Gao Peng, Zhou Geng-Yin, Zhang Qing-Hui, Su Zhong-Xue, Zhang Ting-Guo, Xiang Lei, Wang Yan, Zhang Shun-Li, Mu Kun
Department of Pathology, School of Medicine, Shandong University, Jinan, PR China.
J Pathol. 2009 Jun;218(2):192-200. doi: 10.1002/path.2523.
Lymphatic metastasis is an important way that gastric carcinomas can spread. However, little is known about the mechanisms of lymphangiogenesis and its clinical significance in gastric carcinomas. In the present study, lymphatic vessel density (LVD), VEGF-C expression, and proliferative activity of lymphatic endothelium were determined in human gastric carcinomas and xenografts of gastric cancer cells in nude mice. The development of lymphangiogenesis and its correlation with patient prognosis were investigated. The results showed that lymphatic vessels were observed mainly in peripheral tumour tissue with significantly (p < 0.05) higher P-LVD (peri-tumoural-LVD) than I-LVD (intra-tumoural-LVD). The expression of VEGF-C was heterogeneous within tumours, with a significantly higher expression (immunostaining score) at the margin than at the tumour centre (p < 0.05). A significant correlation was found between VEGF-C expression at the margin (but not at the centre) and P-LVD (r = 0.72, p < 0.01). High proliferative activity of lymphatic endothelium was also observed in the peripheral tissues, with a significant correlation between proliferative activity of lymphatic endothelium and VEGF-C expression (p < 0.05). These data imply that the increased lymphatics may have been newly formed following stimulation by VEGF-C. High VEGF-C expression at the margin of gastric carcinomas could induce lymphangiogenesis in the peri-tumoural stroma and contribute to the increased P-LVD. The data from mice tumour xenografts also suggested that VEGF-C produced from the transplanted gastric carcinoma cells could induce lymphangiogenesis around them. In patients, VEGF-C expression at tumour margins was associated with nodal metastasis, lymphatic vessel invasion, poor recurrence-free survival, and poor overall survival, and could serve as an independent predictor for patients with gastric carcinoma.
淋巴转移是胃癌扩散的重要途径。然而，关于胃癌中淋巴管生成的机制及其临床意义知之甚少。在本研究中，测定了人胃癌组织及裸鼠胃癌细胞异种移植瘤中的淋巴管密度（LVD）、VEGF-C表达以及淋巴管内皮细胞的增殖活性。研究了淋巴管生成的发展及其与患者预后的相关性。结果显示，淋巴管主要见于肿瘤周边组织，肿瘤周边LVD（P-LVD）显著高于肿瘤内LVD（I-LVD）（p<0.05）。肿瘤内VEGF-C表达呈异质性，边缘处的表达（免疫染色评分）显著高于肿瘤中心（p<0.05）。边缘（而非中心）VEGF-C表达与P-LVD之间存在显著相关性（r = 0.72，p<0.01）。在周边组织中也观察到淋巴管内皮细胞的高增殖活性，淋巴管内皮细胞的增殖活性与VEGF-C表达之间存在显著相关性（p<0.05）。这些数据表明，增加的淋巴管可能是在VEGF-C刺激后新形成的。胃癌边缘高VEGF-C表达可诱导肿瘤周边基质中的淋巴管生成，并导致P-LVD增加。小鼠肿瘤异种移植的数据也表明，移植的胃癌细胞产生的VEGF-C可诱导其周围的淋巴管生成。在患者中，肿瘤边缘的VEGF-C表达与淋巴结转移、淋巴管侵犯、无复发生存期差和总生存期差相关，可作为胃癌患者的独立预测指标。
