The role of inflammatory mediators in the development of prostatic hyperplasia and prostate cancer.

Benign prostatic hyperplasia and prostate cancer remain the most prevalent urologic health concerns affecting elderly men in their lifetime. Only 20% of benign prostatic hyperplasia and prostate cancer cases coexist in the same zone of the prostate and require a long time for initiation and progression. While the pathogenesis of both diseases is not fully understood, benign prostatic hyperplasia and prostate cancer are thought to have a multifactorial etiology, their incidence and prevalence are indeed affected by age and hormones, and they are associated with chronic prostatic inflammation. At least 20% of all human malignancies arise in a tissue microenvironment dominated by chronic or recurrent inflammation. In prostate malignancy, chronic inflammation is an extremely common histopathologic finding; its origin remains a subject of debate and may in fact be multifactorial. Emerging insights suggest that prostate epithelium damage potentially inflicted by multiple environmental factors such as infectious agents, dietary carcinogens, and hormones triggers procarcinogenic inflammatory processes and promotes cell transformation and disease development. Also, the coincidence of chronic inflammation and tumorigenesis in the peripheral zone has recently been linked by studies identifying so-called proliferative inflammatory atrophy as a possible precursor of prostatic intraepithelial neoplasia and prostate cancer. This paper will discuss the available evidence suggesting that chronic inflammation may be involved in the development and progression of chronic prostatic disease, although a direct causal role for chronic inflammation or infection in prostatic carcinogenesis has yet to be established in humans. Further basic and clinical research in the area, trying to understand the etiology of prostatic inflammation and its signaling pathway may help to identify new therapeutic targets and novel preventive strategies for reducing the risk of developing benign and malignant tumors of the prostate.

Tissue-based quantification of 8-hydroxy-2'-deoxyguanosine in human prostate biopsies using quantitative fluorescence imaging analysis.

OBJECTIVES: To quantify 8-hydroxy-2'-deoxyguanosine (8-OHdG) in prostate stromal and acini tissue compartments from benign and cancer-containing prostate specimens using a new quantitative fluorescence imaging analysis protocol. METHODS: Prostate biopsy specimens from 20 age-matched benign (control) and cancer-containing tissue sections were used to quantify 8-OHdG. 8-OHdG was quantified within individual acini nuclei and the surrounding stroma nuclei. Paraffin sections were treated with RNAse and protease to expose the nuclear chromatin, reacted with anti-8-OHdG mouse monoclonal antibody bound to saturation and detected with secondary goat anti-mouse IgG labeled with Alex Fluor 488, and quantified with a calibrated quantitative fluorescence imaging analysis system. The results were analyzed using a paired Student's t test. RESULTS: 8-OHdG was successfully quantified within individual cellular compartments without the need for laser tissue dissection, using the mean pixel intensity of fluorescent-labeled 8-OHdG. Matched-pair analysis of the global expression of 8-OHdG, as well as the acini and stroma individually, revealed no difference between the cancerous and control prostatic tissue. All patients with prostate cancer and those with benign findings had significantly greater 8-OHdG within the acini compared with the surrounding stoma (P < .05). CONCLUSIONS: A protocol to quantify 8-OHdG in paraffin-embedded human prostatic tissue was successfully developed. 8-OHdG was not significantly elevated in the acini or stroma of cancer-containing prostatic tissue compared with age-matched benign prostatic tissue. Although 8-OHdG was significantly elevated in the acini nuclei compared with the surrounding stroma nuclei in both cancer-containing and benign prostatic tissue, it, by itself, was not a strong biomarker for prostate cancer risk assessment.

The role of inflammation and infection in the pathogenesis of prostate carcinoma.

