Urinary Bladder Carcinogenesis

Abstract

Urinary bladder carcinogenesis in rodents bears numerous similarities to the diseases in humans. In rats, the process progresses through the morphologic stages of simple hyperplasia, papillary and nodular hyperplasia, papilloma, noninvasive, and invasive carcinoma. In mice, the pathogenesis can be similar or can follow a sequence of marked dysplasia with or without hyperplasia, leading to carcinoma in sirir and ultimately to high-grade invasive carcinoma. Although the papillary and nonpapillary diseases appear to be related in rodents and in humans, they are distinct morphologically, biologically, and molecularly. Numerous classes of genotoxic chemicals have been identified as bladder carcinogens in rodents, and some of these have also been identified as carcinogenic in humans, most notably, aromatic amines, nitrosamines, and cyclophosphamide. In contrast, nongenotoxic chemicals appear to be highly specific with respect to species, strain, diet, agent, dose, and mechanism. For some, it is unclear whether the results at high doses in rodents can be extrapolated to low doses or to humans, e.g., chemicals that cause bladder cancer only at high doses related to the formation of calculi. Numerous observations in rodents can assist in identifying possible mechanisms involved for these nongenotoxic chemicals and therefore can be important for a rational evaluation of human risk.Keycords. Bladder cancer; genotoxic chemicals; calculi; cell proliferation; hyperplasia URINARY BLADDER CANCER PATHOGENESIS Evidence increasingly is accumulating to support the hypothesis that transitional cell carcinoma of the urinary bladder actually represents 2 distinct, albeit related diseases (24, 44). The first type is papillary transitional cell carcinoma, which is usually low grade and noninvasive but tends to recur frequently following treatment. The second disease is the nonpapillary type that tends to be high grade and invasive, and it is frequently lethal to the patient due to local aggressiveness and/or distant metastases. In addition to differing pathogenetic processes, these 2 diseases appear to involve different molecular events (44). In animal models, these 2 diseases are similar to those in humans but tend to occur separately (9).In rats, bladder cancer is nearly always of the papillary type (9). The pathogenetic process for this disease involves the initial appearance of simple hyperplasia that may be diffuse or focal. This gradually evolves into focal areas of nodular and/or papillary hyperplasia, followed by evolution to a papilloma and ultimately to noninvasive low-grade carcinoma. In contrast to the disease in humans (9, 24), the papillary low-grade tumors eventually evolve into high-grade lesions and invasion, but they only rarely metastasize. Some other distinctions between the rat model and the human disease include the morphologic appearance of the papillomas, particularly the larger ones. In rats, these more closely resemble the inverted type of papilloma of humans rather the typical fronds of papillary trans...

Quantitation of Acrolein-Derived (3-Hydroxypropyl)mercapturic Acid in Human Urine by Liquid Chromatography−Atmospheric Pressure Chemical Ionization Tandem Mass Spectrometry: Effects of Cigarette Smoking

“…Acrolein did not induce tumors in several studies in mice and rats and, when administered by inhalation to hamsters, did not enhance the carcinogenicity of either benzo [a]pyrene or N-nitrosodiethylamine (7). It did however produce bladder tumors in rats when given as a tumor initiator, followed by promotion with dietary uracil (18). The potential role of acrolein in cigarette smoke induced lung cancer requires further research.…”

Perfluorooctanesulfonate and other fluorochemicals in the serum of American Red Cross adult blood donors.

“…PFOS is not likely to be insoluble in human urine (solubility, 305 µg/mL at 23-24°C) at the serum concentrations present in these workers (Ellefson 2001). In a review article, Cohen (1998) reported that all of the chemical agents listed as known bladder cancer agents were genotoxic and had metabolites that were genotoxic or precipitated in the urine. Given the consistency of the data analyzed, we hypothesize that the average serum PFOS concentrations in nonoccupational adult populations may range from 30 to 40 ppb, with 95% of a population's serum PFOS concentrations below 100 ppb.…”

Interstrand DNA Cross-Links Induced by α,β-Unsaturated Aldehydes Derived from Lipid Peroxidation and Environmental Sources

“…22 Acrolein is mutagenic in bacterial and mammalian cells, 23,24 including human, 25,26 and is carcinogenic in rats. 27 Crotonaldehyde is genotoxic and mutagenic in human lymphoblasts 28 and induces liver tumors in rodents. 29 4-HNE induces a DNA damage response in Salmonella typhimurium ,30,31 but is inactive in bacterial mutagenesis assays.…”