UMLS:C0596263 - FACTA Search

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Query: UMLS:C0596263 (carcinogenesis)
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Bladder neoplasms are common around the world. Incidences are particularly high in the Nile River Valley secondary to schistosomiasis, which is frequently associated with the development of squamous cell carcinoma similar to that of other chronic inflammatory processes of the lower urinary tract. However, elsewhere, most bladder tumors are of the urothelial (transitional) cell type. There is a marked male predominance and there are extensive racial differences. It is predominantly a neoplasm that occurs in patients aged >50 years. Urothelial carcinomas comprise two distinct diseases both biologically and molecularly: a low-grade papillary tumor which frequently recurs; and a high-grade malignancy which can present as dysplasia or carcinoma in situ, but frequently presents as invasive disease. However, epidemiological investigations of urothelial malignancies have generally not distinguished between preneoplastic and invasive neoplasms or between these two types of urothelial neoplasms. It is recommended that future studies should distinguish between these entities. The most common etiologic factor of urothelial malignancies besides schistosomiasis is cigarette smoking. In addition, numerous specific chemicals have been identified as bladder carcinogens in humans, some relating to specific occupational exposures. Bladder carcinogens include aromatic amines and amides, such as 4-aminobiphenyl, benzidine, 2-naphthylamine and phenacetin-containing analgesics, and certain cancer chemotherapeutic agents, such as phosphoramide mustards. More recently, occupational exposure to various combustion gases, such as diesel exhaust, has been related to an increased risk of developing bladder neoplasms. Also, exposure to chlorination by-products in drinking water and to arsenic has been suggested as increasing the risk of bladder neoplasia. As numerous specific chemicals appear to be related to the development of bladder tumors, various polymorphisms of enzymes involved in their metabolism have been suggested as affecting the susceptibility to their carcinogenicity. This has been particularly true with respect to the role of acetyltransferases in relation to aromatic amine carcinogenesis. Dietary influences have also been suggested as affecting bladder neoplasia susceptibility. Various heterocyclic amines generated by pyrolysis of food have been suggested as potential dietary factors increasing the risk of bladder cancer, particularly in relation to the ingestion of red meat. Despite the existence of several identifiable factors that increase or decrease the risk of bladder cancer, many patients have no known carcinogens or risk factors.
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PMID:Epidemiology and etiology of premalignant and malignant urothelial changes. 1114 90

Carcinoma of the bladder is the most prevalent cancer in Egypt and in most African countries. At the National Cancer Institute (NCI), Cairo, it constitutes 30.3% of all cancers. The median age at diagnosis is 46 years, with a male preponderance of 5:1. Whether in Egypt or other African countries such as Sudan, Kenya, Uganda, Gold Coast, and Senegal, it is mostly of the squamous cell type, and arises in a background of schistosomiasis or bilharziasis. Tumors are usually advanced at the time of presentation. Bladder carcinogenesis is probably related to bacterial and human papilloma virus (HPV) infections, usually associated with bilharzial infestation. Management is mainly surgery, with 5-year survival rates after radical cystectomy increasing from 35% in the 1970s to 48% in the 1990s. The addition of adjuvant and neoadjuvant radiotherapy and chemotherapy to surgery since 1976 significantly improved both disease-free and overall survival rates. Molecular genetic studies concerning potential prognostic markers, tumorigenesis, and tumor progression in bilharzial bladder cancer are limited. However, a comprehensive detailed analysis of these factors is underway. Bilharzial bladder cancer is a preventable malignant disease. Primary prevention could be possible if the parasite is eliminated nationwide. Chemoprevention using retinoids or cyclooxygenase 2 (COX-2) inhibitors is a possible alternative. Semin Oncol 28:174-178.
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PMID:Bladder cancer in Africa: update. 1130 80

