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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Renal cell carcinoma remains a challenge to clinical medicine, with curative therapy experienced by a minority of patients. Mounting evidence suggests that the biological response modifiers, which consistently produce durable responses in some patients, may not need to be given in the high doses that have been associated with considerable, even fatal, toxicity; low-dose regimens in combination with conventional chemotherapeutic agents are yielding comparable, and possibly superior, results. Molecular biologic techniques have now advanced to the point where better classification schemes and prognostic variables are being elucidated, which may allow better optimization of specific treatment programs by allowing better patient discrimination. Further, with a better understanding of the molecular mechanisms of renal carcinogenesis, new agents and approaches to the problem of advanced renal cell carcinoma can be developed.
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PMID:Renal cell carcinoma. 879 53

Specific expression of the structure-specific recognition protein (SSRP) gene was investigated in rat fetal, adult, and tumor tissues using a 2.0-kb partial sequence of rat SSRP cDNA isolated from a cDNA library of rat renal cell carcinoma. The results revealed that it was rather specifically expressed in rat fetal kidney and renal cell carcinoma induced by Fenitrilotriacetate, but not in adult kidney, when various organs were tested by Northern blot analysis. In situ hybridization further demonstrated that it was located in the neoplastic cells of renal cell carcinoma and in the epithelial cells of fetal kidney but undetectable in any cells of normal adult kidney. These observations seem to imply the involvement of SSRP gene, which is believed to recognize structural alterations of DNA, in kidney development and carcinogenesis of certain types of kidney cancer.
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PMID:Expression of structure-specific recognition protein mRNA in fetal kidney and Fe-nitrilotriacetate-induced renal carcinoma in the rat. 884 83

To investigate cumulative genetic alterations during development and progression of renal cell carcinoma (RCC), we examined DNAs that were isolated from 148 RCCs for allelic imbalance (AI) at four loci on chromosome arm 3p and at 26 loci on chromosome arm 14q by using polymorphic microsatellite markers and densitometric scanning. Because the analysis of solid tumor unbalanced rearrangements remains difficult due to the large proportion of cells that infiltrate from the stroma, we developed a method for the detection and quantification of AI between control and tumor samples by using polymerase chain reaction (PCR) amplification of microsatellite markers. This technique allows detection down to 20% of contaminating cells with good accuracy. We detected AI on 3p and 14q in 57 and 28% of RCC, respectively. A comparison of genetic changes with clinicopathological data showed that, in marked contrast to AI on 3p, AI on 14q was correlated significantly with the stage and grade of the tumors, with 56 and 58% of RCC in Stage IV and Grade 4, respectively, showing AI. Our results suggest that tumor suppressor genes on 3p, including the von Hippel-Lindau gene, may be involved in early steps of carcinogenesis in clear cell carcinoma and that AI on 14q may play an important role in the progression of clear cell and papillary chromophilic cell carcinomas. Loss of heterozygosity (LOH) on 14q may be a new prognostic factor in RCC. Despite the size of the series of tumors and the number of markers used, only rearrangements that involved the whole length of the long arm of chromosome 14 were observed in the present study. The localization of the putative tumor suppressor gene on 14q will require further investigation of RCC with structural rearrangements of 14q.
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PMID:Correlations of allelic imbalance of chromosome 14 with adverse prognostic parameters in 148 renal cell carcinomas. 894 3

Renal cell carcinoma can be divided into sporadic and inheritable forms. One of the most common inheritable forms occurs in von Hippel-Lindau disease (VHL). VHL is a multisystem neoplastic disorder in which individuals develop tumors and cysts in multiple organs including the kidneys. Careful linkage analysis and cloning identified the VHL gene on chromosome 3p. In accordance with Knudson's hypothesis and tumor suppression theory, the VHL gene has been shown to have an important role in sporadic renal carcinoma as well. Further understanding of the VHL protein is likely to enhance our understanding of renal carcinogenesis, and clinical implications are beginning to evolve.
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PMID:Molecular genetics of renal cell carcinoma. 894 25

