Differential Telomerase Activities Shape The Genomic Landscape Driving Prostate Cancer Metastasis
    By Jennifer Wong | January 19th 2013 02:16 PM | Print | E-mail | Track Comments

    Studies by Ding et al (Cell 2012) revealed that telomerase dysfunction early in disease onset creates genomic aberrations crucial for telomerase-driven prostate cancer metastasis into the lumbar spine.  Using a murine prostate cancer model driven by PTEN/P53 deletions, the authors discovered that while telomerase-dysfunction appears to hinder prostate adenocarcinoma initiation, telomerase reactivation at 24 weeks resulted in prostate cancer metastasis into the lumbar spine. In contrast, PTEN/P53-deleted animals with intact TERT activity (constant throughout life) supported rapid prostate tumor initiation, but not metastasis. 

    Importantly, genomic analysis revealed that PTEN/P53-deleted animals that were initially telomerase- dysfunctional carried much higher occurrences of cytogenetic aberrations compared to TERT intact PTEN/P53-deleted animals. These aberrations strongly mimicked the genomic aberrations seen in human prostate cancers, and resulted in similar gene deletions including TGFbeta and SMAD4 deletions. Moreover, deletion of SMAD4 in TERT-intact PTEN/P53-deleted mice resulted in bone metastasis, even without a previous period of telomerase-dysfunction. The data strongly supports the hypothesis that genomic aberrations, triggered by telomerase-dysfunction, contribute to bone metastasis upon telomerase reactivation.

    The Novel LSL-mTERT-PTEN/P53 In Vivo Mouse Model 
    For this study, the authors created a G0-PTEN/P53 prostate cancer model that can mimic the fluctuations of TERT expression required to support the onset and progression of prostate cancers. Specifically, G0-PTEN/P53 mice were rendered telomerase dysfunctional with TERT-knockin approach using Cre-lox technology. The Cre-lox elements include the lox-stopper-lox (LSL) cassette that is knocked-into the TERT locus, and the probasin-controlled Cre-recombinase element that triggers removal of the LSL cassette in response to androgen. This allows TERT to be reactivated when animals reach sexual maturity. Controls for this study included G0-PTEN/P53 mice that are TERT-intact or TERT-deleted, where TERT activity (or lack of activity) remains constant before and after sexual maturity.

    Telomerase History of Prostate Cancer Research
    Telomerase dysfunction is a feature of early prostate cancers, and is supported by human genomic sequence data revealing the presence of telomere erosion in prostate cancer genomes (Stratton et al., 2009). However, functional studies thus far resulted in unexpected findings that seem to oppose the genomic data. For example, recent studies revealed that telomerase dysfunction itself failed to drive spontaneous prostate tumor initiation in mice, even in the presence of P53 deletions (Artandi et al., 2000). Likewise, the authors here further revealed that telomerase dysfunction greatly hindered PTEN/P53 induced initiation of spontaneous prostate tumors. In contrast, telomerase activation during the later onset of disease contributed to the malignant progression and metastasis of prostate cancers (Shay and Wright, 2006).

    With the recent in vivo studies by Ding et al (2012), a better understanding of how telomerase regulates prostate cancer development has finally emerged from the previous body of disparaging findings. Encompassing the results from genomic and telomerase functional studies, Ding et al (2012) presents a model in which telomerase dysfunction shapes the genomic landscape that later supports tumor metastasis in response to telomerase reactivation. Future studies on how telomerase becomes reactivated from a telomerase dysfunctional background may be an interesting direction to pursue.

    Ding, K. et al. (2012) Cell 148, 896–907.
    Stratton, M.R., Campbell, P.J., and Futreal, P.A. (2009). Nature 458, 719–724.
    Shay, J.W., and Wright, W.E. (2006). Nat. Rev. Drug Discov. 5, 577–58.
    Artandi, S.E., et al. (2000). Nature 406, 641–645.