- Email: [email protected]
Re: TERT Promoter Mutations and Telomerase Reactivation in Urothelial Cancer
Urological Survey Uro-Science Re: TERT Promoter Mutations and Telomerase Reactivation in Urothelial Cancer S. Borah, L. Xi, A. J. Zaug, N. M. Powell, G. M. Dancik, S. B. Cohen, J. C. Costello, D. Theodorescu and T. R. Cech Howard Hughes Medical Institute, University of Colorado BioFrontiers Institute, and Departments of Chemistry and Biochemistry, and Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, and University of Colorado Comprehensive Cancer Center and Department of Pharmacology, University of Colorado Anschutz Medical Campus and Department of Surgery, University of Colorado, Aurora, Colorado, Department of Mathematics and Computer Science, Eastern Connecticut State University, Willimantic, Connecticut, and Children’s Medical Research Institute and University of Sydney, Westmead, New South Wales, Australia Science 2015; 347: 1006e1010.
Abstract for this article http://dx.doi.org/10.1016/j.juro.2015.06.021 available at http://jurology.com/ Editorial Comment: Reactivation of some mechanism for telomere maintenance is considered essential for oncogenesis. Because urothelial cancer (UC) does not typically use the alternative lengthening of telomeres mechanism, the authors originally hypothesized that all 23 human UC cell lines would have a similar level of telomerase up-regulation, that is the promoter mutations would represent only one of several equally effective mechanisms for telomerase reverse transcriptase reactivation. Instead the authors observed that 1) the urothelial cancer cell lines varied widely (up to 100-fold) in the level of TERT protein and telomerase activity, which correlated with their respective telomere lengths and 2) although the mere presence of promoter mutations did not necessarily lead to high telomerase activity, those cell lines with the greatest levels of activity harbored such mutations. These results suggest that TERT promoter mutations provide a particularly effective mechanism for high level telomerase reactivation in UC. Future studies will be needed to test whether urothelial cell tumors harboring high levels of telomerase activity are particularly susceptible to treatment with targeted telomerase inhibition. Anthony Atala, MD
Suggested Reading Eissa S, Swellam M, Ali-Labib R et al: Detection of telomerase in urine by 3 methods: evaluation of diagnostic accuracy for bladder cancer. J Urol 2007; 178: 1068. Bravaccini S, Sanchini MA, Granato AM et al: Urine telomerase activity for the detection of bladder cancer in females. J Urol 2007; 178: 57.
Re: SAHA Triggered MET Activation Contributes to SAHA Tolerance in Solid Cancer Cells L. Ding, Z. Zhang, G. Liang, Z. Yao, H. Wu, B. Wang, J. Zhang, M. Tariq, M. Ying and B. Yang Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China Cancer Lett 2015; 356: 828e836.
Abstract for this article http://dx.doi.org/10.1016/j.juro.2015.06.022 available at http://jurology.com/ 0022-5347/15/1943-0848/0 THE JOURNAL OF UROLOGY® Ó 2015 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
848
j
www.jurology.com
AND
RESEARCH, INC.
http://dx.doi.org/10.1016/j.juro.2015.06.021 Vol. 194, 848-850, September 2015 Printed in U.S.A.
LAPAROSCOPY/NEW TECHNOLOGY
849
Editorial Comment: The aim of this study was to determine whether MET activation contributes to SAHA resistance in solid cancer cells and how MET is activated. The authors also sought to determine whether the combination of SAHA and a MET inhibitor has a synergic effect in cancer therapy. Their findings indicate that SAHA induces MET activation, which in turn contributes to resistance to SAHA in solid cancer cells. The study also demonstrated that MET inhibition enhanced the anticancer activity of SAHA in vitro and in vivo. Continued clinical investigation of the XL184/vorinostat combination is particularly warranted since it was well tolerated in vivo. This study provides a promising rationale for the design of clinical trials to evaluate the efficacy of SAHA in combination with XL184. Anthony Atala, MD
Re: A Human Prostatic Bacterial Isolate Alters the Prostatic Microenvironment and Accelerates Prostate Cancer Progression B. W. Simons, N. M. Durham, T. C. Bruno, J. F. Grosso, A. J. Schaeffer, A. E. Ross, P. J. Hurley, D. M. Berman, C. G. Drake, P. Thumbikat and E. M. Schaeffer Brady Urological Institute, Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland J Pathol 2015; 235: 478e489.
