Increased heparanase expression is caused by promoter hypomethylation and up-regulation of transcriptional factor early growth response-1 in human prostate cancer.

PURPOSE: Heparanase degrades heparan sulfate and has been implicated in tumor invasion and metastasis. The transcription factor, early growth response 1 (EGR1), is associated with the inducible transcription of the heparanase gene. We hypothesize that CpG hypomethylation in the heparanase promoter coupled with up-regulation of EGR1 levels may induce heparanase expression in human prostate cancer. EXPERIMENTAL DESIGN: Cultured prostate cancer cell lines (Du145, DuPro, LNCaP, and PC-3) with and without 5'-aza-2-deoxycytidine treatment, 177 prostate cancer samples, and 69 benign prostatic hyperplasia (BPH) samples were used. The frequency and level of heparanase promoter methylation were analyzed by methylation-specific primers which covered the core binding motif of EGR1 (GGCG) or SP1 (GGGCGG) or both. RESULTS: In cultured Du145, DuPro, LNCaP, and PC-3 cell lines, mRNA transcripts of heparanase were significantly increased after 5'-aza-2-deoxycytidine treatment, suggesting that promoter methylation was involved in the regulation of heparanase mRNA transcript. Significantly higher methylation was found in BPH samples than in prostate cancer samples (P < 0.0001), whereas mRNA transcripts of the heparanase gene were inversely lower in BPH samples than in prostate cancer samples (P < 0.01). EGR1 expression in prostate cancer tissues was significantly higher than in BPH tissues (P < 0.001) and correlated with heparanase expression (P < 0.0001). Moreover, multiple regression analysis revealed that up-regulation of EGR1 contributed significantly more to heparanase expression than did promoter CpG hypomethylation in prostate cancer samples (P < 0.0001). CONCLUSIONS: To our knowledge this is the first comprehensive study demonstrating that increased heparanase expression in prostate cancer tissues is due to promoter hypomethylation and up-regulation of transcription factor EGR1.

CpG hypermethylation of MDR1 gene contributes to the pathogenesis and progression of human prostate cancer.

Multidrug resistance 1 (MDR1) gene encodes for P-glycoprotein (P-gp), a Mr 170,000 transmembrane calcium-dependent efflux pump that is inactivated in prostate cancer. We hypothesize that inactivation of the MDR1 gene through CpG methylation contributes to the pathogenesis and progression of prostate cancer. To test this hypothesis, CpG methylation status of the MDR1 promoter and its correlation with clinicopathological findings were evaluated in 177 prostate cancer samples and 69 benign prostate hypertrophy (BPH) samples. Cellular proliferation index and apoptotic index were determined by proliferating cell nuclear antigen (PCNA) and single-strand DNA immunostaining, respectively. After 5-aza-2'-deoxycytidine treatment, increased expression of MDR1 mRNA transcript was found in prostate cancer cell lines (DU145, DuPro, and ND1). MDR1 methylation frequency was significantly higher in prostate cancer samples compared with BPH samples (54.8 versus 11.6%, respectively, P < 0.001). Logistic regression analysis revealed that PC patients are 11.5 times more likely to have MDR1 methylation than BPH patients (95% confidence interval 4.87-27.0) and that MDR1 methylation is independent of the age. Significant correlation of MDR1 methylation was observed with high pT category (P < 0.001), high Gleason sum (P = 0.008), high preoperative prostate-specific antigen (P = 0.01), and advancing pathological features. In addition, PCNA-labeling index were significantly higher in methylation-specific PCR (MSP)-positive than in MSP-negative prostate cancer samples (P = 0.048). In contrast, no significant difference in apoptotic index was found between MSP-positive and -negative prostate cancer samples. These findings suggest that CpG hypermethylation of MDR1 promoter is a frequent event in prostate cancer and is related to disease progression via increased cell proliferation in prostate cancer cells.

Chronic periglandular inflammation on prostate needle biopsy does not increase the likelihood of cancer on subsequent biopsy.

