Mouse models of prostate cancer: picking the best model for the question

Abstract

When the NIH Mouse Models of Human Cancer Consortium (MMCC) initiated the Prostate Steering Committee 15 years ago, there were no genetically engineered mouse (GEM) models of prostate cancer (PCa). Today, a PubMed search for “prostate cancer mouse model” yields 3,200 publications and this list continues to grow. The first generation of GEM utilized the newly discovered and characterized probasin (PB) promoter driving viral oncogenes such as SV40 large T antigen to yield the LADY and TRAMP models. As the PCa research field has matured, the second generation of models has incorporated the single and multiple molecular changes observed in human disease, such as loss of PTEN and over-expression of Myc. Application of these models has revealed that mice are particularly resistant to developing invasive PCa, and once they achieve invasive disease, the PCa rarely resembles human disease. Nevertheless, these models and their application have provided vital information on human PCa progression. The aim of this review is to provide a brief primer on mouse and human prostate histology and pathology, provide descriptions of mouse models, as well as attempt to answer the age old question: Which GEM model of PCa is the best for my research question?

Functional screen identifies kinases driving prostate cancer visceral and bone metastasis

“…Greater than 80% of mice injected with cells overexpressing ARAF (7/8 mice) and MERTK (5/6 mice) developed bone metastasis, whereas BRAF, CRAF, and NTRK2 promoted bone metastasis in at least 50% of mice. In comparison, the few genetically engineered mouse models that develop prostate cancer metastasis have a lower penetrance (12.5-25%) of bone metastases (52)(53)(54). Intracardiac or direct bone injection of human prostate cancer cell lines results in a higher frequency of metastasis, but the incidence and location of bone metastasis vary widely between studies (55,56).…”

Regulation of vascular endothelial growth factor in prostate cancer

“…These include the inability to encompass the full complexity of the human disease and the inherent resistance to the development of invasive PCa. Nevertheless, several mouse models have been developed for the study of PCa, and these have been comprehensively reviewed elsewhere (Wu et al 2013, Grabowska et al 2014, Berman-Booty & Knudsen 2015. In the present review, we focus on those that more closely recapitulate the progression of the human disease (Table 1).…”

“…For instance, simultaneous inactivation of p53 and Rb results in the formation of highly metastatic tumors that are resistant to castration and show NE differentiation (Zhou et al 2006). The best of (Wang et al 2003, Grabowska et al 2014. Even though VEGF is the main angiogenic factor involved in PCa progression and metastasis, few studies have examined the role of VEGF in PCa animal models.…”

Docetaxel Resistance in Prostate Cancer: Taking It Up a Notch

“…The majority of men with lethal prostate cancer have bone metastases, whereas the majority of animal models of prostate cancer do not develop bone metastases for example, limiting our ability to determine drug resistance mechanisms in this bone microenvironment. This clinical phenotype is dominant, yet animal models poorly recapitulate bone metastasis, instead relying on direct inoculation or micrometastases to bone (8,9).…”