Pre-Clinical Models to Study Human Prostate Cancer

Abstract

Prostate cancer is a common cancer among men and typically progresses slowly for several decades before becoming aggressive and spreading to other organs, leaving few treatment options. While large animals have been studied, the dog's prostate is anatomically similar to humans and has been used to study spontaneous prostate cancer. However, most research currently focuses on the mouse as a model organism due to the ability to genetically modify their prostatic tissues for molecular analysis. One milestone in this research was the identification of the prostate-specific promoter Probasin, which allowed for the prostate-specific expression of transgenes. This has led to the generation of mice with aggressive prostatic tumors through overexpression of the SV40 oncogene. The Probasin promoter is also used to drive Cre expression and has allowed researchers to generate prostate-specific loss-of-function studies. Another landmark moment in the process of modeling prostate cancer in mice was the orthoptic delivery of viral particles. This technology allows the selective overexpression of oncogenes from lentivirus or the use of CRISPR to generate complex loss-of-function studies. These genetically modified models are complemented by classical xenografts of human prostate tumor cells in immune-deficient mice. Overall, pre-clinical models have provided a portfolio of model systems to study and address complex mechanisms in prostate cancer for improved treatment options. This review will focus on the advances in each technique.

Keywords: adenocarcinoma; allografts; androgen; clustered regularly interspaced short palindromic repeats; mice; prostate; prostatic intraepithelial neoplasia; prostatic neoplasms; transgenes; tumor suppressor.

Figure 1

Genetically modified mice exhibit different phenotypes in the prostatic epithelium. (A) In certain cases, a single gene alteration can induce transformation of the epithelium and lead to the development of prostatic intraepithelial neoplasia (PIN) over time. (B) Loss of Pten is a hallmark in mouse models of prostate cancer (PCa), and this single gene alteration can drive PIN formation, eventually progressing to PCa and metastasis in secondary tissues. The combined loss of Pten with other gene mutations, including the loss of Trp53, Nkx3.1, members of the AP1 gene family, and others, has been shown to accelerate the phenotype. (C) Certain genetic alterations, when combined with the loss of Pten, promote the formation of metastasis.

Figure 2

Isolated cells from human prostate cancer (PCa) can be inoculated into immunodeficient mice. Classical cell lines are derived from tumor tissues and grown in vitro before being grafted onto a mouse. Alternatively, patient-derived xenografts (PDX) can be used, where tumor tissues are directly used for grafting. Tumor cells can be inoculated into different locations, each with its own advantages. Subcutaneous grafting is commonly performed, allowing for the easy monitoring of tumor progression and growth to a large size with minimal implications for the animal. Orthotopic grafting involves grafting tumor cells into the mouse prostate, enabling the development of tumors in the organ of origin. Intracardiac or tail vein injections allow for the dissemination of tumor cells and the development of tumors in other organs, serving as a model for metastatic cancer. This can be further expanded by femur injection to establish metastasis in the bone of the recipient mouse.