This Month in Investigative Urology

Article Outline

• Constituent of Cigarette Smoke Induces Chromosome 3p Deletions That May Predict Renal Cell Carcinoma
• Detection of Bladder Cancer in Human Urine by Metabolomic Profiling
• Nicotinic Signaling Ameliorates Acute Bladder Inflammation
• Bladder Dysfunction Secondary to Long-Term Fructose Feeding
• Differential Regulation in Peyronie's Plaque Fibroblasts
• Copyright

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Constituent of Cigarette Smoke Induces Chromosome 3p Deletions That May Predict Renal Cell Carcinoma 

Cigarette smoking is a risk factor for renal cell carcinoma. Benzo[α]pyrene diol epoxide (BPDE), a major constituent of cigarette smoke, induces 3p aberrations that are associated with susceptibility to other smoking associated cancers. Because chromosome 3p deletions are known to be the most frequent genetic alterations in renal cell carcinoma, Zhu et al (page 2416) from Houston, Texas tested whether 3p sensitivity to BPDE predicted susceptibility to renal cell carcinoma. Cultured peripheral blood lymphocytic cells from 170 cases and 135 controls were treated with BPDE, and assessed for 3p deletions by fluorescence in situ hybridization using probes directed to 3p25.2, 3p21.3, 3p14.2 and 3p12.2. A probe for 3q13 was used as a control. At each locus BPDE induced 3p deletions were significantly more common in cases than in controls. No significant differences between cases and controls were observed for deletions in 3q13. There were dose dependent relationships between the number of deletions at each locus and the risk of renal cell carcinoma. This study demonstrates that chromosome 3p may be a specific molecular target of cigarette carcinogens and that BPDE sensitivity in chromosome 3p may reflect the genetic susceptibility of an individual to renal cell carcinoma.

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Detection of Bladder Cancer in Human Urine by Metabolomic Profiling 

Current use of cystoscopy for screening and detecting bladder cancer is invasive and expansive. Various urine based biomarkers have been used for this purpose with limited success. Metabolomics is the quantitative measurement of the metabolic response to pathophysiological stimuli. This analysis provides a metabolite pattern that can be characteristic of various benign and malignant conditions. Isaaq et al (page 2422) from Frederick, Maryland evaluated high performance liquid chromatography (HPLC) coupled online with a mass spectrometer metabolomic approach to differentiate urine samples from healthy individuals and patients with bladder cancer. Urine specimens were collected from 48 healthy individuals and 41 patients with transitional cell carcinoma, and analyzed using a HPLC system coupled online with a hybrid triple-quad time-of-flight mass spectrometer. The resulting total ion chromatograms of each sample were submitted for statistical analysis. Using positive ionization mass spectrometry orthogonal partial least square-discriminate analysis correctly predicted 48 of 48 healthy and 41 of 41 bladder cancer urine samples, while principal component analysis, an unsupervised profiling statistical method, confirmed these results and correctly predicted 46 of 48 healthy and 40 of 41 bladder cancer urine samples. The results of this proof of concept study indicate that metabolomics using HPLC/mass spectrometry has the potential to become a noninvasive early detection test for bladder cancer.

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Nicotinic Signaling Ameliorates Acute Bladder Inflammation 

Nicotinic afferent pathways may be involved in the regulation of bladder inflammation. Starkman et al (page 2440) from Nashville, Tennessee investigated the role of nicotinic signaling in a comparative analysis of 2 models of experimental bladder inflammation using protamine sulfate and cyclophosphamide. Protamine sulfate and cyclophosphamide were used to induce acute bladder inflammation. Nicotinic agonists and antagonists were given concomitant to the bladder inflammatory agents. Histologically cyclophosphamide induced more inflammatory changes than protamine sulfate during acute bladder inflammation. Antagonizing nicotinic signaling with mecamylamine induced further inflammatory changes on histology when used with cyclophosphamide but not with protamine sulfate. However, antagonizing nicotinic signaling in combination with protamine sulfate induced greater increases in mRNA expression of the inflammatory cytokine interleukin (IL)-6 compared to combination treatments of cyclophosphamide and mecamylamine. The activation of nicotinic signaling attenuated acute bladder inflammation by protamine sulfate and cyclophosphamide independently through the down-regulation of increased IL-6 expression. Acutely cyclophosphamide treatment results in a greater frank bladder inflammation model in mice than protamine sulfate. However, cholinergic signaling can inhibit inflammation by either mechanism of induced bladder injury. IL-6 gene expression is present and can be regulated by afferent neuronal signaling even in the absence of observed histological changes in acute bladder inflammatory models.