Abstract for this article http://dx.doi.org/10.1016/j.juro.2015.06.023 available at http://jurology.com/ Editorial Comment: Inflammation contributes to cancer initiation and progression in a variety of organs, and has been shown to act directly by inducing genetic changes and indirectly by altering the microenvironment through immune cell infiltrate and cytokine expression. Epidemiological and histopathological evidence suggests that prostate cancer risk also correlates with inflammation, although a causal relationship has been difficult to establish. While previous reports describe reactive inflammatory changes and preinvasive mouse prostatic intraepithelial neoplasia in mice with chronic prostatitis, the effect of prostatic inflammation on prostate cancer progression is unknown. The authors chose to use a recently developed model of bacterial prostatitis using the Escherichia coli isolate CP1. This strain of bacteria differs from other reported bacterial models in that it was isolated from the prostate of a human and has been shown to induce chronic prostatitis in several mouse strains. The authors show that CP1 induces chronic inflammation characterized by an influx of macrophages and Th17 lymphocytes, and accelerates cancer progression in Hi-Myc mice. Additionally they demonstrate distinct cytokine profiles induced by inflammation and cancer. The authors report the first evidence that prostate inflammation accelerates prostate cancer progression, and examine the complex inflammatory infiltrate and cytokine milieu associated with inflammation in the prostate glandular microenvironment. Anthony Atala, MD
Suggested Reading Platz EA and De Marzo AM: Epidemiology of inflammation and prostate cancer. J Urol, suppl., 2004; 171: S36. Nelson WG, De Marzo AM, DeWeese TL et al: The role of inflammation in the pathogenesis of prostate cancer. J Urol, suppl., 2004; 172: S6.
Laparoscopy/New Technology Re: Image-Guided Robot-Assisted Prostate Ablation Using Water Jet-Hydrodissection: Initial Study of a Novel Technology for Benign Prostatic Hyperplasia K. Faber, A. L. de Abreu, P. Ramos, N. Aljuri, S. Mantri, I. Gill, O. Ukimura and M. Desai Department of Urology, University of Southern California, Los Angeles, California J Endourol 2015; 29: 63e69.
Abstract for this article http://dx.doi.org/10.1016/j.juro.2015.06.021 available at http://jurology.com/ Editorial Comment: Reactivation of some mechanism for telomere maintenance is considered essential for oncogenesis. Because urothelial cancer (UC) does not typically use the alternative lengthening of telomeres mechanism, the authors originally hypothesized that all 23 human UC cell lines would have a similar level of telomerase up-regulation, that is the promoter mutations would represent only one of several equally effective mechanisms for telomerase reverse transcriptase reactivation. Instead the authors observed that 1) the urothelial cancer cell lines varied widely (up to 100-fold) in the level of TERT protein and telomerase activity, which correlated with their respective telomere lengths and 2) although the mere presence of promoter mutations did not necessarily lead to high telomerase activity, those cell lines with the greatest levels of activity harbored such mutations. These results suggest that TERT promoter mutations provide a particularly effective mechanism for high level telomerase reactivation in UC. Future studies will be needed to test whether urothelial cell tumors harboring high levels of telomerase activity are particularly susceptible to treatment with targeted telomerase inhibition. Anthony Atala, MD
Suggested Reading Eissa S, Swellam M, Ali-Labib R et al: Detection of telomerase in urine by 3 methods: evaluation of diagnostic accuracy for bladder cancer. J Urol 2007; 178: 1068. Bravaccini S, Sanchini MA, Granato AM et al: Urine telomerase activity for the detection of bladder cancer in females. J Urol 2007; 178: 57.