PURPOSE: Recent literature suggests a role for chronic inflammation in the development of prostate cancer. We investigated the association of chronic periglandular inflammation on prostate needle biopsy with subsequent prostate cancer development and clinical disease features at presentation. METHODS: Six hundred fifty-five patients were abstracted from a prostate/needle biopsy registry from Brigham and Women's Hospital presenting with prostate-specific antigen (PSA) > 4 ng/mL or abnormal digital rectal examination (DRE) between the years 1990 and 2004. DRE, PSA, PSA density, prostate volume, histology, and age were analyzed to identify clinical and pathologic associations with inflammation. Chronic inflammation was defined as an inflammatory cell infiltrate composed predominately of lymphocytes in a periglandular distribution. A subset of patients (n = 308) with follow-up biopsy results were used to identify if prostate inflammation predicted development of prostate cancer. RESULTS: Modeling performed based on 4 biopsy samples revealed prostate volume (P < .001) and DRE (P = .02) as significant predictors of inflammation; DRE lost significance in models accounting for volume. Kaplan-Meier analysis demonstrated inflammation does not predict subsequent prostate cancer (P = .2). Cox models with the same endpoint show inflammation at initial biopsy (P = .3), inflammation at last biopsy (P = .4), and inflammation on any previous biopsy (P = .08) are not associated with time-to-positive biopsy. CONCLUSIONS: Although inflammation on initial and subsequent biopsy does not predict prostate cancer in this cohort, we cannot dismiss its role in prostate cancer pathogenesis. Additional research is necessary to explore the relationship between prostate inflammation and prostate cancer development.

Obesity and prostate cancer clinical risk factors at presentation: data from CaPSURE.

PURPOSE: We investigated the association of obesity with prostate cancer case demographics and clinical disease features at presentation. MATERIALS AND METHODS: Data were abstracted from CaPSURE (Cancer of the Prostate Strategic Urologic Research Endeavor), a disease registry of 10,018 men with prostate cancer. A total of 2,952 men were included who were treated between 1989 and 2002, and had complete body mass index (BMI) information. BMI classes were defined as normal (less than 25 kg/m), overweight (25 to 29.9 kg/m), obese (30 to 34.9 kg/m) or very obese (35 kg/m or greater). Patients were categorized as having low, intermediate or high risk disease based on the D'Amico classification. Associations among BMI, risk and demographics were analyzed using univariate and multivariate models. RESULTS: Of the patients 29% had a normal BMI, 51% were overweight, 16% were obese and 5% were very obese. Patients who were overweight or obese were more likely to be young, have hypertension and diabetes, and have a lower education level. The overweight group had a lower serum prostate specific antigen (p = 0.010) and lower stage disease (p = 0.030) at diagnosis, but there was no association between Gleason score and obesity (p = 0.57). However, among men with a BMI of 25 kg/m or greater there was a positive correlation between increasing BMI and risk of being in a worse prognostic group at diagnosis (p = 0.018). CONCLUSIONS: Overweight and obese patients are more likely to be young at diagnosis and have multiple comorbidities. Men in the overweight and obese groups presented with lower risk prostate cancer at diagnosis. This may be due to earlier disease detection secondary to more frequent interaction with the medical community. Among overweight and obese patients increased obesity is associated with a slightly increased chance of having high risk prostate cancer at diagnosis.

Impact of obesity on prostate cancer recurrence after radical prostatectomy: data from CaPSURE.

OBJECTIVES: To determine the association between obesity and prostate cancer recurrence after primary treatment with radical prostatectomy. METHODS: Data were abstracted from CaPSURE, a disease registry of 10,018 men with prostate cancer. We included 2131 men who had undergone radical prostatectomy between 1989 and 2003 and had body mass index (BMI) information available. Recurrence was defined as two consecutive prostate-specific antigen (PSA) levels of 0.2 ng/mL or greater or any second treatment. Patients were risk stratified using the PSA level, Gleason grade, and clinical T stage. RESULTS: Patients were followed up for a median of 23 months. Of the 2131 patients, 251 (12%) developed recurrence at a median of 13 months (range 1 to 107); 183 (9%) of these men had PSA failure and 68 (3%) received a second treatment. After adjusting for risk group, ethnicity, age, and comorbidities, a significant association was found between an increasing BMI and disease recurrence (P = 0.028). Very obese patients (BMI 35 kg/m2 or more) were 1.69 times more likely to have recurrence relative to men of normal weight (BMI less than 25.0 kg/m2; 95% confidence interval [CI] 1.01 to 2.84). An increasing PSA level (P <0.0001) and Gleason grade (P <0.0001) were also associated with recurrence. Ethnicity was not significantly associated with either BMI or PSA recurrence (P = 0.685 and P = 0.068, respectively). CONCLUSIONS: The results of our study have shown that obesity is an independent predictor of prostate cancer recurrence. Because of the increased comorbidities and greater rates of recurrence, obese individuals undergoing radical prostatectomy need vigilant follow-up care.

