Development Of Urinary Bladder Tumors Research Articles

Matrix metalloproteinases in urinary system tumors. Part II - Matrix metalloproteinases in urinary bladder carcinoma

Matrix metalloproteinases (MMPs), also referred to as matrixines, provide a group of proteolytic enzymes. They belong to the family of endopeptidases that break down elements of the extracellular matrix, resulting in its continuous remodeling. Their activity is regulated at multiple levels, while tissue inhibitors of metalloproteinases play a major role in this process. Metalloproteinases play a significant part in neoplastic processes due to their contribution to local tumor invasion, the formation of distant metastases, as well as to angiogenesis Urinary tract tumors pose a significant diagnostic and therapeutic challenge and their incidence tends to grow every year. The aim of this second part of the review is to describe the urinary system structure and function, and to highlight the contribution of matrix metalloproteinases to the development of urinary bladder tumors

Id Proteins Contribute to Tumor Development and Metastatic Colonization ina Model of Bladder Carcinogenesis.

Background: Bladder cancer is one of the most common malignant genitourinary diseases worldwide. Despite advances in surgical technique, medical oncology and radiation therapy, cure of invasive tumors remains elusive for patients with late stage disease. Therefore, new therapeutic strategies are needed to improve the response rates with regard to recurrence, invasion and metastasis. Objective: Inhibitor of DNA binding (Id) proteins have been proposed as therapeutic targets due to the key regulatory role they exert in multiple steps of cancer. We aimed to explore the role of Id proteins in bladder cancer development and the pattern of expression of Id proteins in bladder carcinomas. Methods: We used a well-established chemically induced model of bladder carcinogenesis. Wild type and Id-deficient mice were given N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in the drinking water and urinary bladder lesions were analyzed histopathologically and stained for Id1. We assessed the effects of Id1 inactivation in cultured bladder cancer cells and in a model of metastatic lung colonization. We also performed Id1 staining of human urothelial carcinoma samples and matched lymph node metastases. Results: Id1 protein was overexpressed in the BBN-induced model of bladder cancer. Id1 deficiency resulted in the development of urinary bladder tumors with areas of extensive hemorrhage and decreased invasiveness when compared to wild type mice. Id1 inactivation led to decreased cell growth in vitro and lung colonization in vivo of human bladder cancer cells. Immunohistochemistry performed on human urothelial carcinoma samples showed Id1 positive staining in both primary tumors and lymph node metastases. Conclusions: In summary, our studies reveal the physiological relevance of Id1 in bladder cancer progression and suggest that targeting Id1 may be important in the development of novel therapies for the treatment of bladder cancer.

TP53 Intronic Mutations in Bovine Enzootic Hematuria–Associated Urinary Bladder Tumors

Tumor protein 53 (TP53) is a tumor suppressor gene that is frequently mutated in urinary bladder tumors in both humans and animals. In cattle, urinary bladder tumors have been reported as occurring spontaneously as well as in conjunction with bracken fern consumption-induced bovine enzootic hematuria (BEH). The goal of this study was to evaluate various types of bovine urinary bladder neoplasms for the presence of TP53 alterations, using the polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) method. DNA was extracted from both epithelial and mesenchymal urinary bladder tumor samples in cattle, associated with the chronic consumption of bracken fern. PCR was performed using primers targeted to exons 5 to 8, following electrophoresis and isolation, and the products were assessed by SSCP. Tumors in which alterations in the electrophoresis patterns were noted included hemangiomas, papillomas, and carcinomas in situ. Exemplars of these tumor types were selected for sequencing, and although no changes were noted in the 5 to 8 exon range, on either side of the designed primers for exon 6, there was some portion of intron 6 in which sequencing demonstrated a deletion of the thyamine nucleotide at position 9332. In summary, although mutations were not observed within exons 5 to 8, this represents the first report of an intronic mutation in the TP53 gene in association with bovine urinary bladder tumors. Mutations within introns can predispose tissues to the development of cancer, and therefore, a possible association between mutations of the introns of TP53 and the development of urinary bladder tumors in cattle with BEH should be further investigated.

