Urologic Oncology: Seminars and Original Investigations

Editorial Board

2010-07-01

Masthead

2010-07-01

Improving urologic cancer care

Ted A. Skolarus, Sean Zhang, Brent K. Hollenbeck — 2010-05-10

To state the obvious, the challenges facing the U.S. health care system are daunting. While Congress and the Executive Branch carefully handle the political “hot potato” known as health care reform, the crux of the problem will inevitably persist, regardless of what, if any, legislation ultimately emerges into law. As Americans, we pay more per capita for health care than any other industrialized society in the world . While we have more MRI machines per capita than any other society , our infant mortality rate and overall life expectancy lag behind 27 and 23 other nations, respectively . Indeed, the discrepancy between what we pay for and what we get in terms of health is not trivial.

Sarcoidosis and testicular cancer: A case series and literature review

Jonathan Dick, Richard H. Begent, Tim Meyer — 2008-12-15

Abstract: The coincidence of testicular carcinoma and sarcoidosis can result in diagnostic errors and inappropriate treatment unless patients are appropriately investigated. We report 3 such cases; 1 in which sarcoidosis preceded the diagnosis, 1 of coincident diagnoses, and 1 in which the sarcoidosis was diagnosed after testicular carcinoma. We review the investigations that can be used to resolve diagnostic uncertainty and the evidence for an association between the 2 diseases.

Kinetics of serum total and free prostate-specific antigen (PSA) after extended multisite prostate biopsy: Comparison among biopsy, transurethral resection of the prostate (TURP), and biopsy plus TURP

2008-12-29

Abstract: Background: The kinetics and reproducibility of serum prostate-specific antigen (PSA) following extended multisite biopsies are unknown. The aim of this study was to examine the kinetics of hematogenous leakage of PSA molecules by comparing the postintervention PSA manner among extended biopsies, transurethral resection of the prostate (TURP) and biopsy plus TURP.Methods: Total and free PSA values were examined before and sequentially after intervention (at 1 hour, 24 hours, 2 days, 14 days, and 28 days), in patients who underwent 14-core prostate biopsy (Biopsy, n = 53), TURP (TURP, n = 21), or prostate biopsy plus TURP (Biopsy+TURP, n = 18).Results: Ten patients in the Biopsy group were histologically diagnosed as having prostate cancer, and all other patients were diagnosed with non-malignant disorders. One hour after intervention, the increase in total PSA in the Biopsy group (mean 19.58 ± 24.78-fold) and Biopsy+TURP group (mean 14.00 ± 10.52-fold) was higher than that of the TURP group (mean 6.189 ± 7.567-fold) (P = 0.0207 and 0.0119, respectively). The increase in total PSA in the Biopsy+TURP group was not different from that of the Biopsy group. The increase in free PSA in the Biopsy group (mean 36.52 ± 21.18-fold or more) was greater than that of the TURP group (mean 15.57 ± 18.17-fold) (P = 0.0002 or less). Both total and free PSA values in the Biopsy group recovered to the initial levels 28 days after intervention (P = 0.380 and P = 0.0873, respectively). The course of both total and free PSA values in the Biopsy group was not different between prostate cancer and non-malignant disorders.Conclusions: Extended multisite biopsies caused marked elevation of both total and free PSA compared with ordinary sextant protocol or TURP, and they reduced to the preoperative levels in about 4 weeks. The postintervention increase of PSA and its manner of recovery were comparable between the Biopsy and Biopsy+TURP groups, suggesting that the hematogenous leakage of PSA by biopsies occurs in an early phase just after biopsy and rapidly reduces also in the early phase.

Altered antioxidant status and lipid peroxidation in Indian patients with urothelial bladder carcinoma

Nitika Badjatia, Abhigyan Satyam, Prabhjot Singh, Amlesh Seth, Alpana Sharma — 2009-01-27

