Knockin of SV40 Tag oncogene in a mouse adenocarcinoma of the prostate model demonstrates advantageous features over the transgenic model

被引:27
作者
Duan, WM
Gabril, MY
Moussa, M
Chan, FL
Sakai, H
Fong, GH
Xuan, JW
机构
[1] Univ Western Ontario, Dept Surg, London, ON, Canada
[2] Univ Western Ontario, Dept Pathol, London, ON, Canada
[3] Chinese Univ Hong Kong, Dept Anat, Hong Kong, Hong Kong, Peoples R China
[4] Nagasaki Univ, Sch Med, Dept Urol, Nagasaki 852, Japan
[5] Univ Connecticut, Dept Physiol, Farmington, CT USA
关键词
prostate cancer; SV40 Tag oncogene; mouse cancer modeling; knockin mouse; tumorigenesis and progression; PSP94( beta microseminoprotein);
D O I
10.1038/sj.onc.1208229
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:1510 / 1524
页数:15
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