Background Chronic inflammation is hypothesized to influence prostate cancer development, although a definitive link has not been established. Methods Prostate cancer cases (N=191) detected on a for-cause (clinically indicated) or end-of-study (protocol directed) biopsy, and frequency-matched controls (N=209), defined as negative for cancer on an end-of-study biopsy, were sampled from the placebo arm of the Prostate Cancer Prevention Trial. Inflammation prevalence and extent in benign areas of biopsy cores were visually assessed using digital images of H&E stained sections. Logistic regression was used to estimate associations. Results 86.2% of cases and 78.2% of controls had at least one biopsy core (of 3 assessed) with inflammation in benign areas, most of which was chronic. Men who had at least one biopsy core with inflammation had 1.78 (95% CI 1.04–3.06) times the odds of prostate cancer compared with men who had zero cores with inflammation. The association was stronger for high-grade disease (Gleason sum 7–10, N=94; odds ratio [OR]=2.24, 95% CI 1.06–4.71). These patterns were present when restricting to cases and controls in whom intraprostatic inflammation was the least likely to have influenced biopsy recommendation because their PSA was low (<2 ng/mL at biopsy). Conclusion Inflammation, most of which was chronic, was common in benign prostate tissue, and was positively associated with prostate cancer, especially high-grade. The association did not appear to be due to detection bias. Impact This study supports an etiologic link between inflammation and prostate carcinogenesis, and suggests an avenue for prevention by mitigating intraprostatic inflammation.

Current prognostic indicators are imperfect predictors of outcome in men with clinicallylocalized prostate cancer. Thus, tissue-based markers are urgently needed to improve treatment and surveillance decision-making. Given that shortened telomeres enhance chromosomal instability and such instability is a hallmark of metastatic lesions, we hypothesized that alterations in telomere length in the primary cancer would predict risk of progression to metastasis and prostate cancer death. To test this hypothesis, we conducted a prospective cohort study of 596 surgically treated men who participated in the ongoing Health Professionals Follow-up Study. Men who had the combination of more variable telomere length among prostate cancer cells (cell-to-cell) and shorter telomere length in prostate cancer-associated stromal cells were substantially more likely to progress to metastasis or die of their prostate cancer. These findings point to the translational potential of this telomere biomarker for prognostication and risk stratification for individualized therapeutic and surveillance strategies.

PTEN (phosphatase and tensin homolog on chromosome 10) is one of the most frequently lost tumor suppressor genes in human cancers and it has been described in more than two-thirds of patients with advanced/aggressive prostate cancer. Previous studies suggest that, in prostate cancer, genomic PTEN loss is associated with tumor progression and poor prognosis. Thus, we evaluated whether immunohistochemical PTEN expression in prostate cancer glands was associated with higher risk of recurrence, using a nested case–control study that included 451 men who recurred and 451 men who did not recur with clinically localized prostate cancer treated by radical prostatectomy. Recurrence was defined as biochemical recurrence (serum prostate-specific antigen >0.2 ng/ml) or clinical recurrence (local recurrence, systemic metastases, or prostate cancer-related death). Cases and controls were matched on pathological T stage, Gleason score, race/ethnicity, and age at surgery. Odds ratios of recurrence and 95% confidence intervals were estimated using conditional logistic regression to account for the matching factors and to adjust for year of surgery, preoperative prostate-specific antigen concentrations, and status of surgical margins. Men who recurred had a higher proportion of PTEN negative expression (16 vs 11%, P = 0.05) and PTEN loss (40 vs 31%, P = 0.02) than controls. Men with markedly decreased PTEN staining had a higher risk of recurrence (odds ratio = 1.67; 95% confidence intervals 1.09, 2.57; P = 0.02) when compared with all other men. In summary, in patients with clinically localized prostate cancer treated by prostatectomy, decreased PTEN expression was associated with an increased risk of recurrence, independent of known clinicopathological factors.