Prostatitis and prostate carcinoma are both frequent entities of prostatic diseases. Epidemiological studies show significant associations between infection and inflammation and prostatic carcinoma. However, because of various confounding factors the results of these studies are inconclusive. Further findings are therefore needed to confirm the hypothesis that prostatic infection and inflammation might be a cause of prostatic carcinoma. We reviewed selected reports on the role of inflammation and infection in the pathogenesis of prostate carcinoma. Extensive genetic analyses show that several gene products, e.g. 2'-5'-oligoadenylate (2-5 A)-dependent Rnase, macrophage scavenger receptor 1 and Toll-like receptor-4, influence the susceptibility of prostate cells to infectious agents. Proliferative inflammatory atrophy (PIA) could be a connection between prostatitis and prostatic carcinoma. In the transition from PIA to prostatic intraepithelial neoplasia, the function of cellular detoxification is gradually lost by silencing of glutathione-S transferase, a detoxifying enzyme. This cellular feature leads to an increased susceptibility of the prostatic epithelial cells to genomic damage by inflammatory oxidants or nutritional carcinogens. Consecutive somatic genome damage might then arise which modulates the further pathogenesis of prostate carcinoma. Summarising these epidemiological, genetic and cell biological aspects, infectious prostatitis might have a causative role in the complex and multifactorial process of prostate carcinogenesis.

Quantitative fluorescence imaging analysis for cancer biomarker discovery: application to beta-catenin in archived prostate specimens.

The surprising disparity between the number of protein-encoding genes ( approximately 30,000) in the human genome and the number of proteins ( approximately 300,000) in the human proteome has inspired the development of translational proteomics aimed at protein expression profiling of disease states. Translational proteomics, which offers the promise of early disease detection and individualized therapy, requires new methods for the analysis of clinical specimens. We have developed quantitative fluorescence imaging analysis (QFIA) for accurate, reproducible quantification of proteins in slide-mounted tissues. The method has been validated for the analysis of beta-catenin in archived prostate specimens fixed in formalin. QFIA takes advantage of the linearity of fluorescence antibody signaling for tissue epitope content, a feature validated for beta-catenin in methacarn-fixed prostate specimens analyzed by reverse-phase protein array analysis and QFIA (r = 0.97). QFIA of beta-catenin in formaldehyde-fixed tissues correlated directly with beta-catenin content (r = 0.86). Application of QFIA in a cross-sectional study of biopsies from 42 prostate cancer (PC) cases and 42 matched controls identified beta-catenin as a potential field marker for PC. Receiver operating characteristic plots revealed that beta-catenin expression in the normal-appearing acini of cancerous glands identified 42% (95% confidence intervals, 26-57%) of cancer cases, with 88% (95% confidence intervals, 80-96%) specificity. The marker may contribute to a PC biomarker panel. In conclusion, we report the development and validation of a new method for fluorescence quantification of proteins in archived tissues and its application to archived specimens for an evaluation of beta-catenin expression as a biomarker for PC.

Chronic bacterial infection and inflammation incite reactive hyperplasia in a mouse model of chronic prostatitis.

BACKGROUND: Chronic inflammation is postulated to contribute to prostate carcinogenesis. We developed a mouse model of chronic prostatitis to test whether infection-induced chronic inflammation would incite reactive changes in prostatic epithelium. METHODS: Prostate tissues harvested from either phosphate-buffered saline (PBS) or E. coli-infected mice were evaluated for histological changes and immunostained for markers of oxidative stress and epithelial cell proliferation. RESULTS: As compared to PBS-treated controls, mice infected with E. coli bacteria for 5 days showed foci of uniformly acute inflammation in the glandular lumen and a persistent inflammation at 12 weeks post-inoculation in the stroma. Prostatic glands showing varying degrees of atypical hyperplasia and dysplasia had stronger staining for oxidative DNA damage and increased epithelial cell proliferation than normal prostatic glands. CONCLUSIONS: These data demonstrate that chronic inflammation induces reactive hyperplasia associated with oxidative stress injury and support the proposed linkage among inflammation, oxidative DNA damage, and prostate carcinogenesis.

Mouse model for acute bacterial prostatitis in genetically distinct inbred strains.

