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Re: Autonomic Nerve Development Contributes to Prostate Cancer Progression
EUROPEAN UROLOGY 65 (2014) 665–670
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Words of Wisdom Re: Men with Low Preoperative Sexual Function May Benefit from Nerve-Sparing Radical Prostatectomy Harris C, Punned S, Carroll PR J Urol 2013;190:981–6 Expert’s summary: The authors evaluated a multi-institutional database including 1322 patients undergoing radical prostatectomy. They stratified patients by whether the men had bilateral, unilateral, or no nerve sparing and correlated this characteristic with recovery of both sexual and urinary function. Patients with poor preoperative sexual function showed no apparent benefit from nerve sparing with regard to recovery of erectile function. However, urinary function and return of control were positively affected in all men, including men with poor preoperative erectile function. The authors concluded that patients who are suitable candidates may benefit from nerve-sparing surgery even if they have poor baseline sexual function. Expert’s comments: Whether cavernosal nerves, which are important for erectile function, affect the recovery of urinary control after radical prostatectomy is an important topic, but one that is still debated. A common dilemma facing a surgeon is whether or not to perform nerve sparing for a patient who already has
Re: Autonomic Nerve Development Contributes to Prostate Cancer Progression Magnon C, Hall SJ, Lin J, et al. Science 2013;341:1236361 Experts’ summary: Magnon et al. report on how the two arms of the autonomic nervous system have complementary roles in tumor initiation and dissemination. Through the use of prostate cancer (PCa) xenograft and transgenic mouse models, the authors monitored tumor growth and progression by systematically modulating the sympathetic and parasympathetic nerves using pharmacologic and surgical ablative techniques. The researchers concluded that the sympathetic nervous system (SNS) promotes survival of cancer cells and initial tumor growth by releasing norepinephrine, which stimulates adrenergic b2 0302-2838/$ – see back matter
poor erectile function. I have commonly faced this situation, with personal experience of >4000 robot-assisted laparoscopic prostatectomies. It is always difficult to compare patients who are good candidates for nerve sparing and patients who are not based on tumor characteristics. The authors partly overcame this obstacle by evaluating urinary function in men who underwent nerve sparing despite poor preoperative erectile function. The authors observed improved urinary control when nerve sparing was performed. There are enough limitations in the data of this publication that it can hardly be considered definitive. However, it only makes sense not to remove tissue unnecessarily in any operation. A properly performed nerve-sparing procedure does not compromise surgical margins in appropriately selected patients. Since nerve sparing might help with urinary control, it makes sense to limit damage to the neurovascular bundle. Conflicts of interest: The author has nothing to disclose.
Joseph A. Smith Jr. Department of Urologic Surgery, Vanderbilt University Medical Center, A 1302 Medical Center North, Nashville, TN 37232-2765, USA E-mail address: [email protected]. http://dx.doi.org/10.1016/j.eururo.2013.11.020
and b3 receptors found on the surface of the stromal cells, while the cholinergic fibers of the parasympathetic nervous system (PNS) are responsible for the invasion and metastasis of PCa cells by releasing acetylcholine, which stimulates type 1 muscarinic receptors expressed on stromal cells. To evaluate the relevance of these findings in human PCa, the researchers analyzed densities of sympathetic and parasympathetic nerve fibers in prostatic adenocarcinoma specimens from 43 patients and found that aggressive cancers were associated with increased density of nerve fibers compared with less aggressive tumors. Experts’ comments: The human prostate gland is a well-developed fibromuscular compound tubuloalveolar exocrine gland of the male reproductive system. The prostate contains fibroblasts, endothelial cells, nerves, and smooth muscle cells. It is innervated through
666
EUROPEAN UROLOGY 65 (2014) 665–670
hypogastric and pelvic nerves by both the SNS (innervates stromal smooth muscle cells), which causes discharge of prostatic secretions, and the PNS (innervates epithelial secretory cells), which is responsible for secretions. The role of neural innervation of the prostate gland in its growth and maintenance is well known, but the function of this innervation in PCa initiation and dissemination was poorly understood until recently. A few studies have reported on evidence linking the involvement of nerves to cancer growth and progression. Perineural invasion—the process by which tumor cells invade around nerves—and its correlation with poor prognosis and increased density in prostatic preneoplastic and neoplastic lesions are well known [1]. In analogy to neoangiogenesis, which is vascularization of tumors due to release of angiogenic factors and recently postulated lymphangiogenesis, cancer-related axonogenesis and neoneurogenesis were proposed [2]. The role of nerves in PCa is further reinforced by studies demonstrating that patients with spinal cord injury rarely develop PCa [3]. These new findings raise the possibility of new pharmaceuticals targeting neoneurogenic processes as useful therapies for PCa. This idea is further substantiated by evidence provided by epidemiologic studies demonstrating that PCa patients on b-blockers have low mortality [4]. Designing new drugs to specifically target these b-receptors will not be trivial, however, as these receptors are involved in a wide array of vital processes. These insights, along with a much more clear understanding of how neurostimulation leads to different stages of PCa, may help us in determining the appropriate timing for drugbased therapies to disrupt the neoneurogenic mechanisms involved in the development and progression of PCa.
