Vascular Endothelial Growth Factor C Stimulates Progression of Human Gastric Cancer via Both Autocrine and Paracrine Mechanisms
Vascular Endothelial Growth Factor C Stimulates Progression of Human Gastric Cancer via Both Autocrine and Paracrine Mechanisms
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DOI：
10.1158/1078-0432.ccr-08-0818
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发表时间：
2008-11-15
影响因子：
11.5
通讯作者：
Chayama, Kazuaki
中科院分区：
文献类型：
--
作者：
Kodama, Michiyo;Kitadai, Yasuhiko;Chayama, Kazuaki
目的：血管内皮生长因子(VEGF)-C通过激活由淋巴内皮细胞表达的VEGF受体(VEGFR)-3诱导淋巴管生成。在几种恶性细胞中也检测到VEGFR-3，但VEGFR-3在恶性细胞中的表达意义尚不清楚。在本研究中，我们检测了VEGFR-3在胃癌细胞中的表达和功能。实验设计：我们检测了4种人胃癌细胞系和36例胃癌手术标本中VEGFR-3的表达。我们还利用cDNA微阵列技术检测了VEGF-C对表达vegfr -3的KKLS细胞基因表达的影响。为了自分泌刺激VEGF-C/VEGFR-3信号，将VEGF-C表达载体转染到KKLS细胞中，建立稳定的转染载体。然后将这些细胞移植到裸鼠的胃壁中。结果：4株胃癌细胞系中有2株表达VEGFR-3 mRNA。在36例胃癌标本中，17例肿瘤细胞检测到vegfr -3特异性免疫反应性。体外用VEGF-C处理KKLS细胞可刺激细胞增殖，并增加编码cyclin D1、胎盘生长因子和自分泌运动因子的mrna的表达。将转染vegf - c的细胞和对照细胞接种于裸鼠胃壁后，与对照细胞相比，转染vegf - c的细胞的肿瘤生长速度大大加快。vegf - c转染肿瘤的血管生成和淋巴管生成也比对照肿瘤大。结论：胃癌细胞表达VEGF-C和VEGFR-3。VEGF-C可能通过自分泌和旁分泌机制在人胃癌的进行性生长中发挥作用。
Purpose: Vascular endothelial growth factor (VEGF)-C induces lymphangiogenesis by activating the VEGF receptor (VEGFR)-3, which is expressed by lymphatic endothelial cells. VEGFR-3 has also been detected on several malignant cells, but the significance of VEGFR-3 expression on malignant cells remains unclear. In this study, we examined the expression and function of VEGFR-3 in gastric carcinoma cells.Experimental Design: We examined the expression of VEGFR-3 by four human gastric carcinoma cell lines and in 36 surgical specimens of gastric carcinoma. We also used cDNA micro-arrays to examine the effect of VEGF-C on gene expression in VEGFR-3-expressing KKLS cells. To stimulate VEGF-C/VEGFR-3 signaling in an autocrine manner, the VEGF-C expression vector was transfected into KKLS cells, and stable transfectants were established. These cells were then transplanted into the gastric walls of nude mice.Results: Two of the four gastric carcinoma cell lines expressed VEGFR-3 mRNA. In 17 of 36 gastric carcinoma specimens, VEGFR-3-specific immunoreactivity was detected on tumor cells. In vitro treatment of KKLS cells with VEGF-C stimulated cell proliferation and increased expression of mRNAs encoding cyclin D1, placental growth factor, and autocrine motility factor. Following inoculation of VEGF-C-transfected and control cells into the gastric walls of nude mice, tumor growth of the VEGF-C-transfected cells was greatly accelerated in comparison with that of control cells. Greater angiogenesis and lymphangiogenesis were also detected in VEGF-C-transfected tumors than in control tumors.Conclusions: Gastric carcinoma cells express VEGF-C and VEGFR-3. VEGF-C may play a role in the progressive growth of human gastric carcinoma through both autocrine and paracrine mechanisms.