When distinguishing between indolent and potentially harmful prostate cancers, the Gleason score is the most important variable, but may be inaccurate in biopsies due to tumor under-sampling. This study investigated whether a molecular feature, PTEN protein loss, could help identify which Gleason score 6 tumors on needle biopsy are likely to be upgraded at radical prostatectomy. 71 patients with Gleason score 6 tumors on biopsy upgraded to Gleason score 7 or higher cancer at prostatectomy (cases) were compared to 103 patients with Gleason score 6 on both biopsy and prostatectomy (controls). A validated immunohistochemical assay for PTEN was performed, followed by fluorescence in situ hybridization (FISH) to detect PTEN gene deletion in a subset. PTEN protein loss and clinical-pathologic variables were assessed by logistic regression. Upgraded patients were older than controls (61.8 vs. 59.3 years), had higher pre-operative PSA levels (6.5 vs. 5.3 ng/mL), and a higher fraction of involved cores (0.42 vs. 0.36). PTEN loss by immunohistochemistry was found in 18% (13/71) of upgraded cases compared to 7% (7/103) of controls (p=0.02). Comparison between PTEN immunohistochemistry and PTEN FISH showed the assays were highly concordant, with 97% (65/67) of evaluated biopsies with intact PTEN protein lacking PTEN gene deletion, and 81% (13/16) of the biopsies with PTEN protein loss showing homozygous PTEN gene deletion. Tumors with PTEN protein loss were more likely to be upgraded at radical prostatectomy than those without loss, even after adjusting for age, preoperative PSA, clinical stage and race (odds ratio = 3.04 [1.08–8.55; p=0.035]). PTEN loss in Gleason score 6 biopsies identifies a subset of prostate tumors at increased risk of upgrading at radical prostatectomy. These data provide evidence that a genetic event can improve Gleason score accuracy and highlight a path towards the clinical use of molecular markers to augment pathologic grading.

Prostate cancer is the second leading cause of cancer death among United States men. However, disease aggressiveness is varied, with low-grade disease often being indolent and high-grade cancer accounting for the greatest density of deaths. Outcomes are also disparate among men with high-grade prostate cancer, with upwards of 65% having disease recurrence even after primary treatment. Identification of men at risk for recurrence and elucidation of the molecular processes that drive their disease is paramount, as these men are the most likely to benefit from multimodal therapy. We previously showed that androgen-induced expression profiles in prostate development are reactivated in aggressive prostate cancers. Herein, we report the down-regulation of one such gene, Sparcl1, a secreted protein, acidic and rich in cysteine (SPARC) family matricellular protein, during invasive phases of prostate development and regeneration. We further demonstrate a parallel process in prostate cancer, with decreased expression of SPARCL1 in high-grade/metastatic prostate cancer. Mechanistically, we demonstrate that SPARCL1 loss increases the migratory and invasive properties of prostate cancer cells through Ras homolog gene family, member C (RHOC), a known mediator of metastatic progression. By using models incorporating clinicopathologic parameters to predict prostate cancer recurrence after treatment, we show that SPARCL1 loss is a significant, independent prognostic marker of disease progression. Thus, SPARCL1 is a potent regulator of cell migration/invasion and its loss is independently associated with prostate cancer recurrence.Hevin | synaptic cleft 1 | urogenital sinus | extracellular matrix P rostate cancer is the most common noncutaneous malignancy and the second leading cause of cancer death in United States men. Controversy currently exists over the best treatment strategy for men with high-risk disease (clinical stage ≥T2c, Gleason score 8-10 or prostate-specific antigen > 20 ng/mL) because 56-65% of these men recur after definitive local therapy (1-5). This finding highlights the need for a better understanding of the biologic determinants driving disease progression for both prognostic and therapeutic development.We and others have recently illustrated that pathways essential for prostate organogenesis are reactivated in prostate cancer (6, 7). During organogenesis, androgens induce epithelialmesenchymal interactions in the urogenital sinus (UGS) and drive its differentiation into a prostate (8). We examined early prostate organogenesis shortly after initial androgen exposure, when urogenital sinus epithelia (UGE) migrate and invade into the surrounding mesenchyme and determined that the genes defining this developmental stage were similarly regulated in the transition between low-and high-grade prostate cancers (6). Among these genes, SPARCL1 (SPARC-like 1/Hevin/SC1), a member of the secreted protein, acidic and rich in cysteine (SPARC) family of matricellular proteins, was down-regulated specifically during embryoni...

