Antiangiogenic activity of prostate-specific antigen
Antiangiogenic activity of prostate-specific antigen
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DOI：
10.1093/jnci/91.19.1635
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发表时间：
1999-10-06
期刊：
影响因子：
--
通讯作者：
Holaday, JW
中科院分区：
文献类型：
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作者：
Fortier, AH;Nelson, BJ;Holaday, JW
背景：血清前列腺特异性抗原（PSA）水平的测定被广泛用作前列腺癌的筛查工具。然而，PSA不是前列腺特异性的，已经在乳腺癌、肺癌和子宫癌中检测到。在一项研究中，乳腺肿瘤PSA水平较高的患者比PSA水平较低的患者预后更好。为了验证PSA可能具有抗血管生成特性的假设，我们评估了PSA对内皮细胞增殖、迁移和侵袭的影响，这些是血管生成的关键步骤，血管生成是肿瘤发展血液供应的过程。研究方法：为了评估PSII的抗增殖作用，我们处理了牛内皮细胞和人内皮细胞系，（HUVEC和HMVEC-d）与纯化的人PSA（0.1-10 μ M），然后用10 ng/mL成纤维细胞生长因子-2（FGF-2）刺激，对FGF-2或血管内皮生长因子（VEGF）刺激的内皮细胞迁移、侵袭的影响，和管形成通过仅使用一种细胞系（HUVEC）PSA来测量。在静脉内接种B16 BL 6黑素瘤细胞后以9 μ M连续11天给予小鼠以评价其抑制肺集落形成的能力（即，转移性肿瘤）。结果：PSA在IC抑制内皮细胞增殖、迁移和侵袭（即，抑制为50%时的浓度）值范围为0.3-5 μ M。此外，PSA抑制内皮细胞对所测试的血管生成刺激因子FGF-2和VEGF的反应。在转移性疾病的小鼠模型中，与磷酸盐缓冲盐水治疗相比，每日PSA治疗导致肺肿瘤结节的平均数量减少40%（双侧P =.003）。结论：据我们所知，这是第一个报告，PSA可能作为一种内源性抗血管生成蛋白在肿瘤中发挥作用。这种功能可以部分解释前列腺癌的自然缓慢进展。我们的研究结果对前列腺癌治疗中抑制PSA表达的各种策略提出了质疑。
Background: Measurement of serum levels of prostate-specific antigen (PSA) is widely used as a screening tool for prostate cancer. However, PSA is not prostate specific, having been detected in breast, lung, and uterine cancers. In one study, patients whose breast tumors had higher levels of PSA had a better prognosis than patients whose tumors had lower PSA levels, To test the hypothesis that PSA may have antiangiogenic properties, we evaluated the effects of PSA on endothelial cell proliferation, migration, and invasion, which are key steps in angiogenesis, the process by which tumors develop a blood supply. Methods: To assess the antiproliferative effects of PSII, we treated bovine endothelial cells and human endothelial cell lines (HUVEC and HMVEC-d) with purified human PSA (0.1-10 mu M) and then stimulated them with 10 ng/mL, fibroblast growth factor-2 (FGF-2), Effects on FGF-2- or vascular endothelial growth factor (VEGF)-stimulated endothelial cell migration, invasion, and tube formation were measured by use of one cell line only (HUVEC), PSA. was administered to mice at 9 mu M for 11 consecutive days after intravenous inoculation of B16BL6 melanoma cells to assess its ability to inhibit the formation of lung colonies (i.e., metastatic tumors). Results: PSA inhibited endothelial cell proliferation, migration, and invasion at IC,, (i.e., the concentration at which inhibition was 50%) values ranging from 0.3-5 mu M. In addition, PSA inhibited endothelial cell responses to both angiogenic stimulators tested, FGF-2 and VEGF. In a mouse model of metastatic disease, daily PSA treatment resulted in a 40% reduction in the mean number of lung tumor nodules compared with phosphate-buffered saline treatment (two-sided P =.003). Conclusion: To our knowledge, this is the first report that PSA may function in tumors as an endogenous antiangiogenic protein. This function may explain, in part, the naturally slow progression of prostate cancer. Our findings call into question various strategies to inhibit the expression of PSA in the treatment of prostate cancer.