Mei Kai, Cai Xiao-Hong, Du Lei, Chen Yan-Fang, Huang Shuang, Chen Jing, Yin Xu-De, Zhang Zhi-Xuan, Zhao Xin, Zhou Cheng-Ya, Yu Jing-Rui
Department of Medical Oncology,Sichuan Cancer Hospital, Chengdu, Sichuan 610041, People's Republic of China.
Chin J Cancer. 2010 Jan;29(1):32-7. doi: 10.5732/cjc.009.10246.
Studies have shown that nitric oxide (NO) derived from endothelial nitric oxide synthase (eNOS) is expressed widely in tumor tissues and regulates tumor angiogenesis. However, the results are controversial. This study was to investigate the effect of NO on tumor angiogenesis and its mechanism.
C57BL/6 mice inoculated with Lewis lung cancer cells were randomly divided into three groups. Mice in the NO group were inoculated with lung cancer cells transfected with eNOS gene, mice in the L-NAME group with L-NAME, an eNOS antagonist, and mice in the control group with normal saline. Plasma concentration of NO and the number of endothelial progenitor cells (EPCs) in peripheral blood were detected . Tumor vessel density, CD133+ cells, and the expression of VEGF-VEGFR in tumor tissues were also measured.
Four weeks after inoculation of Lewis cells, tumor volume was significantly larger in control group [ (3022 +/- 401) mm(3)] than in the L-NAME group [ (1204 +/-97) ) mm(3)] and in the eNOS group [(1824 +/- 239) mm(3)] (P<0.01). eNOS protein and NO production increased significantly in Lewis lung cancer cells transfected with eNOS gene. But the number of CD133-positive cells and vessel density in tumors were significantly lower in the eNOS group than in the control group [(48+/-19) / HPF vs. ( 103 +/- 27)/ HPF, (19+/- 7) HPF vs. (31 +/- 9) HPF, P<0.05]. The number of EPCs in peripheral blood was not statistically different between each group. The levels of NO in blood and tumor tissue significantly decreased after the treatment of L-NAME, while the tumor vessel density reduced to 12+/- 5/ HPF (P<0.01, vs. the control group; P<0.05, vs the eNOS transfected group). The number of EPCs in blood and that of CD133-positive cells in tumor tissue were significantly smaller in the L-NAME group than in the control group (P<0.05).
No derived from eNOS inhibits angiogenesis and tumor growth, which may be due to its suppression on either the mobilization or homing of EPCs via VEGF binding to VEGFR.
研究表明，内皮型一氧化氮合酶（eNOS）产生的一氧化氮（NO）在肿瘤组织中广泛表达并调节肿瘤血管生成。然而，结果存在争议。本研究旨在探讨NO对肿瘤血管生成的影响及其机制。
将接种Lewis肺癌细胞的C57BL/6小鼠随机分为三组。NO组接种转染eNOS基因的肺癌细胞，L-NAME组接种eNOS拮抗剂L-NAME，对照组接种生理盐水。检测血浆中NO浓度及外周血中内皮祖细胞（EPC）数量。同时测量肿瘤血管密度、CD133+细胞数量以及肿瘤组织中VEGF-VEGFR的表达。
接种Lewis细胞4周后，对照组肿瘤体积[（3022±401）mm³]显著大于L-NAME组[（1204±97）mm³]和eNOS组[（1824±239）mm³]（P<0.01）。转染eNOS基因的Lewis肺癌细胞中eNOS蛋白和NO生成显著增加。但eNOS组肿瘤中CD133阳性细胞数量和血管密度显著低于对照组[（48±19）/HPF对（103±27）/HPF，（19±7）HPF对（31±9）HPF，P<0.05]。各组外周血中EPC数量无统计学差异。L-NAME处理后血液和肿瘤组织中NO水平显著降低，同时肿瘤血管密度降至12±5/HPF（P<0.01，与对照组相比；P<0.05，与转染eNOS组相比）。L-NAME组血液中EPC数量和肿瘤组织中CD133阳性细胞数量显著少于对照组（P<0.05）。
eNOS产生的NO抑制血管生成和肿瘤生长，这可能是由于其通过VEGF与VEGFR结合抑制EPC的动员或归巢所致。