Promoting Effect of Sodium L-Ascorbate on N-Butyl-N-(4-hydroxybutyl)nitrosamine-induced Renal Pelvic Carcinogenesis in SD/cShi Rats of Both Sexes

Susceptibility to the promoting effects of sodium L-ascorbate (Na-AsA) on the development of pelvis and urinary bladder tumors in male and female SD/cShi rats, featuring spontaneous hydronephrosis, was investigated. Rats received 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in their drinking water for 4 weeks and subsequently given basal diet with or without a 5% Na-AsA supplement for 32 weeks. Histopathological examination revealed the promoting effect of Na-AsA on not only the development of urinary bladder tumors but also renal pelvic tumors in the animals of both sexes in this two-stage carcinogenesis experiment, the effect being more prominent in males. Administration of either BBN or Na-AsA alone also induced papillomas and papillary or nodular hyperplasia of renal pelvis or urinary bladder, respectively, in male but not female rats. However, the 5-bromo-2'-deoxyuridine-labeling index of urothelium in the pelvis and bladder increased slightly in male rats and significantly in female rats given Na-AsA alone for 8 weeks. N-butyl-N-(3-carboxypropyl)nitrosamine, which is a metabolite of BBN and proximate carcinogen, was found more in the urine of urinary bladder than that of renal pelvis. These results indicate that the urothelium of the renal pelvis and urinary bladder in SD/cShi rats is susceptible to promoting effects of Na-AsA in the present two stage model urinary tract carcinogenesis, with the urinary bladder of male rats as the most sensitive organ.

Effects of Isoliquirithigenin on the Development of Preneoplastic Liver Lesions Caused by a Choline-Deficient, L-Amino Acid-Defined Diet and on the Urinary Bladder Carcinogenesis by N-Butyl-N-(4-hydroxybutyl)nitrosamine in Rats

Cancer chemopreventive efficacy of a chalcone, isoliquiritigenin (ISO), was assessed on the rat hepatocarcinogenesis associated with fibrosis caused by a choline-deficient, L-amino acid-defined (CDAA) diet, using glutathione S-transferase placental form (GST-P)-positive preneoplastic foci as the end point lesion, and on the rat superficial bladder carcinogenesis initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). ISO, when given to F344 male rats at the doses of 12.5, 50, 100, and 200 ppm in the CDAA diet for 15 weeks, did not significantly affect the number and size of GST-P-positive foci and the % liver area occupied by the foci. However, it tended to decrease the grade of liver fibrosis. ISO, which was given in a basal diet at doses of 12.5, 25, and 100 ppm for 12 weeks to F344 male rats initiated by 0.05% BBN in drinking water for 12 weeks, also exhibited no clear chemopreventive effects on the development of urinary bladder tumors. Nevertheless, it tended to decrease the multiplicity of nodulo-papillary hyperplasia but not of transitional cell carcinoma (TCC), and differentiation grade of TCCs. The results indicate that ISO at least at the doses used in the present study, possesses no clear cancer chemopreventive efficacy on rat hepatocarcinogenesis caused by a CDAA diet and on rat superficial urinary bladder carcinogenesis by BBN.

Strain differences in sensitivity to the promoting effect of sodium L-ascorbate in a two-stage rat urinary bladder carcinogenesis model.

Rat strain differences in sensitivity to the promoting effect of sodium L‐ascorbate (SA) on the development of urinary bladder tumors were investigated. In experiment 1, WS/Shi (WS), ODS/Shi‐od/od (ODS), and LEW/Crj (LEW) rats were initiated with 0.05%N‐butyl‐N‐(4‐hydroxybutyl)‐nitrosamine (BBN) in their drinking water and subsequently given basal Oriental MF diet (M) with or without a 5% SA supplement. In LEW rats the SA treatment increased the induction of neoplastic lesions in the urinary bladder, whereas WS and ODS animals proved unresponsive to its promoting effects. In experiment 2, WS and F344 rats were maintained on two kinds of commercial basal diets, M and CLEA CA‐1 (C), during administration of SA, since dietary factors can influence promoting effects. Feeding M during the promotion period in F344 rats yielded significantly more neoplastic lesions than feeding C, but in WS rats no such dietary influence was apparent. In experiment 3, strain differences in biosynthesis of α‐2u‐globulin (α2u‐g) were assessed because both α2u‐g in the urine and administration of sodium salts of organic acids such as SA have been reported to be involved in tumor promotion. Immunohistochemical analysis of renal tubules and Western blotting analysis of urine revealed the presence of α2u‐g in all three strains examined. These data suggest that differences in susceptibility to promotion are due to genetic factors rather than dietary factors and the ability to synthesize . α2u‐g.

Lack of promotion of N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine‐initiated urinary bladder carcinogenesis in mice by rat cancer promoters

The effects of dietary exposure to sodium L-ascorbate (Na-AsA), butylated hydroxyanisole (BHA), and diphenyl on the development of urinary bladder tumors in a mouse two-stage carcinogenesis model were examined. Male B6C3F1 mice received 0.05% N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in the drinking water for 4 weeks and were then treated with 5% Na-AsA, 1% BHA, or 1% diphenyl for 32 weeks. None of these chemicals enhanced the development of either preneoplastic or neoplastic lesions in the urinary bladder. Furthermore, DNA synthesis levels of urinary bladder epithelium in mice treated with each substance alone for 8 weeks were not elevated significantly, although Na-AsA was associated with a significant increase in the urinary pH value and Na+ concentration. The results indicate that Na-AsA, BHA, and diphenyl do not exert an enhancing influence on mouse bladder carcinogenesis, in clear contrast to the case in the rat.

