Tony T. Wu

LNCaP progression model of human prostate cancer: Androgen‐independence and osseous metastasis

Clinically, the lethal phenotypes of human prostate cancer are characterized by their progression to androgen‐independence and their propensity to form osseous metastases. We reported previously on the establishment of androgen‐independent (AI) human prostate cancer cell lines derived from androgen‐dependent (AD) LNCaP cells, with androgen independence defined as the capability of prostate cancer cells to grow in castrated hosts. One of the sublines, C4‐2, was found to be AI, highly tumorigenic, and metastatic, having a proclivity for metastasis to the bone.

Establishing human prostate cancer cell xenografts in bone: Induction of osteoblastic reaction by prostate‐specific antigen‐producing tumors in athymic and SCID/bg mice using LNCaP and lineage‐derived metastatic sublines

LNCaP lineage‐derived human prostate cancer cell lines C4‐2 and C4‐2B4 acquire androgen independence and osseous metastatic potential in vivo. Using C4‐2 and C4‐2B4 the goals of the current investigation were 1) to establish an ideal bone xenograft model for prostate cancer cells in intact athymic or SCID/bg mice using an intraosseous route of tumor cell administration and 2) to compare prostate cancer metastasis by administering cells either through intravenous (i.v.) or intracardiac administration in athymic or SCID/bg mice. Subsequent to tumor cell administration, prostate cancer growth in the skeleton was assessed by radiographic bone density, serum prostate‐specific antigen (PSA) levels, presence of hematogenous prostate cancer cells and histopathologic evaluation of tumor specimens in the lymph node and skeleton. Our results show that whereas LNCaP cells injected intracardially failed to develop metastasis, C4‐2 cells injected similarly had the highest metastatic capability in SCID/bg mice. Retroperitoneal and mediastinal lymph node metastases were noted in 3/7 animals, whereas 2/7 animals developed osteoblastic spine metastases. Intracardiac injection of C4‐2 in athymic hosts produced spinal metastases in 1/5 animals at 8–12 weeks post‐injection; PC‐3 injected intracardially also metastasized to the bone but yielded osteolytic responses. Intravenous injection of either LNCaP or C4‐2 failed to establish tumor colonies. Intrailiac injection of C4‐2 but not LNCaP nor C4‐2B4 cells in athymic mice established rapidly growing tumors in 4/8 animals at 2–7 weeks after inoculation. Intrafemoral injection of C4‐2 (9/16) and C4‐2B4 (5/18) but not LNCaP (0/13) cells resulted in the development of osteoblastic bone lesions in athymic mice (mean: 6 weeks, range: 3–12 weeks). In SCID/bg mice, intrafemoral injection of LNCaP (6/8), C4‐2 (8/8) and C4‐2B4 (8/8) cells formed PSA‐producing, osteoblastic tumors in the bone marrow space within 3–5 weeks after tumor cell inoculation. A stepwise increase of serum PSA was detected in all animals. Reverse transcription‐polymerase chain reaction (RT‐PCR) to detect hematogenously disseminated prostate cancer cells could not be correlated to either serum PSA level or histological evidence of tumor cells in the marrow space. We have thus established a PSA‐producing and osteoblastic human prostate cancer xenograft model in mice. Int. J. Cancer 77:887–894, 1998.© 1998 Wiley‐Liss, Inc.

THE ROLE OF BCL-2, p53, AND KI-67 INDEX IN PREDICTING TUMOR RECURRENCE FOR LOW GRADE SUPERFICIAL TRANSITIONAL CELL BLADDER CARCINOMA

