We have invested several years into the establishment of a new experimental model of stepwise prostate carcinogenesis 1-3.

This model was started from benign human epithelial cells (published as basal cells immortalized by hTERT over-expression) 4. The model is unique in that we now have derived tumorigenic and metastatic cells in immunodeficient mice based only upon physiological adaptation and selection, in practice using different growth conditions and long-time selection of cells, as opposed to the use of viral oncogenes or chemical carcinogens to transform cells. The model now encompasses benign transit amplifying epithelial cells (EP156T), benign (EPT1) and pre-malignant (EPT2) mesenchymal type cells, tumorigenic (EPT3-N04/EPT3-PT1) and metastatic (EPT3-M1) cells in mice3. These cell types have very different phenotypes and display progressive accumulation of defined malignant features (Figure). The common genotypes have been verified by forensic grade DNA microsatellite, karyotype and copy number break point analyses, thereby verifying progeny authenticity. Each of the different cell types can be passaged indefinitely and to high cell numbers in sub-confluent monolayers. EMT was an early feature of the model and tumor initiating subpopulations of cells (TICs) have been characterized among the tumorigenic cells. Subpopulations of TICs show activation of the WNT pathway and an autocrine ROS/IL6/STAT3 loop3 and show increased resistance to apoptosis and anoikis. The cells of the experimental model have already been extensively characterized concerning morphology, functional abilities, genome-wide gene and microRNA expression and selected epigenetic and promoter binding patterns 1-3,5-8

1. Ke, X.S., et al. Reprogramming of cell junction modules during stepwise epithelial to mesenchymal transition and accumulation of malignant features in vitro in a prostate cell model. Exp Cell Res 317, 234-247 (2011).

2. Ke, X.S., et al. Epithelial to mesenchymal transition of a primary prostate cell line with switches of cell adhesion modules but without malignant transformation. PLoS ONE 3, e3368 (2008).

3. Qu, Y., et al. Generation of Prostate Tumor-initiating Cells is Associated with Elevation of Reactive Oxygen Species and IL6/STAT3 Signaling. Cancer Res (2013).

4. Kogan, I., et al. hTERT-immortalized prostate epithelial and stromal-derived cells: an authentic in vitro model for differentiation and carcinogenesis. Cancer Res 66, 3531-3540 (2006).

5. Ke, X.S., et al. Global profiling of histone and DNA methylation reveals epigenetic-based regulation of gene expression during epithelial to mesenchymal transition in prostate cells. BMC genomics 11, 669 (2010).

6. Ke, X.S., et al. Genome-wide profiling of histone h3 lysine 4 and lysine 27 trimethylation reveals an epigenetic signature in prostate carcinogenesis. PLoS ONE 4, e4687 (2009).

7. Olsen, J.R., et al. p63 attenuates epithelial to mesenchymal potential in an experimental prostate cell model. PLoS ONE 8, e62547 (2013).

8. Qu, Y., et al. MiR-182 and miR-203 induce mesenchymal to epithelial transition and self-sufficiency of growth signals via repressing SNAI2 in prostate cells. Int J Cancer 133, 544-555 (2013).