High-grade clear cell renal cell carcinoma has a higher angiogenic activity than low-grade renal cell carcinoma based on histomorphological quantification and qRT-PCR mRNA expression profile.
High-grade clear cell renal cell carcinoma has a higher angiogenic activity than low-grade renal cell carcinoma based on histomorphological quantification and qRT-PCR mRNA expression profile.
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DOI：
10.1038/sj.bjc.6603796
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发表时间：
2007-06-18
影响因子：
8.8
通讯作者：
Vermeulen, P B
中科院分区：
文献类型：
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作者：
Baldewijns, M M;Thijssen, V L;Van den Eynden, G G;Van Laere, S J;Bluekens, A M;Roskams, T;van Poppel, H;De Bruine, A P;Griffioen, A W;Vermeulen, P B
透明细胞肾细胞癌（CC-RCC）是一种高度血管化的肿瘤，因此是研究血管生成和在早期临床开发中测试新型血管生成抑制剂的有吸引力的疾病。内皮细胞增殖在血管生成过程中起着关键作用。本研究的目的是比较低核分级（n=87）和高核分级CC-RCC （n=63）的血管生成参数。免疫组化采用一组抗体：CD34/Ki-67、碳酸酐酶IX、缺氧诱导因子1α (HIF-1α)和血管内皮生长因子（VEGF）。评估血管密度（MVD -微血管密度）、内皮细胞增殖分数（ECP%）和肿瘤细胞增殖分数（TCP%）。采用定量RT-PCR检测血管生成刺激因子和抑制因子mRNA表达水平。高级别CC-RCC的ECP% （P=0.049）、TCP% （P=0.009）、VEGF蛋白表达（P<0.001）、MVD （P<0.001）和HIF-1α蛋白表达（P=0.002）均高于低级别CC-RCC。生长因子mRNA表达分析显示，低级别CC-RCC中血管生成素2的表达较高。微血管密度与ECP%呈负相关（Rho= - 0.26， P=0.001）。由于核分级与ECP%或MVD不完全相关，因此CC-RCC也根据低/高MVD和ECP%进行分组。该分析显示，血管成熟和稳定因子（胎盘生长因子、PDGFB1、血管生成素1）在高MVD的CC-RCC中表达较高，而在低核级CC-RCC中高度富集的一组CC-RCC中，ECP%较低。我们的研究结果表明，CC-RCC的血管生成活性和血管成熟的异质性在很大程度上与核分级有关，并且可能具有治疗意义。
Clear cell renal cell carcinoma (CC-RCC) is a highly vascularised tumour and is therefore an attractive disease to study angiogenesis and to test novel angiogenesis inhibitors in early clinical development. Endothelial cell proliferation plays a pivotal role in the process of angiogenesis. The aim of this study was to compare angiogenesis parameters in low nuclear grade (n=87) vs high nuclear grade CC-RCC (n=63). A panel of antibodies was used for immunohistochemistry: CD34/Ki-67, carbonic anhydrase IX, hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF). Vessel density (MVD – microvessel density), endothelial cell proliferation fraction (ECP%) and tumour cell proliferation fraction (TCP%) were assessed. mRNA expression levels of angiogenesis stimulators and inhibitors were determined by quantitative RT–PCR. High-grade CC-RCC showed a higher ECP% (P=0.049), a higher TCP% (P=0.009), a higher VEGF protein expression (P<0.001), a lower MVD (P< 0.001) and a lower HIF-1α protein expression (P=0.002) than low-grade CC-RCC. Growth factor mRNA expression analyses revealed a higher expression of angiopoietin 2 in low-grade CC-RCC. Microvessel density and ECP% were inversely correlated (Rho=−0.26, P=0.001). Because of the imperfect association of nuclear grade and ECP% or MVD, CC-RCC was also grouped based on low/high MVD and ECP%. This analysis revealed a higher expression of vessel maturation and stabilisation factors (placental growth factor, PDGFB1, angiopoietin 1) in CC-RCC with high MVD, a group of CC-RCC highly enriched in low nuclear grade CC-RCC, with low ECP%. Our results suggest heterogeneity in angiogenic activity and vessel maturation of CC-RCC, to a large extent linked to nuclear grade, and, with probable therapeutic implications.