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Bladder Dysfunction Secondary to Long-Term Fructose Feeding 

Insulin resistance is defined as a defect in the ability of insulin to facilitate glucose uptake, and results in a metabolic syndrome characterized by impaired glucose tolerance, hyperinsulinemia and hypertension. Without necessary diet and lifestyle changes the insulin resistance syndrome usually progresses to type 2 diabetes. The metabolic syndrome and type 2 diabetes are known to be risk factors for lower urinary tract symptoms. The presence of lower urinary tract symptoms in patients with type 2 diabetes is caused by a high prevalence of diabetic bladder dysfunction resulting from vesical neuropathy. Additionally, metabolic perturbations have been proposed to be the etiology of lower urinary tract symptoms. However, the impact of insulin resistance or the metabolic syndrome without diabetes on the bladder is still unknown.

Lee et al (page 2470) from Taipei, Taiwan studied the effects of long-term fructose feeding and metabolic perturbations on bladder function in rats. Female rats were fed a fructose enriched (60%) or control diet for 3 and 6 months. All rats fed a fructose enriched diet for 3 months showed insulin resistance, hyperinsulinemia, hypertriglycemia and hypertension. These fructose fed rats showed a decreased contractile response to high concentrations of KCl but not to other parameters tested compared to controls. Eight of the 12 rats showed abnormal cystometry, mainly by increased phasic contractions. In the 6-month fructose fed rats contractile responses to electric field stimulation, KCl and carbachol were decreased significantly. However, responsiveness to high concentrations of adenosine triphosphate was significantly increased. Morphological studies in fructose fed rats showed swollen mitochondria in bladder smooth muscle, increased leukocyte infiltration between interstitial tissue and neutrophil adhesion around the endothelium of vessels. The data show that a significant proportion of fructose fed rats have time related alterations in the biochemical, morphological and functional properties of the bladder. The proinflammation and myopathy of the bladder induced by metabolic perturbations have important roles in causing bladder dysfunction.

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Differential Regulation in Peyronie's Plaque Fibroblasts 

Peyronie's disease is a fibrotic disorder of the tunica albuginea characterized by the localized formation of an inelastic plaque. Del Carlo et al (page 2447) from Chicago, Illinois characterized matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinase (TIMPs) in Peyronie's disease tissue. MMPs and TIMPs were investigated in Peyronie's disease plaque tunica removed from patients with stable Peyronie's disease. IL-1β significantly induced MMP-1, 3, 10 and 13 protein production, endogenous MMP-13 activity (12-fold) and MMP-13 mRNA expression (11-fold) through a Ca²⁺ independent mechanism in cultured fibroblasts. Transforming growth factor (TGF)-β stimulation failed to induce any detectable MMP protein production or activity and conditioned culture medium even had the capacity to inhibit the activity of purified recombinant human MMP-13. Intact Peyronie's disease plaques were highly enriched with TIMP-1 to 4 compared to donor matched perilesional tunica. These data show that while IL-1β strongly induces MMP expression, TGF-β strongly induces TIMP expression without any effect on the MMPs, and may represent an important downstream biochemical mechanism that leads to the progression of Peyronie's disease. The localized accumulation of TIMPs together with decreased MMP activity in the Peyronie's disease lesion may be the biochemical consequence of the TGF-β over expression that has been reported in many fibrotic disorders including Peyronie's disease.