The current state of preclinical prostate cancer animal models

Abstract

Prostate cancer continues to be a major cause of morbidity and mortality in men around the world. The field of prostate cancer research continues to be hindered by the lack of relevant preclinical models to study tumorigenesis and to further development of effective prevention and therapeutic strategies. The Prostate Cancer Foundation held a Prostate Cancer Models Working Group (PCMWG) Summit on August 6th and 7th, 2007 to address these issues. The PCMWG reviewed the state of prostate cancer preclinical models and identified the current limitations of cell line, xenograft and genetically engineered mouse models that have hampered the transition of scientific findings from these models to human clinical trials. In addition the PCMWG identified administrative issues that inhibit the exchange of models and impede greater interactions between academic centers and these centers with industry. The PCMWG identified potential solutions for discovery bottlenecks that include: (1) insufficient number of models with insufficient molecular and biologic diversity to reflect human cancer, (2) a lack of understanding of the molecular events that define tumorigenesis, (3) a lack of tools for studying tumor-host interactions, (4) difficulty in accessing model systems across institutions, and (5) addressing why preclinical studies appear not to be predictive of human clinical trials. It should be possible to apply the knowledge gained molecular and epigenetic studies to develop new cell lines and models that mimic progressive and fatal prostate cancer and ultimately improve interventions.

Fig. 1

Histologic and molecular changes associated with prostate tumorigenesis. For more information, see Refs. [–34]. PIA, proliferative inflammatory atrophy; RNASEL, 2′–5′-oligoadenylate-dependent RNase L; AMACR, a-methylacyl-coenzyme A racemase; EZH2, enhancer of zeste homolog2; PcG, polycomb group. Original magnification 100x. Taken from Taichman et al. [1].

Fig. 2

The development of the Dunning rat prostate adenocarcinoma cell lines. A: Schematic of the development of the Dunning sub lines. B: Characteristics of the Dunning sublines. [Personal communication, J. Isaacs].

Fig. 3

The development of the LNCaP prostate adenocarcinoma cell sublines. Taken from Sobel and Sadar [22].

Fig. 4

The development of the PC-3 prostate adenocarcinoma cell lines. Taken from Sobel and Sadar [22].

Fig. 5

Diagrammatic summary of the onset and progression of prostate cancer resulting from one, two, or multiple genetic disruptions. Taken from Kasper [31].