Effects of various chemicals on the development of mouse urinary bladder tumors induced by N-butyl-N-(4-hydroxybutyl) nitrosamine.

Effects of various chemicals on the development of urinary bladder tumors in mouse treated with N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) were examined, Male C3H/He mice received 0.05% BBN in drinking water for 8 weeks, and were subsequently treated with basal diet containing trisodium nitrilotriacetate monohydrate (Na3NTA·H2O), nitrilotriacetic acid (H3NTA), sodium saccharin, and DL-tryptophan for 12 weeks. DL-tryptophan tended to induce a more significant increase in neoplastic and dysplastic lesions of the urinary bladder as compared to Na3NTA·H2O, H3NTA and sodium saccharin. These data showed that DL-tryptophan was more effective than Na3NTA·H2O, H3NTA and sodium saccharin with regard to promoting potential on the development of urinary bladder tumors in mouse treated with BBN.

Selective induction of rat urinary bladder tumors by simultaneous administration of 3,2'-dimethyl-4-aminobiphenyl (DMAB) and butylated hydroxyanisole or butylated hydroxytoluene is associated with increased DMAB-DNA adduct formation

Modification of 3,2'-dimethyl-4-aminobiphenyl (DMAB) multi-organ carcinogenesis by simultaneous treatment with butylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT) was studied using young and old male F344 rats. Animals, 4 or 54 weeks old, were given DMAB (s.c. injection of 50 mg/kg body wt once a week for 10 weeks) along with BHA (2.0% in diet for 11 weeks) or BHT (1.0% in diet for 11 weeks). The experiments were terminated 55 weeks after the commencement. Combined administration of BHA or BHT with the carcinogen resulted in development of urinary bladder tumors in greater than 90% of both young and old rats thus treated, whereas no tumors were induced in animals given DMAB alone. In contrast, the appearance of preneoplastic lesions in the liver and pancreas was reduced by BHA or BHT treatment. Tumor development (less than 30% incidence) was also evident in the small and large intestines, prostate, preputial glands, skin/subcutis and ear duct, with no modification by BHA or BHT. No ageing effects were evident. The formations of DMAB-DNA adducts, evaluated by the enzyme-linked immunosorbent assay and immunohistochemical staining, correlated well with tumorigenesis in the urinary bladder, liver and pancreas. The selective enhancement of urinary bladder tumor induction by BHA and BHT appeared to be due to both increased DMAB-DNA adduct formation caused by metabolic alteration of DMAB in the liver and increased DNA synthesis in the urothelial cells.

The effect of lifetime sodium saccharin dosing on mice initiated with the carcinogen 2-acetylaminofluorene

Sodium saccharin has been reported to promote the development of urinary bladder tumors in rats following low doses of several carcinogens. To evaluate the generality of this effect between species, an initiation-promotion study was conducted in mice. Weanling female BALB/c mice were initiated with 200 ppm dietary 2-acetylaminofluorene for 90 days. Following a 2-week period of control diet, saccharin was administered at 0, 0.1, 0.5, 1.0, and 5.0% in the diet for the remainder of the 132-week study. An elevated incidence of persistent bladder transitional cell hyperplasia and a low incidence of urothelial and hepatocellular tumors indicated that these organs achieved an adequate dose of the initiator. However, sodium saccharin dosing did not result in an increased incidence of tumors in either the bladder or liver and is therefore not considered to be a promoter of carcinogenesis at these sites in the mouse. Furthermore, sodium saccharin exhibited a modest inhibitory effect on the rate of development of lymphomas in both initiated and noninitiated animals. Interspecies differences in the bladder tumorigenic effect of sodium saccharin and their association with differences in urinary tract physiology are discussed.

Effects of Single Chemotherapeutic Agents on Development of Urinary Bladder Tumor Induced by N-Butyl-N-(4-Hydroxybutyl) Nitrosamine (BBN) in Rats

Chemotherapeutic agents were evaluated for effect on the development of urinary bladder tumors induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in male Wistar strain rats. Seven hundred and two rats were given 0.05% BBN in drinking water for 8 weeks. After BBN treatment, the animals were divided into 26 groups to follow regimens of single chemotherapy. All drugs were administered intraperitoneally except in one group that was treated orally. In our experimental series, 5-fluorouracil (5-FU), N-(2-tetrahydrofuryl)-5-fluorouracil (FT-207), carbazilquinone (CQ), vincristine (VCR) and cis-diamminedichloroplatinum (CDDP) were effective in inhibiting the incidence of bladder tumor, however, adriamycin (ADM), mitomycin C (MMC), neocarsinostatin (NCS), cyclophosphamide (CPM) and bleomycin (BLM) were not effective.

