Temporally and Spatially Controlled Age-Related Prostate Cancer Model in Mice.

Abstract

The initiation and progression of prostate cancer (PCa) are associated with aging. In the history of age-related PCa research, mice have become a more popular animal model option than any other species due to their short lifespan and rapid reproduction. However, PCa in mice is usually induced at a relatively young age, while it spontaneously develops in humans at an older age. Thus, it is essential to develop a method by which the PCa initiation and progression timeline can be strictly controlled to mimic human physiological conditions. One milestone in this field was the identification of the prostate-specific transcription factor, Probasin (Pb), which allowed for the prostate-specific expression of genes knocked into the mice's genome. Another milestone is the establishment of the preclinical mouse model with Pten conditionally knocked out in the prostate tissue, which closely mimics the formation and growth of human PCa. Hereby, we present the prostate-specific temporally and spatially controlled Pten knockout PCa mouse model that can be induced using an adenovirus-based Cre-LoxP system. The Cre recombinase (Cre) is inserted into an adenovirus vector. Unlike Pb-Cre knock-in models (which are spatially but not temporally controlled), the expression of Cre is activated to knock out Pten from the mice's prostate epithelial cells once injected. The viral delivery procedures strictly control the location and time of Pten knockout. This novel approach provides a powerful age-related murine model for PCa, emphasizing the effect of aging on prostate carcinogenesis. Key features • In vivo delivery of Cre recombinase adenovirus (Ad-Cre-Luc) in Pten LoxP/LoxP (L/L) mice. • Generation of Cre-expressing Ad-Cre-Luc-mediated ablation of Pten in anterior prostate epithelial cells of adult Pten L/L mice at different ages. • The Ad-Cre-Luc-mediated ablation of Pten leads to hyperplasia that progresses through prostatic intraepithelial neoplasia (PIN) to adenocarcinoma. • PIN refers to the non-cancerous growth of epithelial cells in the prostate tissue-not cancer but a precursor of prostate cancer [1].