Insulin-like growth factor-binding protein-1 and prostate cancer
Insulin-like growth factor-binding protein-1 and prostate cancer
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DOI：
10.1093/jnci/91.22.1965
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发表时间：
1999-11-17
期刊：
影响因子：
--
通讯作者：
Adami, HO
中科院分区：
文献类型：
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作者：
Signorello, LB;Brismar, K;Adami, HO
有越来越多的实验（1-4）和流行病学（5-7）证据表明，肽激素胰岛素样生长因子-I（IGF-I）是前列腺癌发展的关键因素。由于它们在调节生物可利用的IGF-I中的中心作用，胰岛素样生长因子结合蛋白（IGFBPs）也作为前列腺癌风险的潜在介质受到审查（8-12）。关于IGFBPs中的哪些（如果有的话）与前列腺癌的发展相关，存在相当大的分歧。在流行病学上，IGFBP-3已被检测（5，7），主要是因为超过95%的循环IGF-I与酸不稳定亚基（ALS，一种在肝脏中合成的蛋白质）结合在一起（13）。然而，IGF-I/IGFBP-3/ALS复合物太大（150 kd），无法穿过血管内皮细胞并影响靶组织（14）。IGFBP-1有效地穿梭IGF-I穿过血管膜（15，16）。因此，预计IGFBP-1的血液水平可预测前列腺组织可获得的循环IGF-I的量，从而预测前列腺癌的风险。我们测量了208例前列腺癌患者和70例健康男性对照者血清中的IGFBP-1水平。获得所有受试者的书面知情同意书，并由瑞典Orebro地区医院（Orebro Läns Landsting）的研究伦理委员会批准本研究。先前在这些对照受试者中测量了血清IGF-I和IGFBP-3，结果表明IGF-I增加了前列腺癌的风险，而IGFBP-3没有明显的作用（7）。该研究的详细信息已在此前发表（7）。简单地说，我们确定了1989年1月至1991年9月瑞典奥雷布罗县的所有前列腺癌病例，并将其频率（10岁年龄组）与从县人口登记册中选择的健康对照受试者相匹配。对照组受试者接受直肠指检和血清前列腺特异性抗原筛查试验，以避免纳入患有隐匿性疾病的男性。在对所有参与者进行体格检查时获得身高和体重数据。采集240例病例组和235例对照组的血样，均在上午8：00至10：00之间进行。病例患者提供的大多数血液样本是在首次前列腺癌诊断后4-6周内采集的。所有样品在室温下以1200 g离心10分钟，并作为血清储存在-70 ℃下。可用于本分析的病例患者和对照受试者血清标本的不平衡是研究开始时从病例患者采集的血液多于对照受试者的结果。如前所述（7）测定血清IGF-I和IGFBP-3水平，均使用市售免疫放射测定试剂盒（Diagnostic Systems Laboratories，韦伯斯特，TX）。使用放射免疫测定法测定IGFBP-1的血清水平（17）。所用抗体经兔抗人羊膜蛋白纯化后，与IGFBP-2和IGFBP-3的交叉反应小于0.1%。该测定测量非磷酸化和磷酸化形式。
There is growing and persuasive evidence, both experimental (1–4) and epidemiologic (5–7), that the peptide hormone insulin-like growth factor-I (IGF-I) is a critical factor in the development of prostate cancer. Because of their central role in the regulation of bioavailable IGF-I, the insulin-like growth factor-binding proteins (IGFBPs) have also come under scrutiny as potential mediators of prostate cancer risk (8–12). There is considerable disagreement concerning which, if any, of the IGFBPs are relevant to the development of prostate cancer. Epidemiologically, IGFBP-3 has been examined (5, 7), primarily because more than 95% of circulating IGF-I is bound to this protein (13) together with an acid labile subunit (ALS, a protein synthesized in the liver). The IGF-I/IGFBP-3/ALS complex is too large (150 kd), however, to pass through blood vessel endothelial cells and affect target tissue (14). It is IGFBP-1 that effectively shuttles IGF-I across blood vessel membranes (15, 16). Therefore, it would be expected that blood levels of IGFBP-1 be predictive of the amount of circulating IGF-I available to prostate tissue and thus of prostate cancer risk. We measured IGFBP-1 levels in the serum of 208 patients with prostate cancer and in 70 healthy male control subjects. Informed written consent was obtained from all subjects, and the study was approved by the Research Ethics Committee at the Regional Hospital in Orebro, Sweden (Orebro Läns Landsting). Serum IGF-I and IGFBP-3 were previously measured in these control subjects, and the findings indicated thatIGF-I increased the risk of prostate cancer, whereas no demonstrable effect of IGFBP-3 was noted (7). Details of this study have previously been published (7). Briefly, we identified all incident prostate cancer cases in Orebro County, Sweden, from January 1989 through September 1991 and frequency matched them (in 10-year age groups) to healthy control subjects selected from the county population register. Control subjects underwent a digital rectal examination and a serum prostate-specific antigen screening test to avoid inclusion of men with occult disease. Height and weight data were obtained during a physical examination of all participants. Blood samples were drawn from 240 case patients and 235 control subjects, all between 8: 00 AM and 10: 00 AM. The majority of the blood samples provided by case patients were collected within 4–6 weeks after the initial prostate cancer diagnosis. All samples were centrifuged at 1200g for 10 minutes at room temperature and stored as serum at− 70 C. The imbalance of case patient and control subject serum specimens available for this analysis is a consequence of collecting more blood from the case patients than from the control subjects at the outset of the study. Serum IGF-I and IGFBP-3 levels were determined as previously described (7), both with commercially available immunoradiometric kits (Diagnostic Systems Laboratories, Webster, TX). Serum levels of IGFBP-1 were measured by use of radioimmunoassay (17). The antibodies used were raised in rabbits against purified human amniotic protein, and the cross-reaction with IGFBP-2 and IGFBP-3 was less than 0.1%. The assay measures both nonphosphorylated and phosphorylated forms.