Effects of single chemotherapeutic agents on development of urinary bladder tumor induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in rats.

Chemotherapeutic agents were evaluated for effect on the development of urinary bladder tumors induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in male Wistar strain rats. Seven hundred and two rats were given 0.05% BBN in drinking water for 8 weeks. After BBN treatment, the animals were divided into 26 groups to follow regimens of single chemotherapy. All drugs were administered intraperitoneally except in one group that was treated orally. In our experimental series, 5-fluorouracil (5-FU), N-(2-tetrahydrofuryl)-5-fluorouracil (FT-207), carbazilquinone (CQ), vincristine (VCR) and cis-diamminedichloroplatinum (CDDP) were effective in inhibiting the incidence of bladder tumor, however, adriamycin (ADM), mitomycin C (MMC), neocarsinostatin (NCS), cyclophosphamide (CPM) and bleomycin (BLM) were not effective.

Effects of Intravesical Instillation of Antitumor Chemotherapeutic and Immunotherapeutic Agents on Bladder Lesion Development in Rats Pretreated with N-Butyl-N-(4-Hydroxybutyl)Nitrosamine

The effects of 12 weeks of intravesical instillation of bleomycin, cisplatinum and picibanyl on development of urinary bladder tumors and preneoplastic lesions were examined in rats pretreated with N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) for four weeks. Upon sacrifice at week 36, histopathological examination revealed a significantly reduced incidence of PN hyperplasia and a tendency for decreased papilloma generation in rats given cisplatinum. However, the other treatments were not associated with any effect on carcinogen-induced lesion development. The results demonstrate that cisplatinum has a potential for postinitiation inhibition of rat bladder carcinogenesis.

Trisodium Nitriloacetate Monohydrate: Promoting Effect in Urinary Bladder Carcinogenesis in Rats Treated With <italic>N</italic>-Buty1-<italic>N</italic>-(4-hydroxybutyl)nitrosamine<xref ref-type="fn" rid="FN2">2</xref>

The effect of trisodium nitrilotriacetate monohydrate [(Na3NTA X H2O) CAS: 18662-53-8] on development of urinary bladder tumors in rats initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine [(BBN) CAS: 3817-11-6] was studied. Twenty-one male inbred W rats 6 weeks of age were given drinking water containing 500 ppm of BBN for 4 weeks and then put on diet containing 10,000 ppm of Na3NTA X H2O for 28 weeks. Na3NTA X H2O promoted the development of urinary bladder tumors in rats treated with BBN. The incidences of papilloma and transitional cell carcinomas in the urinary bladder were 90% (18/20) and 25% (4/20), respectively, in rats treated with BBN and then Na3NTA X H2O and 0 in those treated with BBN or Na3NTA X H2O alone. The incidence of papillary or nodular hyperplasia in week 32 was 100% (20/20) in rats treated with BBN and then Na3NTA X H2O and 61% (13/21) in rats treated with BBN only.

The effects of catechol on the urinary bladder of rats treated with N-butyl-N-(4-hydroxybutyl)nitrosamine.

The effect of catechol on the development of urinary bladder tumors in Fischer rats treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was studied. A solution of 0.05% catechol and 0.001% BBN was administered in the drinking water ad libitum for 78 weeks. The urinary bladders were then removed and examined microscopically. No statistically significant difference was observed between the experimental group receiving 0.001% BBN with 0.05% catechol and animals receiving 0.001% BBN alone with respect to the incidence of hyperplasia, papilloma, or carcinoma of the urinary bladder. Animals receiving 0.05% catechol alone in the drinking water had no macroscopic or microscopic lesions significantly different from those in control animals receiving tap water. Analyses of the urine of animals receiving catechol in their drinking water indicated that greater than 99% of the catechol present was in the form of either glucuronide or sulfate conjugates. In a second bioassay, the potential cocarcinogenicity of catechol, administered together with BBN, was explored by direct instillation into the urinary bladder. The development of calculi and possible infections of the urinary tract within all groups of treated animals suggests that this bioassay technique for cocarcinogenicity is of questionable value. These data show that catechol at the dose and mode of administration employed in this study did not affect the epithelium of the urinary bladder or enhance the carcinogenic activity of BBN.

Effects of foreign bodies on development of urinary bladder tumors in rats treated with N-butyl-N-(4-hydroxybutyl nitrosamine) : E. Okajima, T. Hiramatsu, Y. Motomiva, T. Kondo, and Y. Hirao ( 1: 177, 1973)

Effects of foreign bodies on development of urinary bladder tumors in rats treated with N-butyl-N-(4-hydroxybutyl nitrosamine) : E. Okajima, T. Hiramatsu, Y. Motomiva, T. Kondo, and Y. Hirao ( 1: 177, 1973)