Hahn D, Simak R, Steiner G E, Handisurya A, Susani M, Marberger M
Departments of Urology, University of Vienna and Lainz Hospital, Austria.
J Urol. 2000 Aug;164(2):506-10.
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).
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.
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.
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.
血管内皮生长因子（VEGF）是血管生成最有效的调节因子之一，已证明其作用于两种酪氨酸激酶家族受体：c-fms样酪氨酸激酶（Flt-1）和胎儿肝激酶。初步报告强调VEGF受体的表达具有内皮细胞特异性。在本研究中，我们验证了Flt-1蛋白的定位和分布以及前列腺腺癌（CaP）、前列腺上皮内瘤变（PIN）和良性前列腺增生（BPH）中mRNA的表达情况。
通过免疫组织化学对30份经选择的手术标本进行评估，这些标本呈现出CaP、PIN和BPH组织学区域，以检测Flt-1蛋白表达。将结果与肿瘤分化（Gleason评分）、血清PSA及临床随访情况进行比较。使用RT-PCR和内含子跨越引物研究前列腺癌细胞系、新鲜分离的BPH上皮细胞（BPH-EC）及基质细胞中Flt-1的合成情况。
VEGF受体Flt-1特异性抗血清显示前列腺内皮细胞有明显染色，但反应并不局限于内皮细胞。所有标本的BPH上皮细胞均与抗Flt-1有显著反应。相比之下，56%的标本中的肿瘤细胞与抗Flt-1无反应。BPH-EC显示出一致的抗Flt-1反应性，在PIN中这种反应性不太明显且较弱。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，但随肿瘤去分化而增加。有趣的是，所有Gleason评分>8的CaP标本的肿瘤细胞均无抗Flt-1免疫反应性。因此，当使用RT-PCR检测时，PC3、DU145和LNCaP细胞均为阴性，而所有来源于BPH组织的BPH-EC均显示Flt-1编码mRNA表达。
VEGF受体Flt-1在BPH、PIN和前列腺癌标本中广泛分布，提示VEGF在前列腺中的功能并不局限于内皮细胞和血管生成。然而，由于该受体在CaP细胞中及随着肿瘤去分化而丧失，VEGF对上皮细胞的这些未知作用在恶性转化时显然受到抑制。