Abstract: Objectives: Urothelial carcinoma of bladder is the second most common urological malignancy after prostate cancer. Recently, there has been increased interest in research of the role of free radicals and antioxidant materials in the prevention, treatment, and alleviation of therapy-related side effects of cancer. In the present study, we aimed to assess the alterations in the levels of antioxidant vitamins, activities of defense enzymes, circulating lipid peroxide, and total antioxidant activity (AOA) in patients with urothelial carcinoma of bladder and correlate these changes with the grade and severity of the disease.Materials and methods: The study cohort consisted of 90 subjects; 50 patients with bladder UC (25, low grade; 10, high grade; 15, muscle invasive) and 40 healthy controls. Vitamins C and E, malondialdehyde (MDA), and AOA were estimated using standard protocols. Superoxide dismutase (SOD) and glutathione peroxidase (GPx) were assayed using commercially available kits.Results: The serum levels of vitamins C and E, whole blood levels of SOD and GPx, and serum AOA was significantly lower (P < 0.001) while serum MDA levels were significantly higher (P < 0.001) in patients than in controls, indicating presence of oxidative stress in bladder UC patients. The levels of all the biochemical parameters were correlated with the grade and severity of the disease. There were significant differences between the patients with low grade tumors and muscle invasive tumors for all parameters (P < 0.001); except AOA (P < 0.279).Conclusions: The observed redox imbalance in UC of bladder in correlation with the grade and stage, as a consequence of decreased levels of antioxidant vitamins, enzymes, and AOA, along with increased MDA levels in circulation, may be important factors in tumor development and growth. Our results suggest that with advancing stage of bladder UC, the levels of oxidative stress increase, while levels of antioxidant molecules decrease. These findings suggest possible use of antioxidant supplementation as prophylactic agents for prevention and treatment of bladder cancer.

Updated results of bladder-sparing trimodality approach for invasive bladder cancer

2009-04-13

Abstract: Purpose: To update long-term results with selective organ preservation in invasive bladder cancer using aggressive transurethral resection of bladder tumor (TURBT) and radiochemotherapy (RCT) and to identify treatment factors that may predict overall survival (OS).Materials and methods: Between 1990 and 2007, a total of 74 patients with T2-T4 bladder cancer were enrolled in 2 sequential bladder-sparing protocols including aggressive TURB and RCT. From 1990 to 1999, 41 patients were included in protocol no. 1 (P1) that consisted of three cycles of neoadjuvant methotrexate, cisplatin, and vinblastine (MCV) chemotherapy prior to re-evaluation and followed by radiotherapy (RT) 60 Gy in complete responders. Between 2000 and 2007, 33 patients were entered in protocol no. 2 (P2) that consisted of concurrent RCT 64, 8 Gy with weekly cisplatin. In case of invasive residual tumor or recurrence, salvage cystectomy was recommended. Primary endpoints were OS, overall survival with bladder preservation (OSB), and late toxicity.Results: The mean follow-up for the whole series was 54 months (range 9–156), 69 months for patients in P1 and 36 months for patients in P2. The actuarial 5-year OS and OSB for all series were 72% and 60%, respectively. Distant metastases were diagnosed in 11 (15%) patients. Grade 3 late genitourinary (GU) and intestinal (GI) complications were 5% and 1.3%, respectively. There were no significant differences in the incidence of superficial recurrences (P = 0.080), muscle-invasive relapses (P = 0.722), distant metastasis (P = 0.744), grade ≥2 late complications (P = 0.217 for GU and P = 0.400 for GI), and death among the 2 protocols (P value for OS = 0.643; P value for OSB = 0.532).Conclusion: These data confirm that trimodality therapy with bladder preservation represents a real alternative to radical cystectomy in selected patients, resulting in an acceptable rate of the long-term survivors retaining functional bladders.

The International Bladder Cancer Network

H. Barton Grossman, Colin P.N. Dinney, Bernd J. Schmitz-Dräger, Peter J. Goebell — 2010-07-01

The International Bladder Cancer Network (IBCN) is an organization focused on improving the diagnosis, prevention, and treatment of bladder cancer through the application of biologic markers. This relatively young group can trace its origin to 1996 when the United States National Cancer Institute Bladder Cancer Marker Network sponsored an international meeting in Barcelona. The significance of this event was not lost on the participants resulting in an additional meeting in 1998. The discussions from these meetings resulted in the inauguration of a large international multi-center evaluation of p53 alterations in bladder cancer and the first series of consensus reports from this group . The consecutive meetings in 2001 and 2002 led to another international collaboration exploring the utility of bladder cancer tissue microarrays funded through the M. D. Anderson Cancer Center Specialized Programs of Research Excellence (SPORE) in bladder cancer. After another meeting in 2004, the IBCN was incorporated as an official organization in Germany in 2005. The first formal meeting of the incorporated IBCN returned to the location of its origin and was held in 2008. This meeting continued the workshop format used for the prior meetings and resulted in considerable interaction among the participants. This seminar is comprised of presentations and discussions from that meeting.