Re: SAHA Triggered MET Activation Contributes to SAHA Tolerance in Solid Cancer Cells L. Ding, Z. Zhang, G. Liang, Z. Yao, H. Wu, B. Wang, J. Zhang, M. Tariq, M. Ying and B. Yang Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China Cancer Lett 2015; 356: 828e836.
Abstract for this article http://dx.doi.org/10.1016/j.juro.2015.06.022 available at http://jurology.com/ 0022-5347/15/1943-0848/0 THE JOURNAL OF UROLOGY® Ó 2015 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
848
j
www.jurology.com
AND
RESEARCH, INC.
http://dx.doi.org/10.1016/j.juro.2015.06.021 Vol. 194, 848-850, September 2015 Printed in U.S.A.
LAPAROSCOPY/NEW TECHNOLOGY
849
Editorial Comment: The aim of this study was to determine whether MET activation contributes to SAHA resistance in solid cancer cells and how MET is activated. The authors also sought to determine whether the combination of SAHA and a MET inhibitor has a synergic effect in cancer therapy. Their findings indicate that SAHA induces MET activation, which in turn contributes to resistance to SAHA in solid cancer cells. The study also demonstrated that MET inhibition enhanced the anticancer activity of SAHA in vitro and in vivo. Continued clinical investigation of the XL184/vorinostat combination is particularly warranted since it was well tolerated in vivo. This study provides a promising rationale for the design of clinical trials to evaluate the efficacy of SAHA in combination with XL184. Anthony Atala, MD
Re: A Human Prostatic Bacterial Isolate Alters the Prostatic Microenvironment and Accelerates Prostate Cancer Progression B. W. Simons, N. M. Durham, T. C. Bruno, J. F. Grosso, A. J. Schaeffer, A. E. Ross, P. J. Hurley, D. M. Berman, C. G. Drake, P. Thumbikat and E. M. Schaeffer Brady Urological Institute, Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland J Pathol 2015; 235: 478e489.
Abstract for this article http://dx.doi.org/10.1016/j.juro.2015.06.023 available at http://jurology.com/ Editorial Comment: Inflammation contributes to cancer initiation and progression in a variety of organs, and has been shown to act directly by inducing genetic changes and indirectly by altering the microenvironment through immune cell infiltrate and cytokine expression. Epidemiological and histopathological evidence suggests that prostate cancer risk also correlates with inflammation, although a causal relationship has been difficult to establish. While previous reports describe reactive inflammatory changes and preinvasive mouse prostatic intraepithelial neoplasia in mice with chronic prostatitis, the effect of prostatic inflammation on prostate cancer progression is unknown. The authors chose to use a recently developed model of bacterial prostatitis using the Escherichia coli isolate CP1. This strain of bacteria differs from other reported bacterial models in that it was isolated from the prostate of a human and has been shown to induce chronic prostatitis in several mouse strains. The authors show that CP1 induces chronic inflammation characterized by an influx of macrophages and Th17 lymphocytes, and accelerates cancer progression in Hi-Myc mice. Additionally they demonstrate distinct cytokine profiles induced by inflammation and cancer. The authors report the first evidence that prostate inflammation accelerates prostate cancer progression, and examine the complex inflammatory infiltrate and cytokine milieu associated with inflammation in the prostate glandular microenvironment. Anthony Atala, MD
Suggested Reading Platz EA and De Marzo AM: Epidemiology of inflammation and prostate cancer. J Urol, suppl., 2004; 171: S36. Nelson WG, De Marzo AM, DeWeese TL et al: The role of inflammation in the pathogenesis of prostate cancer. J Urol, suppl., 2004; 172: S6.
Laparoscopy/New Technology Re: Image-Guided Robot-Assisted Prostate Ablation Using Water Jet-Hydrodissection: Initial Study of a Novel Technology for Benign Prostatic Hyperplasia K. Faber, A. L. de Abreu, P. Ramos, N. Aljuri, S. Mantri, I. Gill, O. Ukimura and M. Desai Department of Urology, University of Southern California, Los Angeles, California J Endourol 2015; 29: 63e69.