Glucose impairments and insulin resistance in prostate cancer: the role of obesity, nutrition and exercise.

BACKGROUND: Hyperinsulinemia, obesity and related metabolic diseases are associated with prostate cancer development. Prostate cancer patients undergoing androgen deprivation therapy (ADT) are at increased risk for metabolic syndrome, cardiovascular disease and diabetes, while pre-existing metabolic conditions may be exacerbated. PURPOSE: An integrative approach is used to describe the interactions between insulin, glucose metabolism, obesity and prostate cancer. The potential role of nutrition and exercise will also be examined. FINDINGS: Hyperinsulinemia is associated with prostate cancer development, progression and aggressiveness. Prostate cancer patients who undergo ADT are at risk of diabetes in survivorship. It is unclear whether this is a direct result of treatment or related to pre-existing metabolic features (e.g. hyperinsulinemia and obesity). Obesity and metabolic syndrome are also associated with prostate cancer development and poorer outcomes for cancer survivors, which may be driven by hyperinsulinemia, pro-inflammation, hyperleptinemia and/or hypoadiponectinemia. CONCLUSIONS: Independently evaluating changes in glucose metabolism near the time of prostate cancer diagnosis and during long-term ADT treatment is important to distinguish their unique contributions to the development of metabolic disturbances. Integrative approaches, including metabolic, clinical and body composition measures, are needed to understand the role of adiposity and insulin resistance in prostate cancer and to develop effective nutrition and exercise interventions to improve secondary diseases in survivorship.

Oxidative stress in prostate cancer: changing research concepts towards a novel paradigm for prevention and therapeutics.

A mounting body of evidence suggests that increased production of reactive oxygen species (ROS) is linked to aging processes and to the etiopathogenesis of aging-related diseases, such as cancer, diabetes, atherosclerosis and degenerative diseases like Parkinson's and Alzheimer's. Excess ROS are deleterious to normal cells, while in cancer cells, they can lead to accelerated tumorigenesis. In prostate cancer (PC), oxidative stress, an innate key event characterized by supraphysiological ROS concentrations, has been identified as one of the hallmarks of the aggressive disease phenotype. Specifically, oxidative stress is associated with PC development, progression and the response to therapy. Nevertheless, a thorough understanding of the relationships between oxidative stress, redox homeostasis and the activation of proliferation and survival pathways in healthy and malignant prostate remains elusive. Moreover, the failure of chemoprevention strategies targeting oxidative stress reduced the level of interest in the field after the recent negative results of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) trial. Therefore, a revisit of the concept is warranted and several key issues need to be addressed: The consequences of changes in ROS levels with respect to altered redox homeostasis and redox-regulated processes in PC need to be established. Similarly, the key molecular events that cause changes in the generation of ROS in PC and the role for therapeutic strategies aimed at ameliorating oxidative stress need to be identified. Moreover, the issues whether genetic/epigenetic susceptibility for oxidative stress-induced prostatic carcinogenesis is an individual phenomenon and what measurements adequately quantify prostatic oxidative stress are also crucial. Addressing these matters will provide a more rational basis to improve the design of redox-related clinical trials in PC. This review summarizes accepted concepts and principles in redox research, and explores their implications and limitations in PC.

Underexpression of tumour suppressor LKB1 in clear cell renal cell carcinoma is common and confers growth advantage in vitro and in vivo.

BACKGROUND: Evidence suggests that dysregulation of energy-sensing pathways closely associates with renal cell carcinoma (RCC) development. The metabolic regulation is largely controlled by 5'-AMP activated protein kinase (AMPK) which is activated through phosphorylation by LKB1. METHODS: The expression of LKB1 was determined by reverse transcription-PCR using 10 clinical clear cell RCC (ccRCC) samples and their adjacent normal renal parenchyma, and by immunohistochemical staining of two tissue microarrays containing 201 ccRCC and 26 normal kidney samples. Expression of LKB1 was knocked down in human ccRCC 786-O cells (shLKB1) and compared with cells expressing scrambled control shRNA (shControl). AMPK signalling, proliferation, invasion, and VEGF secretion was measured. The cells were subcutaneously injected into mice to determine tumour growth in vivo. RESULTS: At the protein and transcript levels, a significant reduction in LKB1 expression in tumour compared with normal tissue was found. In vitro, knockdown of LKB1 resulted in reduced AMPK signalling and increased cellular proliferation, invasion, and VEGF secretion compared with shControl cells. In vivo, growth of shLKB1 ccRCC xenografts in nude mice was significantly increased compared with shControl xenografts. CONCLUSION: Collectively, our results suggest that LKB1 acts as a tumour suppressor in most sporadic cases of ccRCC and that underexpression of LKB1 is a common event in the disease.

Adiponectin inhibits oxidative stress in human prostate carcinoma cells.