Glycosylation is recognized as one of the most common modifications on proteins. Recent studies have shown that aberrant expression of α (1,6) fucosyltransferase (FUT8), which catalyzes the transfer of fucose from GDP-fucose to core-GlcNAc of the N-linked glycoproteins, modulates cellular behavior that could lead to the development of aggressive prostate cancer. While the relationship between the abnormal expression of FUT8 and glycoprotein fucosylation in different prostate cancer cells has been demonstrated, there is no evidence that shows dysregulated fucosylation might be involved in prostate cancer progression from androgen-dependent to castration-resistant prostate cancer. In this study, using a proteomics approach, we analyzed androgen-dependent and androgen-resistant LAPC4 cells and identified FUT8 to be significantly overexpressed in the androgen-resistant LAPC4 cells. These findings were independently confirmed in LAPC4 cells that were treated with non-steroidal anti-androgen (bicalutamide) and in the in vivo castrated tumor xenograft models. Similarly, we also demonstrated that overexpression of FUT8 might be responsible for the decreased PSA expression in prostate cancer specimens. To our knowledge, this is the first study reporting the functional role of fucosylated enzyme in the development of castration-resistant prostate cancer.

Purpose To support trials testing lifestyle interventions for lower urinary tract symptoms (LUTS), often a consequence of benign prostatic hyperplasia (BPH), we estimated LUTS incidence and progression rates in US men unselected for BPH. Methods We studied men in the Health Professionals Follow-up Study who we asked to report periodically by mailed survey whether they had had surgery or used medications for LUTS and to complete the International Prostate Symptom Score (IPSS) survey. For incidence, we included 25,879 men with an IPSS of 0–7 and no surgery history, who were followed 1992–2008. Incident “moderate or worse” LUTS (N=6,058) was defined as IPSS of ≥15, surgery, or medication use. “Modest or worse” LUTS was similarly defined but with IPSS≥8 (N=11,352). For progression, we included 9,628 men with an IPSS of 8–14 and no surgery, who were followed from when they first reported an IPSS of 8–14 to 2008. Progression to “severe” LUTS (N=2,557) was defined as IPSS of ≥20, surgery, or medication use. We estimated age-specific and age-standardized rates. Results Incidence and progression rates increased with age (P-trend<0.0001); progression rates were higher than incidence rates. The age-standardized rates were: incidence of moderate to worse LUTS 18.5; incidence of modest to worse LUTS 40.5; and progression to severe LUTS 44.9 per 1,000 man-years. Conclusions LUTS incidence and progression rates are high and rise steeply as men age. These rates may be used for planning adequately powered trials to test lifestyle interventions for LUTS well before surgical or pharmacologic treatment is indicated.

BACKGROUND MicroRNAs (miRNAs) are small non-coding RNAs that regulate a broad array of cellular and disease processes. Several miRNAs are differentially expressed in cancer and many are being considered as biomarkers for predicting clinical outcomes. Here we quantified the expression of three miRNAs, miR-21, miR-141, and miR-221, from prostate cancer surgical specimens and evaluated their association with disease recurrence after primary therapy. METHODS A pilot nested case-control study was designed from a large cohort of men who underwent radical prostatectomy between 1993 and 2001. Total RNA was extracted from malignant prostate tissue of 59 cases (recurrence) and 59 controls. Cases and controls were matched on age, race, pathologic stage and grade. The relative expression of each miRNA was then determined for each sample by quantitative real-time RT-PCR. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) of recurrence for tertiles of miRNA expression. We noted block storage time effects and thus, used separate tertile cutpoints based on the controls by calendar year of prostatectomy. RESULTS Lower miR-221 expression was associated with a higher risk of recurrence; the ORs were 3.21 for the lowest tertile and 2.63 for the middle tertile compared with the highest tertile of expression (P-trend=0.02). This pattern was unchanged after multivariable adjustment (P-trend=0.05). No statistically significant trends were observed for miR-21 or miR-141 after multivariable adjustment. CONCLUSIONS Based on this small pilot study, men with localized prostate cancers with lower miR-221 expression may have a greater risk for recurrence after surgery.