Ferrer F A, Miller L J, Lindquist R, Kowalczyk P, Laudone V P, Albertsen P C, Kreutzer D L
Department of Surgery, University of Connecticut Health Center, Farmington 06030-3105, USA.
Urology. 1999 Sep;54(3):567-72. doi: 10.1016/s0090-4295(99)00156-9.
We recently reported the expression and cytokine regulation of vascular endothelial growth factor (VEGF) in human prostate cancer (PCa). VEGF exerts its angiogenic and pro-tumorigenic properties by way of two high affinity receptors, fms-like tyrosine kinase 1 (FLT-1) and fetal liver kinase 1 (FLK-1). We hypothesized that these receptors are expressed and control VEGF functions in the PCa microenvironment. Herein, we evaluate the expression of these receptors in ex vivo PCa tissue, benign prostatic hypertrophy (BPH) tissue, and cultured PCa cell lines.
Ex vivo PCa specimens were obtained from patients undergoing radical retropubic prostatectomy. Specimens were selected to contain both PCa and BPH tissue (n = 15). Immunohistochemical analysis using antihuman FLT-1 and FLK-1 was performed and specimens were analyzed to characterize the expression and distribution of both receptors. Immunocytochemical analysis for FLT-1 and FLK-1 was also performed on cultured PCa cell lines (DU-145 and LNCaP).
PCa cells expressed the VEGF receptor FLT-1 in 100% of specimens evaluated. Expression of FLK-1 was variable and related to tumor grade; high-grade tumors displayed little or no FLK-1 expression. Vascular endothelial cells (VECs) within areas of PCa consistently expressed both FLT-1 and FLK-1 receptors. FLT-1 and FLK-1 were both expressed in BPH tissue. FLT-1 was expressed in the glandular epithelial cells in BPH, but in most cases FLK-1 was localized specifically to the basal cell layer of hypertrophic glands. FLT-1, but not FLK-1, was expressed by the DU-145 and LNCaP cell lines.
Although they are differentially expressed, both FLT-1 and FLK-1 are present in PCa and BPH. Expression of receptors on VECs of tumor vessels supports the well-established role of VEGF in paracrine stimulation of VECs in the tumor microenvironment. The expression of FLT-1 and FLK-1 on tumor cells themselves suggests a potential autocrine function for VEGF (such as regulating tumor cell proliferation). These findings imply that a novel dual role may exist for VEGF, such that it is involved in tumor cell activation (autocrine), in addition to paracrine actions whereby it regulates endothelial cell functions and subsequent neovascular development.
我们最近报道了血管内皮生长因子（VEGF）在人前列腺癌（PCa）中的表达及细胞因子调节情况。VEGF通过两种高亲和力受体，即fms样酪氨酸激酶1（FLT-1）和胎儿肝激酶1（FLK-1）发挥其血管生成和促肿瘤发生特性。我们推测这些受体在PCa微环境中表达并控制VEGF功能。在此，我们评估这些受体在体外PCa组织、良性前列腺增生（BPH）组织及培养的PCa细胞系中的表达情况。
从接受耻骨后根治性前列腺切除术的患者获取体外PCa标本。所选标本同时包含PCa和BPH组织（n = 15）。使用抗人FLT-1和FLK-1进行免疫组织化学分析，并对标本进行分析以确定两种受体的表达和分布特征。还对培养的PCa细胞系（DU-145和LNCaP）进行FLT-1和FLK-1的免疫细胞化学分析。
在评估的100%标本中，PCa细胞表达VEGF受体FLT-1。FLK-1的表达存在差异且与肿瘤分级相关；高级别肿瘤几乎不表达或不表达FLK-1。PCa区域内的血管内皮细胞（VECs）始终表达FLT-1和FLK-1受体。FLT-1和FLK-1在BPH组织中均有表达。FLT-1在BPH的腺上皮细胞中表达，但在大多数情况下，FLK-1特异性定位于增生腺体的基底细胞层。DU-145和LNCaP细胞系表达FLT-1，但不表达FLK-1。
尽管FLT-1和FLK-1表达存在差异，但二者在PCa和BPH中均有存在。肿瘤血管VECs上受体的表达支持了VEGF在肿瘤微环境中对VECs旁分泌刺激作用中已确立的作用。肿瘤细胞自身上FLT-1和FLK-1的表达提示VEGF可能具有自分泌功能（如调节肿瘤细胞增殖）。这些发现意味着VEGF可能存在一种新的双重作用，即除了通过旁分泌作用调节内皮细胞功能及随后的新生血管形成外，还参与肿瘤细胞激活（自分泌）。