A 100-fold increased incidence of bladder cancer is observed with workers exposed to high levels of benzidine (BZ). This review evaluates the overall metabolism of BZ to determine pathways involved in initiation of carcinogenesis. Enzymatic and liver slice incubations demonstrated N-acetylation and N-glucuronidation of BZ and N-acetylbenzidine (ABZ). With rat, N,N'-diacetylbenzidine (DABZ) is the major slice metabolite. With human, ABZ is the major metabolite along with N-glucuronides. Differences between rat and human are attributed to preferential acetylation of BZ and deacetylation of DABZ, resulting in N-glucuronide formation by human liver. Glucuronidation of BZ and its analogues exhibited the following relative ranking of UDP-glucuronosyltransferase (UGT) metabolism: UGT1A9>UGT1A4>>UGT2B7>UGT1A6 approximately UGT1A1. N-Glucuronides of BZ, ABZ, and N'-hydroxy-N-acetylbenzidine (N'HA) are acid labile with the latter having a much longer t(1/2) than the former two glucuronides. O-Glucuronides are not acid labile. In urine from BZ-exposed workers, an inverse relationship between urine pH and levels of free (unconjugated) BZ and ABZ is observed. This is consistent with the presence of labile urinary N-glucuronides. Cytochrome P-450 oxidizes BZ to an inactive product (3-OHz.sbnd;BZ) and ABZ to N'HA and N-hydroxy-N-acetylbenzidine (NHA). Cytochrome P-450, PHS, and horseradish peroxidase activate ABZ to bind DNA forming N'-(3'-monophospho-deoxyguanosin-8-yl)-N-acetylbenzidine (dGp-ABZ). This is the major adduct detected in bladder cells from workers exposed to BZ. An inverse relationship exists between urine pH and levels of bladder cell dGp-ABZ. Bladder epithelium contains relatively high levels of prostaglandin H synthase (PHS) and low levels of cytochrome p-450, suggesting activation by PHS. Activation by PHS involves a peroxygenase oxidation of ABZ to N'HA, while horseradish peroxidase activates ABZ to a diimine monocation. Reactive nitrogen oxygen species (RNOS) offer a new pathway for metabolism and potential activation. Results suggest BZ initiation of bladder cancer is complex, involving multiple organs (i.e. liver, kidney, and bladder) and metabolic pathways (i.e. N-acetylation, N-glucuronidation, peroxidation, and RNOS).
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PMID:Metabolism of N-acetylbenzidine and initiation of bladder cancer. 1235 Nov 42

Bladder neoplasia in humans consists of 2 diseases, a low-grade papillary tumor that does not invade or metastasize, and a high-grade lesion that usually invades and metastasizes. Bladder carcinogenesis in rats is most like the low-grade, papillary tumor, although it eventually does progress and invade. In the mouse, models are available that mimic each of these disease processes. Preneoplastic lesions in humans and rodents include various types of hyperplasia, proliferative cystitis, and dysplasia. These preneoplastic and neoplastic lesions arise throughout the urothelium, from the renal pelvis to the urethra, although most commonly in the bladder. Rarely, benign and malignant mesenchymal lesions occur in rats and mice, with a unique submucosal mesenchymal lesion present in some strains of mice. In addition, eosinophilic and clear inclusions in the superficial layer of urothelium in mice, which do not appear to be associated with toxicity or carcinogenesis, have been reported. An approach to evaluation of carcinogenic mechanisms involved in the urothelium is presented. It focuses on distinguishing between DNA reactive carcinogens vs those that act by increasing cell proliferation. Although rodent models do not precisely mimic the human disease, they have provided useful models for furthering our understanding of the carcinogenic process in the urothelium as it pertains to human diseases.
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PMID:Comparative pathology of proliferative lesions of the urinary bladder. 1251 66