PURPOSE We assess the prognostic significance of bcl-2 expression, p53 mutation and ki-67 index for low grade, superficial transitional cell bladder carcinoma. MATERIALS AND METHODS The medical records of 93 cases of primary, low grade (24 G1, 69 G2), superficial (70 pTa, 23 pT1) transitional cell carcinoma of the bladder were reviewed. Association of bcl-2, p53 and ki-67 index immunoreactivity with tumor grade and stage was examined. Prognostic significance of tumor grade, pathological stage, bcl-2 expression, p53 mutation and ki-67 index in predicting tumor recurrence was assessed. RESULTS Of the tumors 60 (70%) had p53 mutation and 9 (10.5%) expressed bcl-2. These 2 markers did not relate to tumor grade or pathological stage. Median ki-67 index was 10.9% and positively correlated with tumor grade. Recurrence was noted in 34.9% of patients with a median followup of 26 months (range 1 to 84). The ki-67 index was the only significant prognostic indicator in univariate and multivariate analyses. This marker can further distinguish grade 2 tumors with a favorable prognosis from those with an unfavorable outcome. CONCLUSIONS The ki-67 labeling index is an independent predictor of tumor recurrence for patients with primary superficial, low grade bladder cancers.

Risk Factors for Individual Domains of Female Sexual Function

INTRODUCTION Female sexual function contains four major subtypes of desire, arousal, orgasm, and pain. Few studies used validated instruments to determine the dysfunction in these areas and assess their risk factors. AIM To assess the prevalence of and risk factors for individual components of sexual difficulty in women. METHODS A self-administered questionnaire containing the Female Sexual Function Index (FSFI) was given to 2,159 woman employees of two hospitals to assess their sexual function and its correlates. MAIN OUTCOME MEASURES The associations between female sexual difficulty in individual domains defined by the FSFI domain scores and potential risk factors assessed by simple questions. RESULTS Among the 1,580 respondents, 930 womens data were eligible for analysis with a mean age of 36.1 years (range 20-67). Of them, 43.8% had sexual difficulty in one or more domains, including low desire in 31.3%; low arousal, 18.2%; low lubrication, 4.8%; low orgasmic function, 10.4%; low satisfaction, 7.3%; and sexual pain, 10.5%. Compared with the younger women (20-49 years), the oldest age group (50-67 years) had a significantly higher prevalence in low desire, low arousal, and low lubrication, but not in the other domains. Based on multivariate logistic regression analyses, poor relationship with the partner and perception of partners sexual dysfunction were major risk factors for low desire, low arousal, low orgasmic function, and low satisfaction. Age and urge urinary incontinence were associated with low lubrication and sexual pain. Most comorbidities were not related to these difficulties, except diabetes being related to low desire. CONCLUSIONS Relationship factors had substantial impact on female sexual function in desire, arousal, orgasm, and satisfaction. On the other hand, womens lubrication problem and sexual pain were related predominantly with biological factors. These are initial results and future research is needed to confirm them.

Non-inferiority of silodosin to tamsulosin in treating patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH)

Study Type – Therapy (RCT)

Association of vitamin D receptor FokI polymorphism with prostate cancer risk, clinicopathological features and recurrence of prostate specific antigen after radical prostatectomy

To investigate the effect of vitamin D receptor (VDR) FokI polymorphism on susceptibility to prostate cancer and the outcome of the disease in a Taiwanese population, we genotyped a total of 416 prostate cancer patients, 502 age‐matched male controls and 189 non age‐matched symptomatic benign prostatic hyperplasia. Although we did not find a significant association between VDR FokI genotypes and overall prostate cancer risk, we found that in men aged less than or equal to the median age of 73 years with VDR FokI F allele specifically had an increased risk of prostate cancer with a marginal significant trend (OR, 2.08; 95% CI, 1.00–4.34, p for trend = 0.056). The FF genotype was also highly associated with more aggressive prostate cancer (Gleason score 8–10) (OR, 2.47; 95% CI, 1.20–5.08) than did the Ff and ff genotypes. After adjusting other covariates, we found that in patients who had localized prostate cancer for which a radical prostatectomy was performed (n = 131), the VDR FokI FF genotype was associated with worse prostate‐specific antigen (PSA) recurrence‐free survival (hazard ratio = 3.25, 95% CI = 1.32–8.00, p = 0.010). Our findings suggest that the VDR FF genotype may increase the risk of early‐onset prostate cancer and is associated with more aggressive disease. Furthermore, the VDR polymorphism could be used as a prognostic marker for localized prostate cancer after radical prostatectomy.