BACKGROUND: Emerging data suggest that obesity increases the risk of aggressive prostate cancer (PC), but the mechanisms underlying this relationship remain to be fully elucidated. Oxidative stress (OS) is a key process in the development and progression of PC. Adiponectin, an adipocyte-specific hormone, circulates at relatively high levels in healthy humans, but at reduced levels in obese subjects. Moreover, case-control studies also document lower levels of serum adiponectin in PC patients compared with healthy individuals. METHODS: Human 22Rv1 and DU-145 PC cell lines were examined for the generation of OS and detoxification of reactive oxygen species after treatment with adiponectin. Normality was confirmed using the Shapiro-Wilk test and results were analyzed using a one-way analysis of variance. RESULTS: We demonstrate that adiponectin increased cellular anti-oxidative defense mechanisms and inhibited OS in a significant and dose-dependent manner. We show that adiponectin treatment decreased the generation of superoxide anion in both cell lines, whereas the transcript levels of NADPH oxidase (NOX)2 and NOX4 increased. We also found indications of an overall anti-oxidative effect, as the total anti-oxidative potential, catalase activity and protein levels, and manganese superoxide dismutase protein levels increased significantly (P<0.05) in both cell lines after treatment with adiponectin. CONCLUSION: Lower levels of adiponectin in obese individuals may result in higher levels of prostatic OS, which may explain the clinical association between obesity, hypoadiponectinemia and PC.

The clinical importance of visceral adiposity: a critical review of methods for visceral adipose tissue analysis.

As a result of the rising epidemic of obesity, understanding body fat distribution and its clinical implications is critical to timely treatment. Visceral adipose tissue is a hormonally active component of total body fat, which possesses unique biochemical characteristics that influence several normal and pathological processes in the human body. Abnormally high deposition of visceral adipose tissue is known as visceral obesity. This body composition phenotype is associated with medical disorders such as metabolic syndrome, cardiovascular disease and several malignancies including prostate, breast and colorectal cancers. Quantitative assessment of visceral obesity is important for evaluating the potential risk of development of these pathologies, as well as providing an accurate prognosis. This review aims to compare different methods of measuring visceral adiposity with emphasis on their advantages and drawbacks in clinical practice.

Androgens induce oxidative stress and radiation resistance in prostate cancer cells though NADPH oxidase.

Androgen deprivation therapy (ADT) facilitates the response of prostate cancer (PC) to radiation. Androgens have been shown to induce elevated basal levels of reactive oxygen species (ROS) in PC, leading to adaptation to radiation-induced cytotoxic oxidative stress. Here, we show that androgens increase the expression of p22(phox) and gp91(phox) subunits of NADPH oxidase (NOX) and ROS production by NOX2 and NOX4 in PC. Pre-radiation treatment of 22Rv1 human PC cells with NOX inhibitors sensitize the cells to radiation similarly to ADT, suggesting that their future usage may spare the need for adjuvant ADT in PC patients undergoing radiation.

Expression of cyclooxygenase-2 in Wilms tumor: immunohistochemical study using tissue microarray methodology.

PURPOSE: Cyclooxygenase-2, a key enzyme in prostaglandin biosynthesis, has been shown to be involved in the modulation of cell growth, inflammation and apoptosis. Its involvement in the development of several human neoplasms has also been documented as well as the significant antitumor effects of its inhibitors. To our knowledge cyclooxygenase-2 expression in Wilms tumor has not been studied. MATERIALS AND METHODS: A tissue microarray multitissue block was prepared from 14 samples of Wilms tumor, each from a different patient, from xenografts derived thereof, and from normal human lung, liver, renal cortex and medulla tissues as controls. Each sample was represented in the block by 3 or 4 cores 0.6 mm in diameter. After serial slicing to 4 mum the histological slides were stained with hematoxylin and eosin, and immunostained with anti-cyclooxygenase-2 antibodies. Immunostaining was graded semiquantitatively according to the percent of stained cells with the cytoplasmic pattern of staining and according to staining intensity. RESULTS: All authentic human pathological samples except 1 anaplastic Wilms tumor as well as Wilms tumor xenografts expressed cyclooxygenase-2 in all Wilms tumor cellular components except the stroma. Expression was also observed in Wilms tumor lung metastasis and in tumors that overgrew chemotherapy. In comparison, cyclooxygenase-2 expression in normal kidneys was less prominent than in Wilms tumor samples and it was confined to the tubular epithelium in the cortex and medulla. CONCLUSIONS: Cyclooxygenase-2 expression is characteristic of all nonanaplastic Wilms tumors at all stages. It is similar to the previously observed pan-expression of ErbB2 receptors in these tumors. The potential therapeutic role of cyclooxygenase-2 inhibitors should be evaluated for Wilms tumor.

