Ferrer F A, Miller L J, Andrawis R I, Kurtzman S H, Albertsen P C, Laudone V P, Kreutzer D L
Department of Surgery, University of Connecticut Health Center, Farmington, Connecticut, USA.
Urology. 1998 Jan;51(1):161-7. doi: 10.1016/s0090-4295(97)00491-3.
Recently, it was confirmed that angiogenesis is important in the development and spread of a variety of human cancers, including prostate cancer (PCa). Tumor neovascularization is thought to be controlled by chemical signals, known as angiogenic factors (AF). To date, little is known regarding the existence and role of AF in PCa. We previously reported on vascular endothelial growth factor (VEGF) in PCa. Currently, we compare VEGF expression with that of interleukin-8 (IL-8), another putative regulator of angiogenesis. We evaluated the expression of these two important AF in PCa and explored the role of inflammatory cytokines IL-1 and tumor necrosis factor (TNF) in their regulation.
Ex vivo studies involved previously reported immunohistochemical analysis for VEGF and recent evaluation of IL-8 expression and distribution in archival tissue samples of PCa, benign prostatic hyperplasia (BPH), and normal prostate tissue. In vitro studies used PCa cells (DU-145) grown in culture and stimulated with cytokines thought to induce VEGF and IL-8 (ie, IL-1 alpha, IL-1 beta, TNF-alpha, and TNF-beta). After 24 hours, with or without cytokines, cell culture supernatants were analyzed by enzyme-linked immunosorbent assay or radioimmunoassay for VEGF or IL-8 levels.
Immunohistochemical studies of prostate tissue showed that PCa cells stained positively for VEGF and IL-8. Benign prostatic hyperplasia and normal prostate cells displayed little staining for either AF. Low levels of VEGF and IL-8 were produced by unstimulated DU-145 cells. Induction of DU-145 cells with cytokines resulted in differential stimulation whereby TNF was the predominant inducer of VEGF, whereas IL-1 was the predominant inducer of IL-8.
Our results indicate that significant levels of VEGF and IL-8 are present in PCa, but not BPH or normal prostate cells in vivo. In vitro studies suggest that differential regulation of AF expression occurs in PCa. Because IL-1 and TNF are present in the PCa tumor microenvironment, it is likely that differential regulation of AF also occurs in human PCa and contributes to differential tumor growth and metastasis.
最近，已证实血管生成在包括前列腺癌（PCa）在内的多种人类癌症的发生和扩散中起着重要作用。肿瘤新生血管形成被认为受化学信号控制，这些信号被称为血管生成因子（AF）。迄今为止，关于AF在PCa中的存在和作用知之甚少。我们之前报道过PCa中的血管内皮生长因子（VEGF）。目前，我们将VEGF表达与白细胞介素-8（IL-8）（另一种假定的血管生成调节因子）的表达进行比较。我们评估了这两种重要AF在PCa中的表达，并探讨了炎性细胞因子IL-1和肿瘤坏死因子（TNF）在其调节中的作用。
体外研究包括之前报道的对VEGF的免疫组织化学分析以及最近对PCa、良性前列腺增生（BPH）和正常前列腺组织存档样本中IL-8表达和分布的评估。体外研究使用培养的PCa细胞（DU-145），并用被认为可诱导VEGF和IL-8的细胞因子（即IL-1α、IL-1β、TNF-α和TNF-β）进行刺激。24小时后，无论有无细胞因子，通过酶联免疫吸附测定或放射免疫测定分析细胞培养上清液中VEGF或IL-8的水平。
前列腺组织的免疫组织化学研究表明，PCa细胞VEGF和IL-8染色呈阳性。良性前列腺增生和正常前列腺细胞对这两种AF几乎没有染色。未受刺激的DU-145细胞产生低水平的VEGF和IL-8。用细胞因子诱导DU-145细胞导致不同的刺激，其中TNF是VEGF的主要诱导剂，而IL-1是IL-8的主要诱导剂。
我们的结果表明，PCa中存在显著水平的VEGF和IL-8，但在体内BPH或正常前列腺细胞中不存在。体外研究表明，PCa中AF表达存在差异调节。由于IL-1和TNF存在于PCa肿瘤微环境中，AF的差异调节很可能也发生在人类PCa中，并导致肿瘤生长和转移的差异。