Re: Punctuated Evolution of Prostate Cancer Genomes Baca SC, Prandi D, Lawrence MS, et al. Cell 2013;153:666–77 Experts’ summary: The authors profiled 57 prostate cancer (PCa) samples using next-generation whole-genome sequencing (WGS) and highthroughput single-nucleotide polymorphism microarray technologies to map somatic DNA alterations associated with PCa initiation and progression. They discovered characteristic distributions of DNA break points and translocations, resulting in a computational model of complex genomic restructuring. The restructuring event is characterized by a high frequency of interchromosomal deletions resulting in an interdependent and coordinated chain of translocations, termed chromoplexy by the authors. This phenomenon was found in 88% of tumors, affecting well-known oncogenes and tumor suppressors across the genome. The model illustrates a sequence of tumorigenic events during tumor initiation and progression in which few early, mostly clonal genomic lesions accumulate in a chain. Subsequently, this results in mostly subclonal genomic lesions. The punctuated evolution described before transforms cells into incipient
Conflicts of interest: Ashutosh Tewari is the principal investigator on research grants from Intuitive Surgical, Inc. (Sunnyvale, CA, USA), th Prostate Cancer Foundation, and Boston Scientific Corporation. He is a noncompensated director of the Prostate Cancer Institute (Pune, India) and the Global Prostate Cancer Research Foundation. He has received research funding from the Prostate Cancer Foundation, The LeFrak Family Foundation, Mr. and Mrs. Paul Kanavos, Craig Effron & Company, Charles Evans Foundation, and Christian and Heidi Lange Family Foundation.
References [1] DeLancey JO, Wood Jr DP, He C, et al. Evidence of perineural invasion on prostate biopsy specimen and survival after radical prostatectomy. Urology 2013;81:354–7. [2] Sundar SS, Ganesan TS. Role of lymphangiogenesis in cancer. J Clin Oncol 2007;25:4298–307. [3] Patel N, Ngo K, Hastings J, Ketchum N, Sepahpanah F. Prevalence of prostate cancer in patients with chronic spinal cord injury. PM R 2011;3:633–6. [4] Grytli HH, Fagerland MW, Fossa˚ SD, Taske´n KA, Ha˚heim LL. Use of b-blockers is associated with prostate cancer-specific survival in prostate cancer patients on androgen deprivation therapy. Prostate 2013;73:250–60.
Adnan Ali, Sailaja Pisipati, Ashutosh Tewari* Center for Prostate Cancer, Department of Urology, Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY, USA *Corresponding author. Weill Cornell Medical College, New York Presbyterian Hospital, 525 East 68th Street, Starr 900, New York, NY 10021, USA. E-mail address: [email protected] (A. Tewari). http://dx.doi.org/10.1016/j.eururo.2013.11.021
cancer cells and provides them with survival advantages. Therefore, the authors introduced a model for PCa evolution that can be applied to other tumors. This clonal–subclonal hierarchy of coordinated, interdependent rearrangements and deletions occurring in multiple rounds of chromoplexy during tumor development represents an approach to mapping the accumulation of gene alterations.