p53 immunohistochemistry in bladder cancer—a new approach to an old question

2010-07-01

Abstract: Objective: For nearly 20 years, the putative prognostic value of P53 immunohistochemistry in bladder cancer has been controversially discussed, and key questions are still unanswered. The aim of this article was to elucidate the different findings using the new concept of a combined analysis of raw data from previously published material.Materials and methods: Twenty-six of 38 study centers approached contributed patient data sets according to the protocol requirements; 3,421 patients with bladder cancer from 25 centers are included in the further analysis. The entire study group (mean age: 66.5 years) comprised 2,697 males (78.8 %) and 719 females. For 2,298 patients (68%) with non-muscle-invasive tumors Ta (1314), TIS (37), and T1 (947) (38.9, 1.1, and 28%, respectively) a median survival time of 130 months was calculated. The remaining 1,082 patients (32%) had advanced tumors (>T2) and a median survival time of 26 months. Of the 1,241 patients who have died, 744 patients died from bladder cancer and another 497 patients from intercurrent disease.Results: With regard to gender, age, and tumor stage, the patients included reflected a normal bladder cancer population. Statistical analysis revealed a highly significant correlation between P53 positivity vs. tumor grade and tumor stage. Uni- and multivariate analyses showed that P53 positivity was significantly correlated with tumor progression (as defined by the different centers) in T1 disease (P < 0.001) as well as in advanced bladder cancer (P < 0.001), but not in Ta tumors.Conclusions: P53 immunohistochemistry appears to be predictive in high grade bladder cancer, however, the magnitude of this association varies among tumor stages. The results of this trial demonstrate the relevance of sufficient study size, provide a basis to define suitable patient populations, and allow an estimation of an adequate size of study cohorts for prospective trials. It also demonstrates the importance of common recommendations for evaluation and reporting of marker studies. Furthermore, this initiative demonstrates the strong will of a large number of investigators to contribute to combined efforts in order to establish pathways for standardization of marker development and clinical use.

Statistical consideration for clinical biomarker research in bladder cancer

2010-07-01

Abstract: Objective: To critically review and illustrate current methodological and statistical considerations for bladder cancer biomarker discovery and evaluation.Methods: Original, review, and methodological articles, and editorials were reviewed and summarized.Results: Biomarkers may be useful at multiple stages of bladder cancer management: early detection, diagnosis, staging, prognosis, and treatment; however, few novel biomarkers are currently used in clinical practice. The reasons for this disjunction are many and reflect the long and difficult pathway from candidate biomarker discovery to clinical assay, and the lack of coherent and comprehensive processes (pipelines) for biomarker development. Conceptually, the development of new biomarkers should be a process that is similar to therapeutic drug evaluation—a highly regulated process with carefully regulated phases from discovery to human applications. In a further effort to address the pervasive problem of inadequacies in the design, analysis, and reporting of biomarker prognostic studies, a set of reporting recommendations are discussed. For example, biomarkers should provide unique information that adds to known clinical and pathologic information. Conventional multivariable analyses are not sufficient to demonstrate improved prediction of outcomes. Predictive models, including or excluding any new putative biomarker, need to show clinically significant improvement of performance in order to claim any real benefit. Towards this end, proper model building, avoidance of overfitting, and external validation are crucial. In addition, it is important to choose appropriate performance measures dependent on outcome and prediction type and to avoid the use of cutpoints. Biomarkers providing a continuous score provide potentially more useful information than cutpoints since risk fits a continuum model. Combination of complementary and independent biomarkers is likely to better capture the biological potential of a tumor than any single biomarker. Finally, methods that incorporate clinical consequences such as decision curve analysis are crucial to the evaluation of biomarkers.Conclusions: Attention to sound design and statistical practice should be delivered as early as possible and will help maximize the promise of biomarkers for patient care. Studies should include a measure of predictive accuracy and clinical decision-analysis. External validation using data from an independent cohort provides the strongest evidence that a model is valid. There is a need for adequately assessed clinical biomarkers in bladder cancer.

