Ogawa Minoru, Yamamoto Hirofumi, Nagano Hiroaki, Miyake Yasuhiro, Sugita Yurika, Hata Taishi, Kim Byung-No, Ngan Chew Yee, Damdinsuren Bazarragchaa, Ikenaga Masakazu, Ikeda Masataka, Ohue Masayuki, Nakamori Shoji, Sekimoto Mitsugu, Sakon Masato, Matsuura Nariaki, Monden Morito
Department of Surgery and Clinical Oncology, Graduate School of Medicine, Osaka University, Osaka, Japan.
Hepatology. 2004 Feb;39(2):528-39. doi: 10.1002/hep.20048.
We examined the RNA content of the gene encoding angiopoietin (Ang)-2, a modifier of angiogenesis, in hepatic metastases of colorectal cancer (CRC) to explore the role of this protein in neovascularization of metastatic foci. Metastatic CRC exhibited notable blood flow and tumor vessel formation at tumor frontiers. Reverse-transcription polymerase chain reaction assays indicated that the ANG2 RNA content was greater in metastatic CRC than in primary CRC. Investigation of metastatic foci using laser capture microdissection revealed that the RNA content of ANG2, but not ANG1, increased from the bordering liver region to the periphery of the metastatic disease, and also from the periphery to the intermediate portion of the metastatic lesion; immunohistochemical analysis confirmed that there was a corresponding gradual increase in Ang-2 protein expression. Tie-2, a receptor for angiopoietins, was preferentially expressed in the bordering liver region rather than in metastatic CRC. Vascular endothelial growth factor (VEGF) also exhibited an expression pattern similar to that of Ang-2, and there was a significant correlation between the RNA content of ANG2 and that of VEGF in dissected samples (P =.002). Western blot analysis suggested that expression of Ang-1, Ang-2, Tie-2, and VEGF may be regulated at a transcriptional level. The increase in ANG2 RNA content from the peripheral portion of the tumor to the intermediate portion, coinciding with the decrease in recruitment of periendothelial supporting cells around the vascular endothelial cells, suggests that Ang-2 may play a role in the immaturity of tumor vessels. In conclusion, the current study suggests that Ang-2 and VEGF may cooperate to enhance the formation of new blood vessels in metastases of CRC to the liver.
我们检测了血管生成调节因子血管生成素（Ang）-2编码基因的RNA含量，以探讨该蛋白在结直肠癌（CRC）肝转移灶新生血管形成中的作用。转移性CRC在肿瘤边缘表现出显著的血流和肿瘤血管形成。逆转录聚合酶链反应分析表明，转移性CRC中ANG2 RNA含量高于原发性CRC。使用激光捕获显微切割技术对转移灶进行研究发现，ANG2而非ANG1的RNA含量从邻近肝脏区域到转移病灶周边逐渐增加，并且从转移病灶周边到中间部分也逐渐增加；免疫组织化学分析证实Ang-2蛋白表达相应地逐渐增加。血管生成素的受体Tie-2在邻近肝脏区域而非转移性CRC中优先表达。血管内皮生长因子（VEGF）也呈现出与Ang-2相似的表达模式，并且在切割样本中ANG2的RNA含量与VEGF的RNA含量之间存在显著相关性（P = 0.002）。蛋白质印迹分析表明，Ang-1、Ang-2、Tie-2和VEGF的表达可能在转录水平受到调控。ANG2 RNA含量从肿瘤周边部分到中间部分增加，同时血管内皮细胞周围周内皮支持细胞募集减少，这表明Ang-2可能在肿瘤血管不成熟中发挥作用。总之，本研究表明，Ang-2和VEGF可能协同作用以增强CRC肝转移灶中新血管的形成。