Testicular fixation following torsion of the spermatic cord--does it guarantee prevention of recurrent torsion events?

PURPOSE: Patients with history of testicular torsion who have undergone orchiopexy may rarely present with acute scrotum due to recurrent episodes of torsion. Most of the reports in the literature regarding this scenario refer to the era when absorbable sutures were used for testicular fixation. Herein, we review our experience in recent years, focusing upon the surgical technique and sutures' material. MATERIALS AND METHODS: Between 1991 and 2003, 179 patients were operated on at our institute with the clinical diagnosis of unilateral testicular torsion. They ranged in age between neonates to 45 years old (average age 18). In a comprehensive retrospective study we managed to locate 8 patients who experienced recurrent intravaginal testicular torsion following previous fixation performed in our institute. RESULTS: The patients who experienced repeat torsion have initially presented at the mean age of 18.5 years old (range 12 to 30) with unilateral twisted testicle (left 3, right 5). Urgent explorations were generally performed, apart from in 2 cases that underwent spontaneous detorsion which was followed by an elective surgery. Testicular fixation was conducted by suturing of the tunica albuginea to the dartos layer by 2 sutures at each side, using chromic 3-zero in the 3 more early cases, followed by the usage of polyglactin 3-zero stitches in 4 subsequent cases and 3 sutures of polypropylene 4-zero for each testicle, thereafter, in the most recent case. The patients presented with repeat torsion, 0.5 to 23 years subsequently (average 7 years), involving either the ipsilateral testicle in 4 cases or the contralateral gonad in 4. CONCLUSIONS: Recurrent torsion following previous testicular fixation may appear many years following the primary procedure, even in cases in which either polyglactin or, notwithstanding, polypropylene sutures have been applied, in accordance with the common practice used in the last 2 decades. Increased awareness regarding this possibility is imperative for early diagnosis and prevention of testicular loss.

ErbB2 is a tumor associated antigen and a suitable therapeutic target in Wilms tumor.

PURPOSE: The modern multimodality therapeutic approach to Wilms tumor (WT), combining surgery with radiotherapy and chemotherapy results in high cure rates even for high stage disease. However, the combination of radiotherapy and chemotherapy is associated with severe early and late complications such as neutropenic sepsis, growth retardation and secondary malignancies. Therefore, novel therapeutic strategies, which would decrease the treatment burden, are required. We studied the expression of erbB2 growth factor receptor in WT cells as well as its role as a tumor therapeutic target in an in vivo xenograft model of Wilms tumor. MATERIALS AND METHODS: Paraffin embedded pathological samples from 14 different WT cases as well as xenografts derived thereof were immunostained with anti-erbB2 monoclonal antibody. The immunostaining was graded in comparison to a known positive control (breast cancer) and was scored by the intensity of staining (0 to +3) multiplied by the percentage of cells expressing the antigen. The expression of erbB2 in the human WT xenograft was verified also by fluorescence activated cell sorter analysis. In addition, nude mice bearing established subcutaneous human WT xenografts were treated with either 3 intraperitoneal injections of N29 anti-erbB2 monoclonal antibody or irrelevant antibody. RESULTS: All of the authentic human pathological samples, except 1 anaplastic WT as well the WT xenografts (at different stages), expressed erbB2. Expression was also observed in WT metastasis and in tumors which out grew chemotherapy. Systemic administration of anti-erbB2 monoclonal antibody inhibited and even prevented the growth of WT xenograft in vivo. CONCLUSIONS: ErbB2 is a tumor associated antigen in WT. Being expressed in almost all tumor stages, our in vivo model suggests that erbB2 may serve as a WT therapeutic target. Further work is needed to establish the role of erbB2 in the disease and its potential use in decreasing current treatment burden.

Lack of MHC expression and retention of ultrastructural characteristics by xenograft transmissible venereal tumor cells in SCID mice.

Canine transmissible venereal tumor (CTVT) is primarily a tumor of adult dogs with a high incidence of spontaneous regression. We recently reported a xenograft model of CTVT (XTVT) in NOD/SCID mice. XTVT cells retain cytological and histological features of CTVT as well as characteristic rearranged LINE/c-MYC junction [Am. J. Vet. Res. 62 (2001) 907]. In this paper, we demonstrate that XTVT cells maintain ultrastructural characteristics of CTVT and do not express MHC classes I and II molecules.

Use of a murine xenograft model for canine transmissible venereal tumor.

