Expression of the VEGF-receptor Flt-1 in benign, premalignant and malignant prostate tissues
Expression of the VEGF-receptor Flt-1 in benign, premalignant and malignant prostate tissues
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DOI：
10.1016/s0022-5347(05)67414-9
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发表时间：
2000-08-01
影响因子：
6.6
通讯作者：
Mazberger, M
中科院分区：
文献类型：
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作者：
Hahn, D;Simak, R;Mazberger, M
目的：血管内皮生长因子（Vascular endothelial growth factor，VEGF）是血管生成最有效的调节因子之一，它作用于两种酪氨酸激酶家族受体：c-fms-like tyrosine kinase（Flt-1）和胎肝激酶（fetal liver kinase）。本研究旨在探讨Flt-1蛋白和mRNA在前列腺腺癌（CaP）、前列腺上皮内瘤变（PIN）和良性前列腺增生（BPH）组织中的定位和分布。材料与方法：选取30例手术切除的前列腺腺癌、前列腺上皮内瘤变（PIN）和良性前列腺增生（BPH）组织标本，采用免疫组织化学方法检测Flt-1蛋白的表达。结果与肿瘤分化程度（Gleason-Score）、血清PSA和临床随访进行比较。结果：VEGF受体Flt-1特异性抗血清可显著标记前列腺内皮细胞，但不局限于前列腺内皮细胞。所有标本的BPH-上皮细胞与抗Flt-1反应显着。相反，在56%的标本中，肿瘤细胞未能与抗Flt-1反应。BPH-EC显示出均匀的抗Flt-1反应性，这在PIN中不太明显且较弱。前列腺肿瘤细胞抗Flt-1反应性的丧失与术前PSA血清水平无关，但随着肿瘤去分化而增加。有趣的是，Gleason评分>8的所有CaP标本的肿瘤细胞均未显示抗Flt-1免疫反应性。因此，当使用RT-PCR测试时，PC 3、DU 145和LNCaP细胞均为阴性时，所有BPH组织来源的BPH-EC均显示Flt-1编码mRNA表达。VEGF受体Flt-1在BPH中广泛分布，PIN和前列腺癌标本表明，前列腺中的VEGF功能不限于内皮细胞和血管生成。然而，由于受体在CaP细胞中丢失并伴随肿瘤去分化，VEGF对上皮细胞的这些尚未知晓的作用在恶性转化中被明显抑制。
Purpose: Vascular endothelial growth factor (VEGF) is one of the most potent regulators of angiogenesis and has been shown to act upon two tyrosine kinase family receptors: c-fms-like tyrosine kinase (Flt-1) and fetal liver kinase, Preliminary reports have emphasized that expression of VEGF receptors is endothelial cell-specific. In this study we verified the localization and distribution of Flt-1 protein and mRNA expression in prostatic adenocarcinoma (CaP) as well as prostate intraepithelial neoplasia (PIN) and benign prostatic hyperplasia (BPH).Materials and Methods: 30 selected surgical specimens exhibiting areas with CaP, PIN and BPH histology were evaluated for Flt-1 protein expression by immunohistochemistry. Results were compared with tumor differentiation (Gleason-Score), serum-PSA and clinical followup. Flt-1 synthesis by prostatic carcinoma cell lines, freshly isolated BPH epithelial cells (BPH-EC) and stromal cells was investigated using RT-PCR and intron spanning primer.Results: VEGF receptor Flt-1 specific anti-sera revealed significant staining of prostatic endothelial cells, but the reactivity was not restricted to endothelial cells. BPH-epithelial cells of all specimens reacted significantly with anti-Flt-1. In contrast, tumor cells failed to react with anti-Flt-1 in 56% of the specimens. BPH-EC revealed a uniform anti-Flt-1 reactivity, which was less pronounced and weaker in PIN. Loss of anti-Flt-1 reactivity of prostatic tumor cells did not correlate with preoperative PSA serum levels but increased with tumor dedifferentiation. Interestingly, tumor cells of all CaP specimens with a Gleason score of >8 exhibit no anti-Flt-1 immunoreactivity.Accordingly while PC3, DU145 and LNCaP cells were negative when tested using RT-PCR all BPH tissue derived BPH-EC revealed Flt-1 coding mRNA expression.Conclusions: Widespread distribution of VEGF receptor Flt-1 in BPH, PIN and prostate cancer specimens suggests that VEGF function in prostate is not restricted to endothelial cells and angiogenesis. However, since the receptor is lost in CaP cells and with tumor dedifferentiation, these yet unknown effects of VEGF on epithelial cells are obviously suppressed with malignant transformation.