendocrine tumors (75%).
Although Tie-2 and Ang-1 are not differentially expressed in pancreatic tumors, Ang-2 gene and gene product are overexpressed, suggesting a significant role for Ang-2 in pancreatic tumorigenesis. Differential expression of Ang-2 in human tumors may be useful as a diagnostic and therapeutic target.
Tie-2受体配体血管生成素-1和血管生成素-2（Ang-1和Ang-2）平衡紊乱与多种人类肿瘤的生长和分化有关。为评估血管生成因子在胰腺肿瘤发生中的潜在作用，我们通过使用半定量逆转录聚合酶链反应和免疫组织化学分析其在胰腺肿瘤中的表达，证实了先前观察到的基于寡核苷酸的微阵列数据。
从正常胰腺、胰腺腺癌和胰腺神经内分泌肿瘤患者（各9例）获取的组织样本中提取的RNA按组织类型分组、汇集，与cDNA微阵列杂交并确定全局基因表达模式。应用半定量逆转录聚合酶链反应于各个汇集组分，以特异性确定Tie-2、Ang-1和Ang-2的表达。然后使用免疫组织化学对另一组肿瘤和匹配的正常胰腺进行Ang-2蛋白表达染色。
微阵列数据显示，血管生成素-2在胰腺神经内分泌肿瘤（比正常高约8倍）和胰腺腺癌（比正常高约5倍）中上调，而血管生成素-1和Tie-2无差异表达。逆转录聚合酶链反应证实了这些发现，显示血管生成素-2在9例胰腺神经内分泌肿瘤中的9例、9例胰腺腺癌中的8例中强烈表达，在9例正常胰腺中的2例中弱表达。免疫组织化学显示，在15例匹配的胰腺腺癌中有10例（67%）和8例神经内分泌肿瘤中有6例（75%）存在血管生成素-2的肿瘤特异性染色。
尽管Tie-2和血管生成素-1在胰腺肿瘤中无差异表达，但血管生成素-2基因和基因产物过度表达，提示血管生成素-2在胰腺肿瘤发生中起重要作用。血管生成素-2在人类肿瘤中的差异表达可能作为诊断和治疗靶点。