Bladder carcinogenesis remains unclear despite the identification of chemical, environmental and genetic factors. It has recently been reported that the chromosomal region 12q13-q15, containing crucial cancer genes such as MDM2, CDK4 and GLI, is amplified in bladder cancer. In the same region are also located the genes of the locus HOX C, flanked by keratin genes whose protein product may be a prognostic marker of bladder cancer. The HOX genes constitute a network of transcription factors controlling embryonal development and play an important role in crucial adult eukaryotic cell functions. The molecular organization of this 39-gene network is unique in the genome and probably acts by regulating phenotypical cell identity. We have analysed the expression of the whole HOX gene network in pairs of normal-tumour bladder and in tumoral biopsies. Comparison between normal urothelium and bladder tumour has identified dramatic variations of expression in a block of three genes (HOX C4, HOX C5 and HOX C6) localized in the HOX C locus on the chromosome 12q13 and in the paralogous group 11 HOX genes, involved during normal development in the formation of the urogenital system. These data suggest a key involvement of the HOX gene network, and especially the locus C, in bladder cancer.
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PMID:Hyperexpression of locus C genes in the HOX network is strongly associated in vivo with human bladder transitional cell carcinomas. 1450 27

Squamous cell carcinoma (SCC) can occur in both nonbilharzial and bilharzial bladders; the two subtypes differ in epidemiology, pathogenesis and clinicopathological features. The nonbilharzial type occurs in Western countries and represents < 5% of all vesical tumours; it occurs most often in the seventh decade with a slight male predominance. The principal predisposing factor is prolonged indwelling urethral catheterization in patients with spinal cord injury and the main symptom is haematuria. Patients are usually diagnosed at an advanced stage and most of the tumours are of moderate and high grades. At cystoscopy tumours are predominantly ulcerative and commonly involve the trigone and lateral walls. Although distant metastasis is infrequent (8-10%) the prognosis is grave and most patients die after failure of locoregional control; radical cystectomy provides the best therapy. To avoid nonbilharzial SCC, patients with spinal cord injury should be free of catheterization if possible. The outcome can be improved by early detection with frequent cytology, cystoscopy and biopsy. Bilharzial SCC occurs commonly in the Middle East, South-east Asia and South America where schistosomiasis is endemic. In an Egyptian series SCC represented 59% of 1026 cystectomy specimens. The tumour is diagnosed in the fifth decade, and five times more common in men than women. Bladder carcinogenesis is probably related to bacterial and viral infections, commonly associated with bilharzial infestation rather than the parasite itself. The presentation is often with irritative bladder symptoms and haematuria, and many patients present at an advanced stage, although most tumours are of low and moderate grades. At cystoscopy tumours are predominantly nodular and usually arise from the upper vesical hemisphere. Lymph-node metastasis occurs in approximately 19% and significantly decreases survival; radical cystectomy remains the main treatment, giving a 5-year survival rate of 50%. Early detection improves the therapeutic yield and prevention is possible by combining snail control and mass therapy of the infested rural population by oral antibilharzial drugs.
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PMID:Squamous cell carcinoma of the bladder: pathology, diagnosis and treatment. 1469 Apr 86

Bladder exstrophy is associated with an increased incidence of primary adenocarcinoma of the bladder. We report a rare case of squamous cell carcinoma occurring in the unreconstructed, exstrophic bladder of a 53-year-old woman treated with radical cystectomy and radiochemotherapy. This case represents the oldest patient to present with squamous cell carcinoma of an unreconstructed exstrophic bladder. We discuss the potential mechanisms of carcinogenesis in this patient, noting how they may potentially differ from those in a patient with a reconstructed bladder.
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PMID:Primary squamous cell carcinoma in unreconstructed exstrophic bladder. 1641 65

