Knockin of SV40 Tag oncogene in a mouse adenocarcinoma of the prostate model demonstrates advantageous features over the transgenic model
Knockin of SV40 Tag oncogene in a mouse adenocarcinoma of the prostate model demonstrates advantageous features over the transgenic model
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DOI：
10.1038/sj.onc.1208229
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发表时间：
2005-02-24
期刊：
影响因子：
8
通讯作者：
Xuan, JW
中科院分区：
文献类型：
--
作者：
Duan, WM;Gabril, MY;Xuan, JW
前列腺癌（CaP）是北美成年男性中最常见的癌症。由于在小鼠中没有自然发生的前列腺癌，临床前研究规定建立具有接近人类情况的特征的遗传操纵的小鼠CaP模型。鉴于转基因技术衍生的CaP模型的局限性，本文报道了首次应用敲入技术通过将SV 40 Tag靶向前列腺组织特异性基因PSP 94（94个氨基酸的前列腺分泌蛋白）来建立新的小鼠前列腺腺癌模型（PSP-KIMAP）。为了证明其新奇，我们将KIMAP与PSP 94基因导向的转基因小鼠前列腺腺癌（PSP-TGMAP）模型进行了比较。PSP-KIMAP小鼠的CaP发育几乎在青春期后10周龄立即开始，从具有微侵袭的小鼠前列腺上皮内瘤变（mPIN）到分化良好的CaP，并且证明了接近人类的肿瘤生长延长的动力学和分化良好和中等分化的肿瘤的优势。多组织转移（淋巴结、肺和肝等）以及多种侵袭性前列腺肿瘤标志物的免疫组化研究证实了KIMAP模型的侵袭性。PSP-KIMAP模型对雄激素剥夺（去势）有反应。KIMAP模型中的敲入技术展示了高度预测性的CaP发育过程和许多优势特征，这是传统转基因技术衍生的CaP模型在基础和临床研究中无法达到的。这些特征包括表型和基因型的高度稳定性、高度同步的前列腺癌发展、高度和精确的前列腺组织靶向以及没有创始人细胞系变异。两种CaP模型之间的差异归因于引入单个内源性敲入突变，从而导致由PSP 94的前列腺基因启动子/增强子自我调节和控制的CaP模型。
Prostate cancer (CaP) is the most common cancer in adult men in North America. Since there is no naturally occurring prostate cancer in the mouse, preclinical studies stipulate for the establishment of a genetically manipulated mouse CaP model with features close to the human situation. In view of the limitations of transgenic technique-derived CaP models, herein we report the first application of knockin technology to establish a new mouse adenocarcinoma prostate model (PSP-KIMAP) by targeting of SV40 Tag to a prostate tissue-specific gene, PSP94 (prostate secretory protein of 94 amino acids). In order to demonstrate its novelty, we compared KIMAP to a PSP94 gene-directed transgenic mouse adenocarcinoma of the prostate (PSP-TGMAP) model. The CaP development of the PSP-KIMAP mice started almost immediately after puberty at 10 weeks of age from mouse prostatic intraepithelial neoplasia (mPIN) with micro-invasion to well-differentiated CaP, and demonstrated a close-to-human kinetics of prolonged tumor growth and a predominance of well and moderately differentiated tumors. The invasive nature of KIMAP model was demonstrated by multitissue metastases (lymph node, lung and liver etc) and also by immunohistochemical study of multiple invasive prostate tumor markers. PSP-KIMAP model is responsive to androgen deprivation (castration). The knockin technology in our KIMAP model demonstrates highly predictive CaP development procedures and many advantageous features, which the traditional transgenic technique-derived CaP models could not reach for both basic and clinical studies. These features include the high stability of both phenotype and genotype, highly synchronous prostate cancer development, high and precise prostate tissue targeting and with no founder line variation. The differences between the two CaP models were attributed to the introduction of a single endogenous knockin mutation, resulting in a CaP model self-regulated and controlled by a prostate gene promoter/enhancer of PSP94.