Overview of Genetically Engineered Mouse Models of Prostate Cancer and Their Applications in Drug Discovery

Abstract

Prostate cancer (PCa) is the most common malignant visceral neoplasm in males in Western countries. Despite progress made in the early treatment of localized malignancies, there remains a need for therapies effective against advanced forms of the disease. Genetically engineered mouse (GEM) models are valuable tools for addressing this issue, particularly in defining the cellular and molecular mechanisms responsible for tumor initiation and progression. While cell and tissue culture systems are important models for this purpose as well, they cannot recapitulate the complex interactions within heterotypic cells and the tumor microenvironment that are crucial in the initiation and progression of prostate tumors. Limitations of GEM models include resistance to developing invasive and metastatic tumors that resemble the advanced stages of human PCa. Nonetheless, because genetic models provide valuable information on the human condition that would otherwise be impossible to obtain, they are increasingly employed to identify molecular targets and to examine the efficacy of cancer therapeutics. The aim of this overview is to provide a brief but comprehensive summary of GEM models for PCa, with particular emphasis on the strengths and weaknesses of this experimental approach. © 2018 by John Wiley & Sons, Inc.

A Novel Prostate Cell Type-Specific Gene Signature to Interrogate Prostate Tumor Differentiation Status and Monitor Therapeutic Response

“…Multiple GEMMs of prostate cancer are currently available and represent a valid resource for studying the disease [28]. To determine whether GEMMs reproduced a similar variance of the luminal phenotype as seen in human tumors, we applied our metagenes to published transcriptomic data from wild type mice and GEMMs [29].…”

PTEN Mouse Models of Cancer Initiation and Progression

“…LoxP/CRE technology has enabled the generation of tissue-specific PTEN deletion models, which have resulted in tumor development specifically in those tissues subject to loss of PTEN expression (Table 1), while also yielding a number of unexpected biological outcomes (Kishimoto et al 2003;Andres-Pons et al 2007;Renner et al 2008 Mouse model studies have revealed the crucial roles of PTEN in prostate cancer (Civenni et al 2018). Although partial loss of Pten increases cellular growth and proliferation (Trotman et al 2003;Alimonti et al 2010a;Berger et al 2011), complete loss of Pten in the prostate epithelium results in cellular senescence (Chen et al 2005;Alimonti et al 2010b), which functions as a fail-safe mechanism that restricts tumor progression.…”

Comparative pathology of dog and human prostate cancer

“…In most aspects, the histological appearance of the prostate gland parenchyma and stroma is very similar between men and dogs (Figures 1 and 2 ). This becomes even more evident when comparing the human prostate with the gland in other animal species, notably rodents (Roy‐Burman et al., 2004 ), which are commonly used in experimental models but have distinct prostate anatomy (Civenni et al., 2018 ).…”