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

Abstract

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 microinvasion 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.

The Use of Three-Dimensional Ultrasound Micro-Imaging to Monitor Prostate Tumor Development in a Transgenic Prostate Cancer Mouse Model

“…In this study, macroscopic tumors mean prostate tumor larger than 1 mm in diameter. As previously reported, PSP-TGMAP mice classified as negative by ultrasound still possess microscopic foci of various degrees of mouse prostate cancer that have not formed large, fast-growing masses (Gabril et al 2002;Duan et al 2005).…”

“…In brief, the prostate tissue including the ventral prostate (VP), dorsolateral prostate (DLP), anterior prostate (AP, the coagulation gland), the male accessory gland (SV, seminal vesicles), and the whole bladder were removed for gross examination and serial sectioning. Histopathological characterization and standard definitions of various degrees of well, moderately and poorly differentiated CaPs were classified as we previously reported (Gabril et al 2002;Duan et al 2005).…”

“…Transgenic (PSP-TGMAP) mice were identified by a quick polymerase chain reaction (PCR) genotyping protocol as previously reported (Gabril et al 2002;Duan et al 2005). After imaging, mice with tumors were euthanized and the dissection procedure was followed (Gabril et al 2002;Duan et al 2005).…”

“…Transgenic (PSP-TGMAP) mice were identified by a quick polymerase chain reaction (PCR) genotyping protocol as previously reported (Gabril et al 2002;Duan et al 2005). After imaging, mice with tumors were euthanized and the dissection procedure was followed (Gabril et al 2002;Duan et al 2005). In brief, the prostate tissue including the ventral prostate (VP), dorsolateral prostate (DLP), anterior prostate (AP, the coagulation gland), the male accessory gland (SV, seminal vesicles), and the whole bladder were removed for gross examination and serial sectioning.…”

“…This paper reports the first use of three-dimensional ultrasound micro-imaging for measuring tumor progression in a genetically engineered mouse model, the transgenic mouse adenocarcinoma of the prostate (TGMAP), where SV40 T-Ag expression is directed to the prostate by the prostate secretory protein of 94 amino acids (PSP94) gene promoter/enhancer region (Gabril et al 2002;Duan et al 2005). The following sections present cross-sectional and longitudinal imaging studies that demonstrate the sensitivity and specificity of three-dimensional ultrasound for detecting prostate tumors in mice when the tumors are too small to be palpable and illustrate the use of ultrasound imaging to measure the rapid growth of murine prostate tumors in situ.…”