Experts’ comments: Understanding the molecular basis of PCa is key to providing effective health care to patients. This knowledge has been facilitated by the rise of novel high-throughput genomeprofiling technologies in combination with chromoplexy. We believe that these tools might enable the subclassification of PCas based on their genomic profiles, thus tackling the problem of clinical and molecular PCa heterogeneity head on. This study further opens the door to subdividing PCa into relevant homogenous diseases based on molecular signatures. Such a classification may promote a concept of subgrouping and thus a group-specific treatment. The classification is likely to make it more feasible to identify genes representing ‘‘driver events’’ in a homogenous subgroup than in a large, heterogeneous disease. Such a
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Words of Wisdom Re: Men with Low Preoperative Sexual Function May Benefit from Nerve-Sparing Radical Prostatectomy Harris C, Punned S, Carroll PR J Urol 2013;190:981–6 Expert’s summary: The authors evaluated a multi-institutional database including 1322 patients undergoing radical prostatectomy. They stratified patients by whether the men had bilateral, unilateral, or no nerve sparing and correlated this characteristic with recovery of both sexual and urinary function. Patients with poor preoperative sexual function showed no apparent benefit from nerve sparing with regard to recovery of erectile function. However, urinary function and return of control were positively affected in all men, including men with poor preoperative erectile function. The authors concluded that patients who are suitable candidates may benefit from nerve-sparing surgery even if they have poor baseline sexual function. Expert’s comments: Whether cavernosal nerves, which are important for erectile function, affect the recovery of urinary control after radical prostatectomy is an important topic, but one that is still debated. A common dilemma facing a surgeon is whether or not to perform nerve sparing for a patient who already has
Re: Autonomic Nerve Development Contributes to Prostate Cancer Progression Magnon C, Hall SJ, Lin J, et al. Science 2013;341:1236361 Experts’ summary: Magnon et al. report on how the two arms of the autonomic nervous system have complementary roles in tumor initiation and dissemination. Through the use of prostate cancer (PCa) xenograft and transgenic mouse models, the authors monitored tumor growth and progression by systematically modulating the sympathetic and parasympathetic nerves using pharmacologic and surgical ablative techniques. The researchers concluded that the sympathetic nervous system (SNS) promotes survival of cancer cells and initial tumor growth by releasing norepinephrine, which stimulates adrenergic b2 0302-2838/$ – see back matter
poor erectile function. I have commonly faced this situation, with personal experience of >4000 robot-assisted laparoscopic prostatectomies. It is always difficult to compare patients who are good candidates for nerve sparing and patients who are not based on tumor characteristics. The authors partly overcame this obstacle by evaluating urinary function in men who underwent nerve sparing despite poor preoperative erectile function. The authors observed improved urinary control when nerve sparing was performed. There are enough limitations in the data of this publication that it can hardly be considered definitive. However, it only makes sense not to remove tissue unnecessarily in any operation. A properly performed nerve-sparing procedure does not compromise surgical margins in appropriately selected patients. Since nerve sparing might help with urinary control, it makes sense to limit damage to the neurovascular bundle. Conflicts of interest: The author has nothing to disclose.
Joseph A. Smith Jr. Department of Urologic Surgery, Vanderbilt University Medical Center, A 1302 Medical Center North, Nashville, TN 37232-2765, USA E-mail address: [email protected]. http://dx.doi.org/10.1016/j.eururo.2013.11.020
and b3 receptors found on the surface of the stromal cells, while the cholinergic fibers of the parasympathetic nervous system (PNS) are responsible for the invasion and metastasis of PCa cells by releasing acetylcholine, which stimulates type 1 muscarinic receptors expressed on stromal cells. To evaluate the relevance of these findings in human PCa, the researchers analyzed densities of sympathetic and parasympathetic nerve fibers in prostatic adenocarcinoma specimens from 43 patients and found that aggressive cancers were associated with increased density of nerve fibers compared with less aggressive tumors. Experts’ comments: The human prostate gland is a well-developed fibromuscular compound tubuloalveolar exocrine gland of the male reproductive system. The prostate contains fibroblasts, endothelial cells, nerves, and smooth muscle cells. It is innervated through
666
EUROPEAN UROLOGY 65 (2014) 665–670
hypogastric and pelvic nerves by both the SNS (innervates stromal smooth muscle cells), which causes discharge of prostatic secretions, and the PNS (innervates epithelial secretory cells), which is responsible for secretions. The role of neural innervation of the prostate gland in its growth and maintenance is well known, but the function of this innervation in PCa initiation and dissemination was poorly understood until recently. A few studies have reported on evidence linking the involvement of nerves to cancer growth and progression. Perineural invasion—the process by which tumor cells invade around nerves—and its correlation with poor prognosis and increased density in prostatic preneoplastic and neoplastic lesions are well known [1]. In analogy to neoangiogenesis, which is vascularization of tumors due to release of angiogenic factors and recently postulated lymphangiogenesis, cancer-related axonogenesis and neoneurogenesis were proposed [2]. The role of nerves in PCa is further reinforced by studies demonstrating that patients with spinal cord injury rarely develop PCa [3]. These new findings raise the possibility of new pharmaceuticals targeting neoneurogenic processes as useful therapies for PCa. This idea is further substantiated by evidence provided by epidemiologic studies demonstrating that PCa patients on b-blockers have low mortality [4]. Designing new drugs to specifically target these b-receptors will not be trivial, however, as these receptors are involved in a wide array of vital processes. These insights, along with a much more clear understanding of how neurostimulation leads to different stages of PCa, may help us in determining the appropriate timing for drugbased therapies to disrupt the neoneurogenic mechanisms involved in the development and progression of PCa.