To investigate the prostaglandin E2 (PGE2) biosynthetic mechanism in bladder carcinogenesis, we established Wistar rat model of bladder papilloma and transitional cell carcinoma (TCC) induced by 5% terephthalic acid (TPA) treatment. Then, the mRNA level of cytosolic phospholipase A2 (cPLA2), cyclooxygenases (COX)-1 and -2, membrane-bound PGE2 synthases (mPGES)-1 and -2 was detected using reverse transcription polymerase chain reaction (RT-PCR). Immunoblotting was applied to detect the expression of COX-2 protein. Proliferating cell nuclear antigen (PCNA) was determined by immunohistochemistry. In addition, the level of PGE2 was measured by radioimmunoassay (RIA). Bladder papilloma (100%, 8/8) was examined in rats after 24-week treatment, and bladder TCC (80%, 16/20) was found after 48-week treatment. Histopathological changes were not found in control group rats. The incidence of bladder papilloma and TCC in test group was significantly higher than that in control group (P<0.01). The mRNA levels of cPLA2, COX-2 and mPGES-1 in the bladder papilloma and TCC were significantly higher than those in normal bladder (P<0.01), while the mRNA levels of COX-1 and mPGES-2 in TCC were unchanged compared with normal bladder. Bladder TCC exhibited a substantial expression of COX-2 protein. On the contrary, normal bladder tissue barely expresses COX-2 protein. PCNA labeling index (LI) and the level of PGE2 in bladder papilloma are much higher than those in normal bladder (P<0.01), but lower than those in bladder TCC (P<0.05). In conclusion, increasing PGE2 level via cPLA2--COX-2--mPGES-1 pathway may play an important role in rat bladder carcinogenesis. PGE2 may be a biomarker for the development of bladder TCC. cPLA2 and mPGES-1 may be targets for development of novel chemoprevention strategies for bladder TCC.
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PMID:Elevated prostaglandin E2 level via cPLA2--COX-2--mPGES-1 pathway involved in bladder carcinogenesis induced by terephthalic acid-calculi in Wistar rats. 1662 93

Bladder tumors constitute a very heterogeneous disease. Superficial tumors are characterized by a high prevalence of FGFR3 mutations and chromosome 9 alterations. High-grade and muscle-invasive tumors are characterized by Tp53 mutations and aneuploidy. We have analyzed the sequence of exons 9 and 20 of PIK3CA in a panel of bladder tumors covering the whole spectrum of the disease. DNA from formalin-fixed, paraffin-embedded tumor sections was amplified by PCR and products were sequenced. In an unselected panel of tumors representative of the disease, the PIK3CA mutation prevalence was 13% (11 of 87). Mutations occurred mainly at the previously identified hotspots (codons 542, 545, 1007, and 1047). The distribution according to stage was as follows: papillary urothelial neoplasms of uncertain malignant potential (PUNLMP; 11 of 43, 25.6%), T(a) (9 of 57, 16%), T(1) (2 of 10, 20%), and muscle-invasive tumors (0 of 20, 0%; P = 0.019). Mutations were associated with low-grade tumors: grade 1 (6 of 27, 22.2%), grade 2 (3 of 23, 13%), and grade 3 (2 of 37, 5.4%; P = 0.047). Overall, PIK3CA mutations were strongly associated with FGFR3 mutations: 18 of 69 (26%) FGFR3(mut) tumors were PIK3CA(mut), versus 4 of 58 (6.9%) FGFR3(wt) tumors (P = 0.005). Our findings indicate that PIK3CA mutations are a common event that can occur early in bladder carcinogenesis and support the notion that papillary and muscle-invasive tumors arise through different molecular pathways. PIK3CA may constitute a novel diagnostic and prognostic tool, as well as a therapeutic target, in bladder cancer.
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PMID:PIK3CA mutations are an early genetic alteration associated with FGFR3 mutations in superficial papillary bladder tumors. 1688 34

Bladder and kidney cancer together account for about 5% of cancers worldwide, and represent the 9th and 14th most common cancers in terms of absolute numbers, respectively. Our knowledge of these two cancers, however, indicates that they have strikingly different etiology. A number of important occupational, lifestyle and genetic factors have been implicated in bladder carcinogenesis, which have greatly increased our understanding of this disease. In some instances, identification of these factors has contributed to the prevention or reduction of exposure to bladder carcinogens. Conversely, the etiology of kidney cancer is less well elucidated, which limits the possibilities for reducing its incidence by this approach. It is likely that much remains to be uncovered about the causes of these two cancers, and these advances will increase our appreciation of the biology of these cancers and perhaps lead to further possibilities for their prevention. In this article, we evaluate the epidemiology of bladder and kidney cancer and also discuss potential priorities for future research.
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PMID:The epidemiology of bladder and kidney cancer. 1741 53

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