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Activation of glucose transporter-1 (Glut-1) gene expression is a molecular feature of cancer cells that increases glucose uptake and metabolism. Increased glucose uptake is the basis for the clinical localization of primary tumors using positron emission tomography (PET) and 2-deoxy-2-[18F]-fluoro-D-glucose (FDG) as a radiotracer. However, previous studies have demonstrated that a considerable number of cancers, which include prostate cancer (CaP), express low to undetectable levels of Glut-1 and that FDG-PET has limited clinical applicability in CaP. This observation could be explained by a low metabolic activity of CaP cells that may be overcome using different hexoses, such as fructose, as the preferred energy source. However, these hypotheses have not been examined critically in CaP. This review article summarizes what is currently known about transport and metabolism of hexoses, and more specifically fructose, in CaP and provides experimental evidences indicating that CaP cells may have increased capacity to transport and metabolize fructose in vitro and in vivo. Moreover, this review highlights recent findings that allow better understanding of how metabolism of fructose may regulate cancer cell proliferation and how fructose uptake and metabolism, through the de novo lipogenesis pathway, may provide new opportunities for CaP early diagnosis, staging, and treatment.

Androgen deprivation therapy (ADT) provides palliation for most patients with advanced prostate cancer (CaP); however, greater than 80% subsequently fail ADT. ADT has been indicated to induce an acute but transient destabilization of the prostate vasculature in animal models and humans. Human re-hydrated lyophilized platelets (hRL-P) were investigated as a prototype for therapeutic agents designed to target selectively the tumour-associated vasculature in CaP. The ability of hRL-P to bind the perturbed endothelial cells was tested using thrombin- and ADP-activated human umbilical vein endothelial cells (HUVEC), as well as primary xenografts of human prostate tissue undergoing acute vascular involution in response to ADT. hRL-P adhered to activated HUVEC in a dose-responsive manner. Systemically administered hRL-P, and hRL-P loaded with super-paramagnetic iron oxide (SPIO) nanoparticles, selectively targeted the ADT-damaged human microvasculature in primary xenografts of human prostate tissue. This study demonstrated that hRL-P pre-loaded with chemo-therapeutics or nanoparticles could provide a new paradigm for therapeutic modalities to prevent the rebound/increase in prostate vasculature after ADT, inhibiting the transition to castration-recurrent growth.

Objective To determine whether total testosterone and free testosterone levels predict disease reclassification in a cohort of men with prostate cancer (PCa) on active surveillance (AS). Patients and Methods Total testosterone and free testosterone concentrations were determined at the time the men began the AS protocol. Statistical analysis was performed using Student's t-test and a chi-squared test to compare groups. Odds ratios (ORs) with 95% confidence intervals (CIs) were obtained using univariate logistic regression. Receiver–operator characteristic curves were generated to determine the investigated testosterone thresholds. Kaplan–Meier curves were used to estimate time to disease reclassification. A Cox proportional hazard regression model was used for multivariate analysis. Results A total of 154 men were included in the AS cohort, of whom 54 (35%) progressed to active treatment. Men who had disease reclassification had significantly lower free testosterone levels than those who were not reclassified (0.75 vs 1.02 ng/dL, P = 0.03). Men with free testosterone levels

Objective: We evaluated the differences in pathologic findings and outcomes in patients undergoing radical retropubic prostatectomy (RRP) for localized prostate cancer diagnosed by either extended or non-extended prostate needle biopsy techniques. Patients and Methods: Two hundred and seventy eight men with the diagnosis of localized prostate cancer using needle biopsies who underwent RRP were evaluated. Two study groups were identified: the first consisted of 123 patients diagnosed with prostate cancer by the use of extended needle biopsies (10 or more biopsy cores), and the second group consisted of 155 patients diagnosed with cancer by non-extended needle biopsies (9 or less biopsy cores). Median time of follow-up was 45 and 50 months, respectively. Biopsy and RRP specimen characteristics and outcome were compared between the two groups. Results: Patients in the extended biopsy group had a median of 12 biopsy cores Interquartile range (IQR, 10–13; range, 10–16) with a mean of 2.7 cores positive for can...

Purpose: We examined the concordance of Gleason scores in prostate needle biopsy specimens and the corresponding radical retropubic prostatectomy specimens in a cohort of patients grouped according to the number of cores obtained during diagnostic needle biopsy.Materials and Methods: We reviewed clinical and pathological data on a cohort of 466 men diagnosed with localized prostate cancer by needle biopsies who underwent radical retropubic prostatectomy between January 1, 1990 and July 31, 2001. Two study groups were identified, including 126 patients diagnosed with prostate cancer by extended needle biopsies (10 or more cores) and 340 diagnosed with cancer by nonextended needle biopsies (9 or fewer cores). Mean age was 60 years and median prostate specific antigen was 5.8 ng./ml. The median number of cores in the extended and nonextended biopsy groups was 12 and 6, respectively. The concordance of Gleason score in the needle biopsy and prostatectomy specimens was compared and correlated with the number o...

