Establishment of a serum tumor marker for preclinical trials of mouse prostate cancer models
Establishment of a serum tumor marker for preclinical trials of mouse prostate cancer models
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DOI：
10.1158//1078-0432.ccr-05-0953
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发表时间：
2005-11-01
影响因子：
11.5
通讯作者：
Xuan, JW
中科院分区：
文献类型：
--
作者：
Van Huizen, I;Wu, GJ;Xuan, JW
目前前列腺癌的基础和临床前试验研究都采用基因工程小鼠模型。然而，与人类前列腺癌患者不同，啮齿类动物没有对应的前列腺特异性抗原（PSA）用于监测前列腺癌的发生和进展。在这项研究中，我们建立了一个小鼠血清肿瘤标志物从小鼠同源的人前列腺分泌蛋白的94个氨基酸（PSP 94）。对转基因和敲入小鼠前列腺癌模型的不同组织学分级的免疫组织化学研究显示，组织中PSP 94表达下调（P < 0.001），与人类中PSA和PSP 94的表达相同。通过亲和柱和使用多克隆小鼠PSP 94抗体的免疫沉淀纯化来显示小鼠血清PSP 94的存在。建立了竞争性ELISA方案以定量血清PSP 94水平，灵敏度为1 ng/mL。小鼠PSP 94的定量血清水平范围从野生型小鼠的49.84 ng/mL到具有微侵袭的小鼠前列腺上皮内瘤变、高分化、中分化和低分化前列腺癌基因工程小鼠中的113.86、400.45和930.90 ng/mL（P < 0.01，n = 68）。血清PSP 94的这种增加也与年龄和肿瘤重量密切相关。通过纵向监测去势小鼠（雄激素消融治疗）的血清PSP 94水平，我们发现了反应性/难治性前列腺组织与血清PSP 94水平之间的相关性。小鼠血清PSP 94作为激素治疗中的标记物的效用通过三维超声成像进一步证实。第一个啮齿动物前列腺癌血清标志物的建立将极大地促进人类前列腺癌的基础和临床前研究。
Current prostate cancer research in both basic and preclinical trial studies employ genetically engineered mouse models. However, unlike in human prostate cancer patients, rodents have no counterpart of prostatic-specific antigen (PSA) for monitoring prostate cancer initiation and progression. In this study, we established a mouse serum tumor marker from a mouse homologue of human prostate secretory protein of 94 amino acids (PSP94). Immunohistochemistry studies on different histologic grades from both transgenic and knock-in mouse prostate cancer models showed the down-regulation of tissue PSP94 expression (P < 0.001), the same as for PSA and PSP94 in humans. The presence of mouse serum PSP94 was shown by affinity column and immunoprecipitation purification using a polyclonal mouse PSP94 antibody. A competitive ELISA protocol was established to quantify serum PSP94 levels with a sensitivity of 1 ng/mL. Quantified serum levels of mouse PSP94 ranged from 49.84 ng/mL in wild-type mice to 113.86,400.45, and 930.90 ng/mL in mouse prostatic intraepithelial neoplasia with microinvasion, well differentiated, moderately differentiated, and poorly differentiated prostate cancer genetically engineered prostate cancer mice, respectively (P < 0.01, n = 68). This increase in serum PSP94 is also well correlated with age and tumor weight. Through longitudinal monitoring of serum PSP94 levels of castrated mice (androgen ablation therapy), we found a correlation between responsiveness/refractory prostate tissues and serum PSP94 levels. The utility of mouse serum PSP94 as a marker in hormone therapy was further confirmed by three-dimensional ultrasound imaging. The establishment of the first rodent prostate cancer serum biomarker will greatly facilitate both basic and preclinical research on human prostate cancer.