Huizen Isaac Van, Wu Guojun, Moussa Madeleine, Chin Joseph L, Fenster Aaron, Lacefield James C, Sakai Hideki, Greenberg Norman M, Xuan Jim W
Department of Surgery, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.
Clin Cancer Res. 2005 Nov 1;11(21):7911-9. doi: 10.1158/1078-0432.CCR-05-0953.
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.
目前,基础研究和临床试验研究中的前列腺癌研究都采用了基因工程小鼠模型。然而,与人类前列腺癌患者不同的是,啮齿动物没有前列腺特异性抗原(PSA)的对应物来监测前列腺癌的发生和发展。在本研究中,我们从人94个氨基酸的前列腺分泌蛋白(PSP94)的小鼠同源物中建立了一种小鼠血清肿瘤标志物。对转基因和基因敲入小鼠前列腺癌模型不同组织学分级的免疫组织化学研究表明,组织PSP94表达下调(P < 0.001),与人类的PSA和PSP94情况相同。使用多克隆小鼠PSP94抗体通过亲和柱和免疫沉淀纯化显示了小鼠血清PSP94的存在。建立了一种竞争性ELISA方法来定量血清PSP94水平,灵敏度为1 ng/mL。小鼠PSP94的定量血清水平范围从野生型小鼠的49.84 ng/mL到基因工程前列腺癌小鼠中微浸润、高分化、中分化和低分化前列腺癌的前列腺上皮内瘤变小鼠的113.86、400.45和930.90 ng/mL(P < 0.01,n = 68)。血清PSP94的这种升高也与年龄和肿瘤重量密切相关。通过对去势小鼠(雄激素消融治疗)血清PSP94水平的纵向监测,我们发现反应性/难治性前列腺组织与血清PSP94水平之间存在相关性。三维超声成像进一步证实了小鼠血清PSP94作为激素治疗标志物的实用性。首个啮齿动物前列腺癌血清生物标志物的建立将极大地促进人类前列腺癌的基础研究和临床前研究。