Purpose: We investigated the relationship between prostate volume and cancer detection by needle biopsy, and determined the effect of an increased number of cores on the sampling error of needle biopsy on large prostate glands.Materials and Methods: The study cohort included 750 consecutive patients who underwent first time transrectal ultrasound guided prostate needle biopsy from January 1995 to August 2001. Prostate volumes were divided into quartiles (13 to 34, 34.1 to 45, 45.1 to 64 and 64.1 to 244 cc). Multivariate analysis controlling for age, prostate specific antigen (PSA) and biopsy indication was performed to determine the effect of the number of cores and prostate volume on prostate cancer detection.Results: Patients diagnosed with prostate cancer were older (p = 0.0035) and had higher PSA levels (p = 0.0002) than those with no cancer on biopsy. Decreasing cancer detection rates were seen with increasing prostate volume (p = 0.0074). The OR of detection for each additional core was 0.99...

To study the association between the polymorphisms Arg462Gln and Asp541Glu from the RNASEL gene (1q25), and the polymorphisms rs620861, rs1447295, rs6983267, rs7837328 from the chromosome 8q24 with the risk of presenting prostate cancer (PCa) and its clinical characteristics in a Hispanic (Chilean) population. The study was performed on 21 control patients and 83 patients diagnosed with PCa. Polymorphisms were analysed from blood samples through real-time PCR by using TaqMan probes, and the genetic analysis was performed with the SNPStats program. Also, a comparison was performed between clinical characteristics of PCa and the presence of the different polymorphism genotypes by using the Minitab software. There was a significant association between the genotype G/G from the polymorphism rs6983267 with an overall increased risk of PCa, in patients both with or without family history of PCa (OR = 4.47, 95% CI = 1.05–18.94, P = 0.034 and OR = 3.57, 95% CI = 0.96–13.35, P = 0.037, respectively). Regarding clinical parameters, patients carrying the genotype C/C from the polymorphism Asp541Glu had significantly higher prostate-specific antigen (PSA) levels than patients carrying the other genotypes (P = 0.034). Moreover, patients with the genotype G/G of rs6983267 had higher PSA levels (P = 0.024). The polymorphism rs6983267 from region 3 of the chromosome 8q24 appears to be a prominent risk factor for PCa and a biomarker for cancer aggressiveness in the group of patients who presented higher levels of PSA at the time of diagnosis.

This report presents our experience with T therapy in a cohort of T-deficient men on active surveillance (AS) for Gleason 3 + 3 and Gleason 3 + 4 prostate cancer (PCa). A retrospective chart review identified 28 men with T deficiency who underwent T therapy (T group) for at least 6 months while on AS for PCa. A comparison group of 96 men on AS for PCa with untreated T deficiency (no-T group) was identified at the same institution. The AS protocol followed a modified Epstein criteria and allowed inclusion of men with a single core of low-volume Gleason 3 + 4 PCa. Mean age was 59.5 and 61.3 years, and mean follow-up was 38.9 and 42.4 months for the T and no-T groups, respectively. Of all 28 men in the T group, 3 (10.7%) men developed an increase in Gleason score while on AS. Of 22 men in the T group with Gleason 3 + 3 disease, 7 (31.8%) men developed biopsy progression including 3 men (13.6%) who developed Gleason 3 + 4 PCa. Of 6 men with Gleason 3 + 4 disease at baseline, 2 (33.3%) men developed an increase in tumor volume, and none developed upgrading beyond Gleason 3 + 4. All 96 men in the no-T group had Gleason 3 + 3 disease at baseline and, 43 (44.7%) developed biopsy progression, including 9 men (9.38%) with upgrading to Gleason 7 (3 + 4). Biopsy progression rates were similar for both groups and historical controls. Biopsy progression in men on AS appears unaffected by T therapy over 3 years. Prospective placebo-controlled trials of T therapy in T-deficient men on AS should be considered given the symptomatic benefits experienced by treated men.

We determined the relationship between age adjusted free T, and stage, grade and the biochemical-free survival rate in patients with surgically treated prostate cancer.A retrospective cohort study was done between 1995 and 2001 in 333 patients treated for clinically localized prostate cancer with radical retropubic prostatectomy by a single surgeon at our institution. The study cohort consisted of 279 patients (84%) who had free T levels available. Free T was assessed by single cutoff value of 1.5 ng/dl or less, as suggested by the assay manufacturer, or by age adjusted free T. The relationship of low free T as a single cutoff value and age adjusted reference ranges with clinical and pathological measures of disease progression were assessed using the Fisher exact and Wilcoxon rank sum tests with the outcome assessed by the log rank test.Using the assay manufacturer suggested single cutoff value of 1.5 ng/dl or less to define low free T 57% of patients with prostate cancer in the cohort were categorized as hypogonadal. However, using age adjusted free T reference ranges only 2.5% of patients with prostate cancer were categorized as hypogonadal, which is more logical and representative of clinically significant hypogonadism in the general population. Poorly differentiated prostate cancer was associated with low free T when measured by a single cutoff value of 1.5 ng/dl or less, or by age adjusted free T (p = 0.017 and 0.04, respectively).Low age adjusted free T as well as single cutoff free T correlates with poorly differentiated prostate cancer in surgically treated patients.

