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.

The TORC1/TORC2 inhibitor, Palomid 529, reduces tumor growth and sensitizes to docetaxel and cisplatin in aggressive and hormone-refractory prostate cancer cells

“…Two non-tumor prostate epithelial cell lines (BPH1 and EPN (Sinisi et al 2002)), 19 PCa cells lines (CWR22 (Tepper et al 2002), CWR22R-2152 (Tepper et al 2002), CWR22R-2272 (Tepper et al 2002), CWR22R-2274 (Tepper et al 2002), CWR22R-2524 (Tepper et al 2002), 22rv1 (Sramkoski et al 1999), LAPC-4 (Craft et al 1999), LnCaP, LnCaP-C81 (Igawa et al 2002), LnCaP-104S (Kokontis et al 1998), LnCaP-104R1 (Kokontis et al 1998), C4-2B (Lin et al 2001), DU145, PC3, VCaP (Chay et al 2002) and DuCaP (Chay et al 2002), PTENtransfected PC3 (Zhao et al 2004) and AR-transfected PC3 (Bonaccorsi et al 2000), and DU145 (Scaccianoce et al 2003) cells were used (a complete characterization of these cell models is reviewed in Pienta et al (2008)). …”

The diverse and contrasting effects of using human prostate cancer cell lines to study androgen receptor roles in prostate cancer

“…The principles of generation of GEM models are either over-expression of an oncogene (gain-of-function mutation) or knockout of tumor suppressor genes (loss-of-function mutation) to initiate tumorigenesis [74,75]. Popular transgenic mouse models will be discussed here and we will also discuss how to delineate AR functions in selective cells by generating trans genic compound mice.…”

The role of SPARC in the TRAMP model of prostate carcinogenesis and progression

“…Molecular alterations in the tumor as well as the surrounding stroma (Kelloff et al, 2006, and references cited therein) result in a complex microenvironment where malignant epithelial cells interact with host cells within an extracellular matrix (ECM) scaffold. The summation of these interactions ultimately determines the biological characteristics of tumor initiation, progression and organ-specific metastasis (Pienta et al, 2008). Secreted protein acidic and rich in cysteine (SPARC; BM40 or osteonectin) is a nonstructural glycoprotein component of the ECM that has been associated with tissue remodeling and implicated in tumorigenesis (Said et al, 2007b;Podhajcer et al, 2008, and references cited therein).…”

“…Here, we analysed the role of SPARC in primary prostate carcinogenesis and progression, using the C57/B6 TRAMP autochthonous murine prostate cancer model (Pienta et al, 2008). Furthermore, three cell lines derived from primary TRAMP tumors as well as human prostate cancer cell lines were used to evaluate the in vitro and in vivo effect of SPARC in prostate cancer.…”