The impact of obesity on health related quality of life before and after radical prostatectomy (data from CaPSURE).

PURPOSE: Health related quality of life (HRQOL) is an important measure of outcomes among patients with prostate cancer due to disease related and treatment related effects on physical and emotional health. We determined if there are differences in the HRQOL of obese men at diagnosis and after radical prostatectomy compared to the HRQOL of men with normal body mass index (BMI). MATERIALS AND METHODS: Data were abstracted from Cancer of the Prostate Strategic Urological Research Endeavor (CaPSURE), a disease registry of 10,018 men with prostate cancer. A total of 1,884 men were included in study who were treated with radical prostatectomy between 1989 and 2002, had BMI information available and had completed 1 initial HRQOL questionnaire. Of these men 672 who completed at least 2 followup questionnaires were assessed further. RESULTS: The BMI (kg/m) distributions were 24% normal (less than 24.9 kg/m), 56% overweight (25 to 29.9), 16% obese (30 to 34.9) and 4% very obese (greater than 35 kg/m). Higher BMI was associated with worse physical function, bodily pain, general health, vitality and role physical, but better bowel bother at diagnosis independent of race. Higher BMI was also associated with worse HRQOL after radical prostatectomy for physical function, general health and vitality, but better bowel bother. HRQOL differences between BMI groups were similar among times for all measured variables. Compared to the normal group, the higher BMI groups had similar HRQOL after radical prostatectomy. CONCLUSIONS: In the majority of domains men with higher BMI had lower HRQOL at diagnosis than men of normal BMI. Obese men have a similar recovery pattern of HRQOL after radical prostatectomy, with minimal additive long-term impairment in HRQOL relative to men of normal weight.

Differences in complications and outcomes for obese patients undergoing laparoscopic radical, partial or simple nephrectomy.

PURPOSE: Obesity has increased dramatically in American society during the last 2 decades. While the laparoscopic approach is common for patients requiring radical and partial nephrectomy, it is unclear if this procedure leads to worse outcomes and complications in obese patients. We determined if obese patients undergoing laparoscopic radical (RN), partial (PN) and simple (SN) nephrectomy are at risk for worse surgical outcomes or increased complications. MATERIALS AND METHODS: We retrospectively identified patients treated with nontransplant transperitoneal laparoscopic nephrectomies from 1998 to 2003. Patients with missing body mass index (BMI), operative, postoperative or pathological information were excluded from study. Obese patients (BMI 30 or greater) were compared to nonobese patients (BMI less than 30). RESULTS: A total of 189 patients undergoing 117 RN, 44 PN and 30 SNs met study criteria, and 29.0% of patients were obese. Overall obese patients had longer operative times (280 versus 241 minutes, p = 0.003), greater estimated surgical blood loss (230 versus 109 ml, p = 0.0001) and higher transfusion rates (6.8% versus 0.8%, p = 0.032) than nonobese patients. In subgroup analyses obese patients receiving RN and PN had longer operative times and increased blood loss. Obese and nonobese patients have similar open conversion rates, analgesic requirements, hospital stay, time to oral intake, and major and minor complication rates regardless of nephrectomy type. CONCLUSIONS: Laparoscopic nephrectomy is associated with slightly greater operative time, estimated blood loss and transfusion rates in obese patients. Laparoscopic RN, PN and SN are safe and well tolerated in obese patients. Obesity is not a contraindication to laparoscopic renal surgery.