Re: Punctuated Evolution of Prostate Cancer Genomes Baca SC, Prandi D, Lawrence MS, et al. Cell 2013;153:666–77 Experts’ summary: The authors profiled 57 prostate cancer (PCa) samples using next-generation whole-genome sequencing (WGS) and highthroughput single-nucleotide polymorphism microarray technologies to map somatic DNA alterations associated with PCa initiation and progression. They discovered characteristic distributions of DNA break points and translocations, resulting in a computational model of complex genomic restructuring. The restructuring event is characterized by a high frequency of interchromosomal deletions resulting in an interdependent and coordinated chain of translocations, termed chromoplexy by the authors. This phenomenon was found in 88% of tumors, affecting well-known oncogenes and tumor suppressors across the genome. The model illustrates a sequence of tumorigenic events during tumor initiation and progression in which few early, mostly clonal genomic lesions accumulate in a chain. Subsequently, this results in mostly subclonal genomic lesions. The punctuated evolution described before transforms cells into incipient
Conflicts of interest: Ashutosh Tewari is the principal investigator on research grants from Intuitive Surgical, Inc. (Sunnyvale, CA, USA), th Prostate Cancer Foundation, and Boston Scientific Corporation. He is a noncompensated director of the Prostate Cancer Institute (Pune, India) and the Global Prostate Cancer Research Foundation. He has received research funding from the Prostate Cancer Foundation, The LeFrak Family Foundation, Mr. and Mrs. Paul Kanavos, Craig Effron & Company, Charles Evans Foundation, and Christian and Heidi Lange Family Foundation.
References [1] DeLancey JO, Wood Jr DP, He C, et al. Evidence of perineural invasion on prostate biopsy specimen and survival after radical prostatectomy. Urology 2013;81:354–7. [2] Sundar SS, Ganesan TS. Role of lymphangiogenesis in cancer. J Clin Oncol 2007;25:4298–307. [3] Patel N, Ngo K, Hastings J, Ketchum N, Sepahpanah F. Prevalence of prostate cancer in patients with chronic spinal cord injury. PM R 2011;3:633–6. [4] Grytli HH, Fagerland MW, Fossa˚ SD, Taske´n KA, Ha˚heim LL. Use of b-blockers is associated with prostate cancer-specific survival in prostate cancer patients on androgen deprivation therapy. Prostate 2013;73:250–60.
Adnan Ali, Sailaja Pisipati, Ashutosh Tewari* Center for Prostate Cancer, Department of Urology, Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY, USA *Corresponding author. Weill Cornell Medical College, New York Presbyterian Hospital, 525 East 68th Street, Starr 900, New York, NY 10021, USA. E-mail address: [email protected] (A. Tewari). http://dx.doi.org/10.1016/j.eururo.2013.11.021
cancer cells and provides them with survival advantages. Therefore, the authors introduced a model for PCa evolution that can be applied to other tumors. This clonal–subclonal hierarchy of coordinated, interdependent rearrangements and deletions occurring in multiple rounds of chromoplexy during tumor development represents an approach to mapping the accumulation of gene alterations.
Experts’ comments: Understanding the molecular basis of PCa is key to providing effective health care to patients. This knowledge has been facilitated by the rise of novel high-throughput genomeprofiling technologies in combination with chromoplexy. We believe that these tools might enable the subclassification of PCas based on their genomic profiles, thus tackling the problem of clinical and molecular PCa heterogeneity head on. This study further opens the door to subdividing PCa into relevant homogenous diseases based on molecular signatures. Such a classification may promote a concept of subgrouping and thus a group-specific treatment. The classification is likely to make it more feasible to identify genes representing ‘‘driver events’’ in a homogenous subgroup than in a large, heterogeneous disease. Such a