Abstract C66: Establishing clinically relevant in vitro models of prostate cancer

Prostate cancer is the most commonly diagnosed cancer in men. PTEN and/or TP53 deletions in prostate cancer are associated with aggressiveness, castration-resistance, and poor prognosis. One origin of progressive, treatment-resistant prostate cancer has been hypothesized to be androgen-independent, prostate cancer stem cells. In order to investigate molecular mechanisms linking specific gene mutations to tumorigenic properties, we have established and characterized two prostate luminal epithelial cell lines with Pten/TP53 deletions, derived from a prostate epithelial stem/progenitor-enriched cell population and maintained in a serum-free media. Normal mouse prostate epithelium containing floxed Pten and TP53 alleles was subjected to CRE-mediated deletion in vitro followed by serial propagation as protospheres. A polyclonal cell line was established from dissociated protospheres and subsequently a clonal daughter line was derived. Both lines demonstrate a mature luminal phenotype in vitro. The established lines contain a stable minor population of progenitor cells with protosphere-forming ability and multi-lineage differentiation capacity. Both lines formed orthotopic adenocarcinoma tumors with metastatic potential to lung. Intracardiac inoculation resulted in brain and lung metastasis, while intra-tibial injection induced osteoblastic bone formation, recapitulating the bone metastatic phenotype of human prostate cancer. The cells showed androgen receptor dependent growth in vitro. Importantly, in vivo, the deprivation of androgens from established orthotopic tumors resulted in tumor regression and eventually castration-resistant growth. Cells derived from orthotopic tumors have been isolated to develop androgen-dependent versus androgen-independent model. These data suggest that transformed prostate progenitor cells preferentially differentiate toward luminal cells and recapitulate many characteristics of the human disease. Citation Format: Wassim Abou-Kheir, Paul Hynes, Philip Martin, JuanJuan Yin, Yen-Nien Liu, Victoria Seng, Ross Lake, Joshua Spurrier, Kathleen Kelly. Establishing clinically relevant in vitro models of prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C66.