Haplotypes, Loss of Heterozygosity, and Expression Levels of Glycine N-Methyltransferase in Prostate Cancer

Purpose: Glycine N-methyltransferase (GNMT) affects genetic stability by regulating DNA methylation and interacting with environmental carcinogens. In a previous study, we showed that GNMT acts as a susceptibility gene for hepatocellular carcinoma. Here, we report on our efforts to characterize the haplotypes, loss of heterozygosity (LOH), and expression levels of the GNMT in prostate cancer. Experimental Design: Peripheral blood mononuclear cell DNA collected from 326 prostate cancer patients and 327 age-matched controls was used to determine GNMT haplotypes. Luciferase reporter constructs were used to compare the promoter activity of different GNMT haplotypes. GNMT LOH rates in tumorous specimens were investigated via a comparison with peripheral blood mononuclear cell genotypes. Immunohistochemical staining was used to analyze GNMT expression in tissue specimens collected from 5 normal individuals, 33 benign prostatic hyperplasia patients, and 45 prostate cancer patients. Results: Three major GNMT haplotypes were identified in 92% of the participants: A, 16GAs/DEL/C (58%); B, 10GAs/INS/C (19.9%); and C, 10GAs/INS/T (14.5%). Haplotype C carriers had significantly lower risk for prostate cancer compared with individuals with haplotype A (odds ratio, 0.68; 95% confidence interval, 0.48-0.95). Results from a phenotypic analysis showed that haplotype C exhibited the highest promoter activity (P < 0.05, ANOVA test). In addition, 36.4% (8 of 22) of the prostatic tumor tissues had LOH of the GNMT gene. Immunohistochemical staining results showed abundant GNMT expression in normal prostatic and benign prostatic hyperplasia tissues, whereas it was diminished in 82.2% (37 of 45) of the prostate cancer tissues. Conclusions: Our findings suggest that GNMT is a tumor susceptibility gene for prostate cancer.

Cadmium burden and the risk and phenotype of prostate cancer

BackgroundStudies on the association between prostate cancer and cadmium exposure have yielded conflicting results. This study explored cadmium burden on the risk and phenotype of prostate cancer in men with no evident environmental exposure.MethodsHospital-based 261 prostate cancer cases and 267 controls with benign diseases were recruited from four hospitals in Taiwan. Demographic, dietary and lifestyle data were collected by standardized questionnaires. Blood cadmium (BCd) and creatinine-adjusted urine cadmium (CAUCd) levels were measured for each participant. Statistical analyses measured the prostate cancer risk associated with BCd and CAUCd separately, controlling for age, smoking and institution. BCd and CAUCd levels within cases were compared in relation to the disease stage and the Gleason score.ResultsHigh family income, low beef intake, low dairy product consumption and positive family history were independently associated with the prostate carcinogenesis. There was no difference in BCd levels between cases and controls (median, 0.88 versus 0.87 μg/l, p = 0.45). Cases had lower CAUCd levels than controls (median, 0.94 versus 1.40 μg/g creatinine, p = 0.001). However, cases with higher BCd and CAUCd levels tended to be at more advanced stages and to have higher Gleason scores. The prostate cancer cases with Gleason scores of ≥ 8 had an odds ratio of 2.89 (95% confidence interval 1.25-6.70), compared with patients with scores of 2-6.ConclusionHigher CAUCd and BCd levels may be associated with advanced cancer phenotypes, but there was only a tenuous association between cadmium and prostate cancer.

Prognostic Significance of p53 and X-ray Repair Cross-complementing Group 1 Polymorphisms on Prostate-Specific Antigen Recurrence in Prostate Cancer Post–Radical Prostatectomy