OBJECTIVES: Prostatitis is a common urologic disease seen in adult men. As many as 50% of men will experience an episode of prostatitis in their lifetime, and 2% to 3% of men will have bacterial prostatitis. Because the pathogenic mechanisms of prostatitis remain unclear, we developed a reproducible mouse model of bacterial prostatitis in which to study the etiology and host factors associated with infection susceptibility. METHODS: Male BALB/c, C3H/HeJ, C3H/HeOuJ, C57BL/6J, and (BALB/c x C3H/HeJ)F1 mice 13 weeks old were inoculated intraurethrally with 2 x 10(6) or 2 x 10(8) Escherichia coli. Control mice were inoculated with phosphate-buffered saline. The animals were killed at 5 days after inoculation to assess the intensities of the bladder and prostate infections. RESULTS: Significant bladder or prostate infections were not present in the BALB/c, C57BL/6J, or (BALB/c x C3H/HeJ)F1 mice at either inoculum dose. In contrast, both C3H/HeJ and C3H/HeOuJ mice developed high bladder infections and severe, acute prostatitis at both doses. Control mice infected with phosphate-buffered saline had no bladder or prostate infections. The P values were less than 0.01 for the comparison of bladder and prostate colony-forming units between C3H/HeJ or C3H/HeOuJ and BALB/c, C57BL/6J, or F1 mice. CONCLUSIONS: The strain-dependent differences in susceptibility indicate that genetic factors may play a major role in the etiology of bacterial prostatitis. Because F1 mice did not develop significant bladder and prostate infections, similar to the BALB/c parents, it appears that infection susceptibility is a recessive trait. The availability of this model will allow us to investigate the immunology, genetics, and histopathologic features of bacterial infection of the prostate.

Phase 2 clinical trial of a vaginal mucosal vaccine for urinary tract infections.

PURPOSE: Recurrent urinary tract infections (UTIs) in susceptible women remain a common urological condition. With an increasing number of UTIs being caused by antibiotic resistant bacteria there is a need for alternatives to antibiotics. We determined whether multiple doses of a vaginal mucosal vaccine are effective for increasing long-term resistance to recurrent UTIs. MATERIALS AND METHODS: A total of 54 women were entered into a double-blind, placebo controlled, phase 2 clinical trial using a vaginal vaccine containing 10 heat killed uropathogenic bacteria. Patients were withdrawn from prophylactic antibiotics and randomly assigned to 1 of 3 treatment groups, namely placebo only, primary immunization or primary plus booster immunizations. Subjects received treatments at 0, 1, 2, 6, 10 and 14 weeks. Placebo treated patients received suppositories without bacteria. The primary immunization group received vaccine suppositories, followed by 3 doses of placebo. Patients receiving booster immunizations were given 6 vaccine suppositories. All women were followed for 6 months to determine the time until first recurrence, number of infections and adverse reactions. RESULTS: Women receiving 6 vaccine doses remained free of infections for a significantly longer period than those receiving placebo or primary immunizations. Of patients receiving 6 immunizations 55% did not experience an infection, whereas 89% of placebo treated women had UTIs. No women had significant adverse effects. CONCLUSIONS: This study demonstrates that vaginal mucosal vaccine given for a 14-week period increased the time to re-infection in UTI susceptible women. The infrequent, minimal adverse reactions confirm previous observations on the safety of this vaginal mucosal immunization regimen.

Inheritance of susceptibility to induced Escherichia coli bladder and kidney infections in female C3H/HeJ mice.

In the present study, the inheritance of resistance and susceptibility to bladder and kidney infections in BALB/c, C3H/HeJ, F(1), and backcross mice was investigated, and the number of genes contributing to the phenotypes was estimated. Infections were induced in female mice by intravesical inoculation with Escherichia coli, and the number of bacteria in bladder and kidneys was quantified at 10 days. The (BALB/c x C3H/HeJ) F(1) mice had bladder and kidney infection intensities equivalent to those observed in the resistant BALB/c parents. Twelve percent of the (F(1) x C3H/HeJ) backcross mice had severe bladder infections, similar to the susceptible C3H/HeJ parents. Kidney infections ranging in intensity between those observed in BALB/c and C3H/HeJ parents were present in one-half of the backcross mice. Statistical analyses indicated that >/=1 gene is responsible for the increased susceptibility of C3H/HeJ mice and that the trait appears to be recessive.