Molecular pathways of urothelial development and bladder tumorigenesis

2010-07-01

Abstract: Bladder cancer is the fifth most common human malignancy and the second most frequently diagnosed genitourinary tumor after prostate cancer. The majority of malignant tumors arising in the urinary bladder are urothelial carcinomas. Clinically, superficial bladder tumors (stages Ta and Tis) account for 75% to 85% of neoplasms, while the remaining 15% to 25% are invasive (T1, T2–T4) or metastatic lesions at the time of initial presentation. Several studies have revealed that distinct genotypic and phenotypic patterns are associated with early vs. late stages of bladder cancer. Early superficial disease appears to segregate into 2 main pathways: (1) superficial papillary bladder tumors, which are characterized by gain-of-function mutations affecting oncogenes such as H-RAS, FGFR3, and PI3K, and deletions of the long arm of chromosome 9 (9q); (2) Carcinoma in situ, a “flat” high grade lesion considered to be a precursor of invasive cancer, is characterized by loss-of-function mutations affecting tumor suppressor genes, such as p53, RB, and PTEN. Based on these data, a model for bladder tumor progression has been proposed in which 2 separate genetic pathways characterize the evolution of early bladder neoplasms. Several molecular markers have been correlated with tumor stage, but the rationale for these 2 well-defined genetic pathways still remains unclear.Normal urothelium is a pseudo-stratified epithelium that coats the bladder, composed of 3 cell types: basal, intermediate, and superficial (“umbrella”) cells. We have identified a series of markers that are differently expressed in these distinct cells types, and postulated a novel model for urothelium development and configuration. Briefly, it is our working hypothesis that 2 distinct progenitor cells are responsible for basal/intermediate cells and “umbrella” cells, respectively. Basal and intermediate cells are characterized by a p63 positive phenotype, as well as expression of high molecular weight cytokeratins (CKs), such as CK5, CK10, and CK14. On the contrary, “umbrella” cells display a p63 negative phenotype and are characterized by expression of 2 specific low molecular weight CKs: CK18 and CK20. Neither urothelial stem cells nor bladder cancer stem cells have been identified to date. In this review, we will further expand on the issues discussed above.

Bladder cancer or bladder cancers? Genetically distinct malignant conditions of the urothelium

Peter J. Goebell, Margaret A. Knowles — 2010-07-01

Abstract: Despite the fact that the current histopathologic classification for bladder cancer has led to improved concepts for the clinical management of the disease, key questions with regard to assessment of risk for recurrence and/or progression to invasive disease remain. In addition, response to specific therapies cannot be predicted accurately.Bladder tumors comprise a heterogeneous group with respect to both histopathology and clinical behavior. Thus, it is anticipated that a thorough knowledge and interpretation of the molecular alterations involved in tumor development and progression will lead to greater prognostic and predictive power. This may not only lead to better comprehension of the biology of the disease, but may also lead to the development of novel individualized therapies. Novel means of stratification are urgently needed to provide a new subclassification of urothelial lesions.This review discusses and summarizes the genetic alterations that have been reported in bladder cancer and relates these to the current 2-pathway model for tumor development. The molecular pathogenesis of high-grade noninvasive papillary tumors and of T1 tumors is not yet clear, and possibilities are discussed.

Molecular genetics of bladder cancer: Emerging mechanisms of tumor initiation and progression

2010-07-01

Abstract: Urothelial cancer has served as one of the most important sources of information about the mutational events that underlie the development of human solid malignancies. Although “field effects” that affect the entire bladder mucosa appear to initiate disease, tumors develop along 2 distinct biological “tracks” that present vastly different challenges for clinical management. Recent whole genome methodologies have facilitated even more rapid progress in the identification of the molecular mechanisms involved in bladder cancer initiation and progression. Specifically, whole organ mapping combined with high resolution, high throughput SNP analyses have identified a novel class of candidate tumor suppressors (“forerunner genes”) that localize near more familiar tumor suppressors but are disrupted at an earlier stage of cancer development. Furthermore, whole genome comparative genomic hybridization (CGH) and mRNA expression profiling have demonstrated that the 2 major subtypes of urothelial cancer (papillary/superficial and non-papillary/muscle-invasive) are truly distinct molecular entities, and in recent work our group has discovered that muscle-invasive tumors express molecular markers characteristic of a developmental process known as “epithelial-to-mesenchymal transition” (EMT). Emerging evidence indicates that urothelial cancers contain subpopulations of tumor-initiating cells (“cancer stem cells”) but the phenotypes of these cells in different tumors are heterogeneous, raising questions about whether or not the 2 major subtypes of cancer share a common precursor. This review will provide an overview of these new insights and discuss priorities for future investigation.