OBJECTIVE: To develop a murine model for canine transmissible venereal tumor (CTVT). ANIMALS: Thirty-three 6-week-old NOD/LtSz-scid (NOD/SCID) mice and seven 6-week-old C57BL/6J mice. PROCEDURE: Samples of CTVT were excised from a 3-year-old dog and inoculated SC into ten 6-week-old NOD/SCID mice to induce growth of xenograft transmissible venereal tumor (XTVT). To establish mouse-to-mouse transmission, samples of XTVT were removed and inoculated SC into 4 groups of 6-week-old NOD/SCID mice and into a control group. Samples of CTVT were also inoculated into immunocompetent C57BL/6J mice for a mouse antibody production (MAP) test. The canine and xenografted tumors were evaluated cytologically and histologically, and polymerase chain reaction was performed for detection of the rearranged LINE/c-MYC junction. RESULTS: 8 of 10 NOD/SCID mice that were inoculated with CTVT developed tumors 3 to 10 weeks after inoculation. In the second-generation xenograft, all mice developed tumors by postinoculation day 47; 1 X 10(6) of XTVT cells were enough to create a xenograft. Metastases developed in 4 of 20 mice. Xenografted and metastatic tumors retained cytologic, histologic, and molecular characteristics of CTVT. Results of the MAP test were negative for all pathogens. CONCLUSION: We established an NOD/SCID murine model for XTVT and metastasis of CTVT. This model should facilitate study of tumor transplantation, progression, and metastasis and should decrease or eliminate the need for maintaining allogenic transfer in dogs.

WISH-PC2: a unique xenograft model of human prostatic small cell carcinoma.

Prostatic small cell carcinoma is an aggressive subtype of prostate cancer that usually appears as a progression of the original adenocarcinoma. We describe here the WISH-PC2, a novel neuroendocrine xenograft of small cell carcinoma of the prostate. This xenograft was established from a poorly differentiated prostate adenocarcinoma and is serially transplanted in immune-compromised mice where it grows within the prostate, liver, and bone, inducing osteolytic lesions with foci of osteoblastic activity. It secretes to the mouse Chromogranin A and expresses prostate plasma carcinoma tumor antigen-1, six-transmembrane epithelial antigen of the prostate, and members of the Erb-B receptor family. It does not express prostate-specific antigen, prostate stem cell antigen, prostate-specific membrane antigen, and androgen receptor, and it grows independently of androgen. Altogether, WISH-PC2 provides an unlimited source in which to study the involvement of neuroendocrine cells in the progression of prostatic adenocarcinoma and can serve as a novel model for the testing of new therapeutic strategies for prostatic small cell carcinoma.

[Malignant lymphoma of the bladder].

Urinary tract lymphoma is usually reported when the secondarily stem is affected by widespread non-Hodgkin lymphoma. We describe an 83-year-old woman who presented with secondary lymphoma of the bladder 3 years after diagnosis when it initially infiltrated her breast. Treatment included local transurethral excision followed by chemotherapy, during which she died of disseminated disease.

[The Mitrofanoff pouch in lower urinary tract reconstruction].

The Mitrofanoff principle, first described in 1980, consists of implanting a tubular organ such as the appendix, ureter, or fallopian tube into the wall of the bladder (or urinary reservoir) to create a non-refluxing, catherizable urinary conduit. Between 1993-1996, 7 men and 1 woman (aged 48-64, average 59) underwent radical cystectomy and urethrectomy combined with the creation of a MAINZ I urinary reservoir (based on the Mitrofanoff principle). In men the indication for the procedure was the diagnosis of invasive transitional cell carcinoma of the bladder with involvement of the prostatic urethra. All patients had refused urinary diversion to an ileal conduit because of its deleterious effect on the quality of life. In all patients the postoperative course was uneventful, apart from intraperitoneal urinary leakage from the reservoir in 1, successfully managed conservatively. The patients have gained full control of urinary drainage, performing intermittent self-catheterizations every 4-5 hours. In 3 patients there were difficulties with catheterization due to stenosis of the conduit, usually at the skin level. None have suffered leakage from the reservoir, during the day, even when it was full. Our experience shows that creation of a continent urinary reservoir according to the MAINZ I technique is an excellent surgical solution for patients in whom the creation of an orthotopic reservoir is impractical. The use of the umbilicus as a stomal site preserves normal body image and thus does not interfere with quality of life as in those undergoing radical cystectomy.

[Transrectal ultrasound-controlled needle aspiration of a prostatic cyst].

Prostatic cysts are common and are usually acquired and asymptomatic. Congenital prostatic cysts, which may originate from the wolffian system or from remnants of the Muellerian duct, are rare and may cause obstructive symptoms in young adults. Due to the availability of transrectal ultrasonography an increased number of cases of prostatic cysts are being diagnosed. We report a 36-year-old man with a congenital prostatic cyst which caused increasing pain during ejaculation and decreased the force of the urinary stream. It was diagnosed by ultrasonography and treated successfully by ultrasound-controlled, transrectal needle aspiration. There was immediate, complete disappearance of symptoms and no complications.