Purpose: The tumor suppressor p53 and DNA repair gene X-ray repair cross-complementing group 1 (XRCC1) are thought to play important roles on prostate cancer susceptibility and tumor development. We investigated the potential prognostic roles of p53 (codon 72) and XRCC1 (codons 194, 280, and 399) polymorphisms in clinical localized prostate cancer after radical prostatectomy. Experimental Design: A total of 126 clinical localized prostate cancer patients undergoing curative radical prostatectomy at the Kaohsiung Medical University Hospital and Kaohsiung Veterans General Hospital were included in this study. The p53 codon 72 and XRCC1 codons 194, 280 and 399 polymorphisms were determined by the PCR-RFLP method. Their prognostic significance on prostate-specific antigen (PSA) recurrence were assessed using the Kaplan-Meier analysis and Cox regression model. Results: The p53 codon 72 Arg/Arg genotype was associated with increased PSA recurrence risk compared with the Arg/Pro and Pro/Pro genotypes, although the difference did not reach significance (30.3% versus 20.4%, P = 0.247). Of these three XRCC1 polymorphisms, the codon 399 Arg/Gln + Gln/Gn genotypes were significantly associated with higher risk of PSA recurrence after radical prostatectomy compared with the Arg/Arg genotype (34.0% versus 15.1%, P = 0.013) and poorer PSA-free survival (log-rank test, P = 0.0056). After considering for other covariates in a Cox proportional hazard model, the XRCC1 Arg/Gln and Gln/Gln genotypes (hazard ratio, 4.73; 95% confidence interval, 1.61-13.92; P = 0.005) and high Gleason score (Gleason score, 8-10; hazard ratio, 5.58; 95% confidence interval, 1.58-19.71; P = 0.008) were still independent predictors of poor PSA-free survival after radical prostatectomy. The similar significant results were not found in XRCC1 codons 194 and 280. Conclusions: Our results suggest that the XRCC1 codon 399 polymorphism may be a prognostic factor for PSA recurrence after radical prostatectomy.

Androgen receptor gene polymorphism and prostate cancer in Taiwan

BACKGROUND AND PURPOSE The length of polymorphic CAG trinucleotide repeats in the polyglutamine region of the androgen receptor (AR) gene has been suggested to be inversely correlated with the transactivation function of the AR. An increase in androgen activity may be associated with prostate cancer, and ethnic variations in CAG repeat length may contribute to varying prostate cancer risks in different populations. This case-control study investigated the potential role of AR polymorphism in prostate cancer risk in Taiwanese. METHODS Sixty six pathologically-confirmed prostate cancer patients and 104 controls were studied. CAG repeat polymorphism was genotyped by a polymerase chain reaction (PCR)-based direct sequencing method. Logistic regression was used to determine the relative risk of AR gene CAG number on prostate cancer risk. The associations of AR-CAG polymorphism with disease stage, pathologic grade, and age at diagnosis were assessed. AR-CAG repeat number was first treated as a continuous variable, then was divided into short and long groups (n < 23 vs n > or = 23) for categorical analysis. The extreme groups of AR-CAG distribution were also analyzed for these associations (n < or = 20 vs n > or = 26 and n = 21-25 vs n > or = 26). RESULTS The mean number of CAG repeats in patients and controls was similar: 23.2 +/- 3.0 (range, 15 to 31) and 22.9 +/- 3.1 (range, 15 to 31), respectively. No association was found between AR-CAG repeat polymorphism and disease stage (p = 0.30), histological grade (p = 0.49), or age at diagnosis (p = 0.51). After adjusting for other covariates (age, body mass index, education level, smoking, and alcohol status), the number of AR-CAG repeats was not significantly associated with prostate cancer risk [odds ratio (OR) = 0.97, 95% confidence interval (95% CI) = 0.72 to 1.31; p = 0.84]. In categorical analysis, men with short CAG repeats (n < 23) did not have increased risk for prostate cancer (OR = 0.45, 95% CI = 0.29 to 1.05) compared to those with long CAG repeats (n > or = 23). Non-significant differences in prostate cancer risk were also found when comparing the extreme short group (n < or = 20) and the intermediate group (n = 21-25) to the extreme long group (n > or = 26) [n < or = 20 vs n > or = 26: OR = 1.00, 95% CI = 0.34 to 3.00; n = 21-25 vs n > or = 26: OR = 0.82, 95% CI = 0.37 to 1.81]. CONCLUSIONS The results of this study do not support an important effect of AR-CAG repeat polymorphism on prostate cancer risk. A large-scale study is needed to clarify genetic components of prostate cancer risk in the Taiwanese population.