Considerations on implementing diagnostic markers into clinical decision making in bladder cancer

2010-07-01

Abstract: Bladder cancer is a common disease that is often detected late and has a high rate of recurrence and progression. Cystoscopy is the main tool in detection and surveillance of bladder cancer but is invasive and can miss some cancers. Cytology is frequently utilized but suffers from a poor sensitivity. There are several commercially available urine-based tumor markers currently available but their use is not recommended by guideline panels. Markers such as the Urovysion FISH assay and the NMP22 BladderChek test are approved for surveillance and detection in patients with hematuria. The added benefit of these markers and other commercially available markers (e.g. Ucyt+, BTA stat) has not been well investigated though it appears these markers are insufficiently sensitive to replace cystoscopy. Additional studies are needed to determine the clinical scenarios where bladder markers are best utilized (screening, surveillance, early detection, evaluating cytologic atypia) and what impact they should have on clinical decision making. Furthermore, a variety of issues and barriers can affect the movement of clinical tests from research to clinical practice. This article addresses some of the challenges facing research and medical communities in the delivery and integration of markers for bladder cancer diagnosis. Moreover, we attempt to outline criteria for the clinical utility of new bladder cancer diagnostic markers.

New concepts of biobanks—strategic chance for uro-oncology

Peter J. Goebell, Manuel M. Morente — 2010-07-01

Abstract: Cancer, as well as other common diseases, is a complex condition that not only causes a major threat to human health, but also represents a huge burden to society in terms of healthcare cost and loss of economic productivity. Treatment improvements remain elusive, since the causes of cancer are due to a huge number of small and possibly additive effects arising from genetic susceptibility, lifestyle, and environmental conditions. Thus, progress in translational cancer research investigating these changes and their complex interaction is highly dependent on large series of cases (affected and unaffected individuals) including high quality samples and their associated data. Therefore, large and well-organized biobanks have been established, are underway, or are planned in many countries and institutions. The integration of these resources with powerful molecular and “omics” approaches, integrated bioinformatic tools hold the promise to further advance our knowledge of disease development, thus leading to better prevention and treatment strategies. However, these valuable and irreplaceable collections typically suffer from underutilization, due to fragmentation of the collections and their accessibility, lack of common management strategies, including consensus on standard operating procedures, unique policies of utilization, and distribution as well as missing input on a broad basis reflecting research needs on an interdisciplinary, multi-institutional fashion beyond project-driven interest. The uro-oncologic community has not yet contributed to these efforts to its full potential, and broad knowledge on the contemporary developments in the field of biobanking and input into these efforts are still missing. This review presents an overview on biobanking and may serve as an update to be integrated into future discussions on managing biobanks involving uro-oncology. It is based on the discussions at the last meeting of the International Bladder Cancer Network in Barcelona (Spain) in fall 2008 and has been also largely influenced by the works and discussions of the Marble Arch International Working Group on Biobanking for Biomedical Research.

Survey Section Editorial Board

2010-07-01

Commentary on Androgen receptor survival signaling is blocked by anti-{β}2-microglobulin monoclonal antibody via a MAPK/lipogenic pathway in human prostate cancer cells: Huang WC, Zhau HE, Chung LW, Uro-Oncology Research Program, Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA

Kenneth S. Koeneman — 2010-07-01

J Biol Chem 2010;285:7947–56. Epub 2010 Jan 13 A new cis-acting element, sterol regulatory element-binding protein-1 (SREBP-1) binding site, within the 5′-flanking human androgen receptor (AR) promoter region and its binding transcription factor, SREBP-1, was identified to regulate AR transcription in AR-positive human prostate cancer cells. We further characterized the molecular mechanism by which a novel anti-β2-microglobulin monoclonal antibody (β2M mAb), shown to induce massive cell death in a number of human and mouse cancer cell lines, interrupted multiple cell signaling pathways in human prostate cancer cells. β2M mAb decreased AR expression through inactivation of MAPK and SREBP-1. By inactivation of MAPK, β2M mAb decreased prostate cancer cell proliferation and survival. By inhibition of SREBP-1, β2M mAb reduced fatty acid and lipid levels, an integral component of cell membrane, cell signaling mediators, and energy metabolism. These results provide for the first time a molecular link between the β2M intracellular signaling axis mediated by MAPK and SREBP-1 and involving lipid signaling, which collectively regulates AR expression and function. Antagonizing β2M by β2M mAb may be an effective therapeutic approach simultaneously targeting multiple downstream signaling pathways converging with MAPK, SREBP-1, and AR, important for controlling prostate cancer cell growth, survival, and progression.

Commentary on Role of DAB2IP in modulating epithelial-to-mesenchymal transition and prostate cancer metastasis: Xie D, Gore C, Liu J, Pong RC, Mason R, Hao G, Long M, Kabbani W, Yu L, Zhang H, Chen H, Sun X, Boothman DA, Min W, Hsieh JT, Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX

Kenneth S. Koeneman — 2010-07-01

Proc Natl Acad Sci USA 2010;107:2731–2 A single nucleotide polymorphism in the DAB2IP gene is associated with risk of aggressive prostate cancer (CaP), and loss of DAB2IP expression is frequently detected in metastatic CaP. However, the functional role of DAB2IP in CaP remains unknown. Here, we show that the loss of DAB2IP expression initiates epithelial-to-mesenchymal transition (EMT), which is visualized by repression of E-cadherin and up-regulation of vimentin in both human normal prostate epithelial and prostate carcinoma cells as well as in clinical prostate cancer specimens. Conversely, restoring DAB2IP in metastatic CaP cells reversed EMT. In DAB2IP knockout mice, prostate epithelial cells exhibited elevated mesenchymal markers, which is characteristic of EMT. Using a human prostate xenograft-mouse model, we observed that knocking down endogenous DAB2IP in human carcinoma cells led to the development of multiple lymph node and distant organ metastases. Moreover, we showed that DAB2IP functions as a scaffold protein in regulating EMT by modulating nuclear β-catenin/T-cell factor activity. These results show the mechanism of DAB2IP in EMT and suggest that assessment of DAB2IP may provide a prognostic biomarker and potential therapeutic target for CaP metastasis.

Commentary on Dasatinib inhibits the growth of prostate cancer in bone and provides additional protection from osteolysis: Koreckij T, Nguyen H, Brown LG, Yu EY, Vessella RL, Corey E, Department of Urology, University of Washington, Seattle, WA

Kenneth S. Koeneman — 2010-07-01

Br J Cancer 2009;101:263–8 Dasatinib is a small molecule kinase inhibitor that has recently been shown to inhibit Src family kinases (SFK) and also has activity against CaP. Of importance to metastatic CaP, which frequently metastasizes to bone, SFK are also vital to the regulation of bone remodeling. We sought to determine the ability of dasatinib to inhibit growth of CaP in bone.

Commentary on Telomerase enzyme inhibition (TEI) and cytolytic therapy in the management of androgen independent osseous metastatic prostate cancer: Li Y, Malaeb BS, Li ZZ, Thompson MG, Chen Z, Corey DR, Hsieh JT, Shay JW, Koeneman KS, Department of Urologic Surgery, Center for Prostate Cancer, University of Minnesota, Minneapolis, MN

Kenneth S. Koeneman — 2010-07-01

Prostate 2009 Dec 30 [Epub ahead of print] Recurrent prostate cancer can be osseous, androgen independent, and lethal. The purpose is to discern the efficacy of synthetic small molecule telomerase enzyme inhibitors (TEI) alone or in combination with other cytotoxic therapies in controlling metastatic osseous prostate cancer.

