The angiogenic switch for vascular endothelial growth factor (VEGF)-A, VEGF-B, VEGF-C, and VEGF-D in the adenoma-carcinoma sequence during colorectal cancer progression
The angiogenic switch for vascular endothelial growth factor (VEGF)-A, VEGF-B, VEGF-C, and VEGF-D in the adenoma-carcinoma sequence during colorectal cancer progression
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DOI：
10.1002/path.1339
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发表时间：
2003-06-01
影响因子：
7.3
通讯作者：
Fox, SB
中科院分区：
文献类型：
--
作者：
Hanrahan, V;Currie, MJ;Fox, SB
血管生成对于肿瘤生长和转移是必不可少的。它由血管生成因子控制，其中最重要的因子之一是血管内皮生长因子（VEGF）A。虽然它的作用已被证明在许多肿瘤类型，包括结直肠癌（CRC），腺瘤，侵袭性肿瘤生长，并进展到转移表型的新的家庭成员的重要性已在CRC的特点不佳。本研究的目的是确定CRC进展过程中VEGF血管生成转换的作用和时间。我们检测了VEGF配体的基因表达，（VEGF-A、VEGF-B、VEGF-C和VEGF-D）及其受体（VEGFR-1，VEGFR-2，和VEGFR-3），正常结肠直肠组织（n = 20），腺瘤（n = 10），和代表不同杜克分期的CRC（n = 71），使用核糖核酸酶保护分析，半定量相对逆转录酶聚合酶链反应，并通过免疫组织化学分析其表达模式。VEGF-A mRNA在结直肠组织中含量最高，其次是VEGF-B、VEGF-C和VEGF-D。与正常组织相比，VEGF-A和VEGF-B mRNA在腺瘤中显著更丰富（分别为p = 0.0003和p = 0.04），而与正常组织相比，VEGF-A和VEGF-C在癌中显著增加（分别为p = 0.0006和p = 0.0009）。与腺瘤相比，癌中VEGF-C mRNA的量显著更大（p = 0.03），而与腺瘤相比，癌中VEGF-B的量显著减少（p = 0.0002）。VEGF-D mRNA在正常组织中的表达明显高于腺瘤（p = 0.0001）和癌（p < 0.0001）。在远离原发肿瘤的正常组织中，与杜克A期肿瘤相比，杜克B期和杜克C期患者的VEGF-A和VEGF-D mRNA的量分别显著更高（分别为p = 0.04和p = 0.01）。免疫组织化学显示，所有配体在组织学正常组织中的基础水平较低，它们在肿瘤上皮中的表达反映了所鉴定的mRNA表达水平。VEGF-A和VEGF-C mRNA水平与肿瘤分级（分别为p = 0.01和p = 0.01）和肿瘤大小（分别为p = 0.001和p = 0.01）显著相关，但与患者年龄、性别、浸润边缘、淋巴细胞反应、血管浸润、杜克分期或淋巴结受累无关（p > 0.05）。VEGF-B mRNA与浸润边缘相关（P = 0.04），但与其他临床病理变量无关，VEGF-D的表达与任何检测参数均无相关性。VEGFR-1与肿瘤分级（p = 0.02）、杜克分期（p < 0.001）和淋巴结受累（P = 0.004）显著相关，VEGFR-2与淋巴结受累（p = 0.02）显著相关，而VEGFR-3与任何检测的临床病理学变量无关。这些结果表明，VEGF-A和VEGF-B在腺瘤形成阶段的肿瘤发展早期发挥作用，VEGF-C在晚期疾病中发挥作用，此时转移扩散的可能性更大。从远离原发性肿瘤的部位收集的正常组织中VEGF-A和VEGF-D表达水平增加的发现表明周围肿瘤环境的变化可能增强肿瘤细胞的随后扩散。版权所有（C）2003约翰威利父子有限公司。
Angiogenesis is essential for tumour growth and metastasis. It is controlled by angiogenic factors, one of the most important being vascular endothelial growth factor (VEGF)A. Although its role has been demonstrated in many tumour types including colorectal carcinoma (CRC), the importance of the newer family members in adenoma, invasive tumour growth, and progression to a metastatic phenotype has been poorly characterized in CRC. The aim of this study was to determine the role and timing of the VEGF angiogenic switch during CRC progression. We measured the gene expression of VEGF ligands (VEGF-A, VEGF-B, VEGF-C, and VEGF-D) and their receptors (VEGFR-1, VEGFR-2, and VEGFR-3), in normal colorectal tissues (n = 20), adenomas (n = 10), and in CRC (n = 71) representing different Duke's stages using ribonuclease protection assay, semi-quantitative relative reverse transcriptase polymerase chain reaction, together with the pattern of their expression by immunohistochemistry. VEGF-A mRNA was the most abundant in colorectal tissue, followed by VEGF-B, VEGF-C, and VEGF-D. VEGF-A and VEGF-B mRNAs were significantly more abundant in adenomas (p = 0.0003 and p = 0.04 respectively) compared with normal tissues, while VEGF-A and VEGF-C were significantly increased in carcinomas compared with normal tissues (p = 0.0006 and p = 0.0009 respectively). A significantly greater amount of VEGF-C mRNA was present in carcinomas compared with adenomas (p = 0.03), whereas there was a significant reduction of VEGF-B in carcinomas compared with adenomas (p = 0.0002). VEGF-D mRNA was significantly more abundant in normal tissues than in adenomas (p = 0.0001) and carcinomas (p < 0.0001). In normal tissues distant from the primary tumour, there was a significantly greater amount of VEGF-A and VEGF-D mRNA in patients with Duke's B and Duke's C respectively, compared with Duke's A stage tumours (p = 0.04 and p = 0.01 respectively). Immunohistochemistry showed low basal levels of all ligands in histologically normal tissues and their expression in the epithelium of tumours reflected the levels of mRNA expression identified. VEGF-A and VEGF-C mRNA levels correlated significantly with tumour grade (p = 0.01 and p = 0.01 respectively) and tumour size (p = 0.001 and p = 0.01 respectively), but not with patient age, sex, presence of infiltrative margin, lymphocytic response, vascular invasion, Duke's stage, or lymph node involvement (p > 0.05). VEGF-B mRNA correlated with an infiltrative margin (P = 0.04) but no other clinicopathological variable, and expression of VEGF-D demonstrated no association with any parameter examined. VEGFR-1 was significantly correlated with tumour grade (p = 0.02), Duke's stage (p < 0.001), and lymph node involvement (P = 0.004), VEGFR-2 with lymph node involvement (p = 0.02), and VEGFR-3 did not correlate with any of the clinicopathological variables tested. These results suggest that VEGF-A and VEGF-B play a role early in tumour development at the stage of adenoma formation and that VEGF-C plays a role in advanced disease when there is more likelihood of metastatic spread. The finding of increased levels of VEGF-A and VEGF-D expression in normal tissues collected from a site distant from the primary tumour indicates changes in the surrounding tumour environment that may enhance the subsequent spread of tumour cells. Copyright (C) 2003 John Wiley Sons, Ltd.