We examined the prognostic significance of clinical and pathological variables on outcome following radical retropubic prostatectomy (RRP) in a cohort of patients in the post-prostate specific antigen (PSA) era.We reviewed the clinical and pathological data on a cohort of 476 patients who underwent RRP for localized prostate cancer between January 1990 and July 2001 by 1 urologist (WCD). Median age, preoperative PSA and followup were 61 years, 5.8 ng/ml and 49 months, respectively. We used Cox proportional hazard modeling to evaluate the prognostic significance of clinical and pathological variables for cancer recurrence, defined as 2 successive PSA determinations 0.3 ng/ml or greater.Of the 476 patients 53 (11%) had recurrence. Estimated cancer nonprogression probability was 86% (95% CI 83 to 90) and 76% (95% CI 68 to 86) at 5 and 10 years, respectively. Two multivariate analyses were performed. The first analysis, using only preoperative indicators, found that the percent of biopsy cores positive for cancer and biopsy Gleason score were the best predictive indicators of recurrence. The second multivariate analysis, using preoperative and postoperative indicators, found that the percent of biopsy cores positive for cancer, RRP Gleason score and the combined pathological stage/margin status variable were the best predictive indicators of recurrence. PSA was not found to be an important predictor of recurrence on either multivariate analysis. Patients with a percent of biopsy cores in the upper half of the distribution (greater than 28% positive) were at significantly increased risk for recurrence compared with those in the lower half of the distribution (28% or less positive) (HR 3.86, p0.001).The percent of cores positive for cancer was a better predictor of cancer recurrence than PSA in this post-PSA era RRP series. In addition, surgical Gleason score and pathological stage/surgical margins were also independent predictors of cancer recurrence after RRP. These 3 predictors are displayed in a nomogram-type format to summarize estimated 5 and 10-year recurrence-free probabilities.

Introduction: Although several pieces of data indicate a critical role of the carcinoma associated stroma (CAS) in the progression of prostate cancer (CaP), little is known about the specific mechanisms by which CAS contributes to the evolution of the castration-recurrent phenotype in locally advanced/metastatic CaP patients. The main challenge in this area has been the ability to obtain primary cultures of human prostate stroma cells (HPSCs) from locally advanced or metastatic CaP, because therapeutic surgery is not a feasible option for these patients. The aim of this study was to standardize a methodology to obtain primary cultures of HPSCs from from needle biopsies of the primary tumor of advanced CaP and to investigate whether HPSCs from different histological/pathological origins have distinct transcriptional programs. Material and Methods: Primary cultures of HPSCs were obtained from explants of needle biopsies from the peripheral zone of primary tumor of advanced/metastatic CaP patients (T3/T4) or from peripheral zone from patients without evidence of neoplasia (BAS). HPSCs were characterized using gene expression profile (Illumina), qPCR, immunocytochemistry and western blot. The phenotypic alterations were analyzed using the stroma cell markers calponin, vimentin, pro-collagen and α-smooth muscle actin. Migration and invasion assays using co-cultures of stroma-epithelium were utilize to evaluate the functional role of CAS. Results: Analysis of primary cultures of HPSCs from benign and locally advanced and/or metastatic CaP tissue explants revealed that CAS are a heterogeneous population of cells, typified by the increment of myofibroblasts/fibroblasts ratio and collagen production. The proliferation rate and doubling time was significantly higher in CAS compared to BAS. Analysis of gene expression profile revealed that CAS exhibited a unique transcriptional program, up-regulating genes involved in cell proliferation migration and cell adhesion. Furthermore, migration and invasion assays using co-cultures of stroma-epithelium demonstrated that HPSCs from CAS, but not BAS, contributed to the invasive potential of CaP cell lines. Discussion: Our studies demonstrated that CAS from the primary tumor of advanced/metastatic CaP patients was intrinsically different from the stroma associated to non-invasive CaP. Accordingly, primary cultures of HPSCs from primary tumors of metastatic patients provide an invaluable tool for modeling the effect of perturbation of the prostate tissue microenvironment during the progression of CaP. Citation Format: Javier Cerda-Infante, Paola F. Conejeros, Romina A. Coronado, Ignacio F. San Francisco, Gary J. Smith, Alejandro S. Godoy, Viviana P. Montecinos. Stromal primary cultures from advanced human prostate cancer obtained from needle biopsies revealed distinctive gene expression pattern and functionality. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 189. doi:10.1158/1538-7445.AM2014-189