Commentary on The effects of telomerase inhibition on prostate tumor-initiating cells: Marian CO, Wright WE, Shay JW, Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX

Kenneth S. Koeneman — 2010-07-01

Int J Cancer 2009 Nov 11 [Epub ahead of print] Prostate cancer is the most common malignancy in men, and patients with metastatic disease have poor outcome even with the most advanced therapeutic approaches. Most cancer therapies target the bulk tumor cells, but may leave intact a small population of tumor-initiating cells (TICs), which are believed to be responsible for the subsequent relapse and metastasis. Using specific surface markers (CD44, integrin α(2)β(2), and CD133), Hoechst 33342 dye exclusion, and holoclone formation, we isolated TICs from a panel of prostate cancer cell lines (DU145, C4-2, and LNCaP). We have found that prostate TICs have significant telomerase activity, which is inhibited by imetelstat sodium (GRN163L), a new telomerase antagonist that is currently in phases I/II clinical trials for several hematologic and solid tumor malignancies. Prostate TICs telomeres were of similar average length to the telomeres of the main population of cells and significant telomere shortening was detected in prostate TICs as a result of imetelstat treatment. These findings suggest that telomerase inhibition therapy may be able to efficiently target the prostate TICs in addition to the bulk tumor cells, providing new opportunities for combination therapies.

Commentary on Metallofullerene nanoparticles circumvent tumor resistance to cisplatin by reactivating endocytosis: Liang XJ, Meng H, Wang Y, He H, Meng J, Lu J, Wang PC, Zhao Y, Gao X, Sun B, Chen C, Xing G, Shen D, Gottesman MM, Wu Y, Yin JJ, Jia L, Chinese Academy of Sciences Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology of China, Beijing, China

Kenneth S. Koeneman — 2010-07-01

Proc Natl Acad Sci USA (Epub 2010 Apr 5, ahead of print) Cisplatin is a chemotherapeutic drug commonly used in clinics. However, acquired resistance confines its application in chemotherapeutics. To overcome the acquired resistance to cisplatin, it is reasoned, based on our previous findings of mediation of cellular responses by [Gd@C(82)(OH)(22)](n) nanoparticles, that [Gd@C(82)(OH)(22)](n) may reverse tumor resistance to cisplatin by reactivating the impaired endocytosis of cisplatin-resistant human prostate cancer (CP-r) cells. Here we report that exposure of the CP-r PC-3-luc cells to cisplatin in the presence of nontoxic [Gd@C(82)(OH)(22)](n) not only decreased the number of surviving CP-r cells but also inhibited growth of the CP-r tumors in athymic nude mice as measured by both optical and MRI. Labeling the CP-r PC-3 cells with transferrin, an endocytotic marker, demonstrated that pretreatment of the CP-r PC-3-luc cells with [Gd@C(82)(OH)(22)](n) enhanced intracellular accumulation of cisplatin and formation of cisplatin-DNA adducts by restoring the defective endocytosis of the CP-r cancer cells. The results suggest that [Gd@C(82)(OH)(22)](n) nanoparticles overcome tumor resistance to cisplatin by increasing its intracellular accumulation through the mechanism of restoring defective endocytosis. The technology can be extended to other challenges related to multidrug resistance often found in cancer treatments.

Information for Authors

2010-07-01

Urologic Oncology: Seminars and Original Investigations

Editorial Board

Contents

Masthead

Improving urologic cancer care

Sarcoidosis and testicular cancer: A case series and literature review

Kinetics of serum total and free prostate-specific antigen (PSA) after extended multisite prostate biopsy: Comparison among biopsy, transurethral resection of the prostate (TURP), and biopsy plus TURP

Altered antioxidant status and lipid peroxidation in Indian patients with urothelial bladder carcinoma

Updated results of bladder-sparing trimodality approach for invasive bladder cancer

The International Bladder Cancer Network

p53 immunohistochemistry in bladder cancer—a new approach to an old question

Statistical consideration for clinical biomarker research in bladder cancer

Molecular pathways of urothelial development and bladder tumorigenesis

Bladder cancer or bladder cancers? Genetically distinct malignant conditions of the urothelium

Molecular genetics of bladder cancer: Emerging mechanisms of tumor initiation and progression

Considerations on implementing diagnostic markers into clinical decision making in bladder cancer

New concepts of biobanks—strategic chance for uro-oncology

Survey Section Editorial Board

Commentary on Dasatinib inhibits the growth of prostate cancer in bone and provides additional protection from osteolysis: Koreckij T, Nguyen H, Brown LG, Yu EY, Vessella RL, Corey E, Department of Urology, University of Washington, Seattle, WA

Commentary on The effects of telomerase inhibition on prostate tumor-initiating cells: Marian CO, Wright WE, Shay JW, Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX

Information for Authors