An iron chelate, ferric nitrilotriacetate (Fe-NTA), induces renal proximal tubular necrosis associated with lipid peroxidation and oxidative DNA damage that finally leads to a high incidence of renal cell carcinoma in rodents. In the present study, we investigated what kinds of C(2-12) saturated and unsaturated aldehydes and C(7-12) acyloins, metabolites of saturated aldehydes, are produced in the kidney and liver within 24 h after single i.p. administration of 15 mg Fe/kg of Fe-NTA, or after repeated (1 or 3 wk) i.p. administration of 5-10 mg Fe/kg of Fe-NTA. Amounts of twenty one aldehydes and five acyloins were determined by capillary column gas chromatography-negative-ion chemical ionization mass spectrometry with ammonia as reagent gas. Most of the aldehydes and all the acyloins measured revealed a significant dose-dependent increase 1 to 3 h after single administration in the kidney, among which 4-hydroxy-2-nonenal (HNE) showed the highest increase (27.3-fold) and malondialdehyde (MDA) was the most abundant aldehyde (2.40 nmol/100 mg wet tissue). In the liver, however, the increase in aldehydes and acyloins was less prominent. After repeated administration of Fe-NTA, only 9 aldehydes (ethanal; furfural; trans,trans-2,4-heptadienal; nonanal; trans-2,cis-6-nonadienal; HNE; decanal; trans-4,cis-4-decenal; MDA) and 4 acyloins (3-hydroxyheptan-2-one; 3-hydroxyoctan-2-one; 3-hydroxynonan-2-one; 3-hydroxydodecan-2-one) showed a significant increase. Immunohistochemistry further demonstrated an increased amount of HNE-modified and MDA-modified proteins in the renal proximal tubules after repeated Fe-NTA administration. Some of the aldehydes measured such as HNE and MDA are reportedly cytotoxic, genotoxic and mutagenic. Accumulation of these aldehydes may play a role in this renal carcinogenesis model.
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PMID:Induction of a wide range of C(2-12) aldehydes and C(7-12) acyloins in the kidney of Wistar rats after treatment with a renal carcinogen, ferric nitrilotriacetate. 903 41

In an animal model of hormone-mediated carcinogenesis, male golden Syrian hamsters develop renal carcinoma following prolonged exposure to 17beta-estradiol. The basis for the species and tissue specificity is unclear. Detailed information on the disposition of 17beta-estradiol in this model is lacking. Because catechol estrogens have been implicated in this model of carcinogenesis, we investigated the metabolism and nephrotoxicity of 17beta-estradiol in golden Syrian hamsters, with emphasis on the formation of catechol estrogen thioethers. 17beta-Estradiol (50 micromol/kg, i.p.) is a mild nephrotoxicant, causing significant elevations in the urinary excretion of gamma-glutamyl transpeptidase (gamma-GT), alkaline phosphatase, glutathione S-transferase (GST) and glucose. Increases in renal protein carbonyls and lipid hydroperoxides, which are markers of oxidative damage, also occur after administration of 17beta-estradiol (50 micromol/kg, i.p.). 17beta-Estradiol-mediated nephrotoxicity is reduced by treating animals with acivicin, an inhibitor of gamma-GT, implying that toxicity is mediated by metabolites requiring metabolism by this enzyme. Following administration of 17beta-[14C]estradiol (100 micromol/kg) to hamsters, 9.7% of the dose is recovered in bile after 5 h, the majority (7.9%) representing aqueous metabolites. Seven catechol estrogen GSH conjugates were identified, 2-hydroxy-1,4-bis-(glutathion-S-yl)-17beta-estradiol, 2-hydroxy-4-(glutathion-S-yl)-17beta-estradiol, 2-hydroxy-4-(glutathion-S-yl)-estrone, 4-hydroxy-1-(glutathion-S-yl)-estrone, 2-hydroxy-1-(glutathion-S-yl)-estrone, 4-hydroxy-1-(glutathion-S-yl)-17beta-estradiol, and 2-hydroxy-1-(glutathion-S-yl)-17beta-estradiol. At 5.4 micromol/kg of 17beta-estradiol, a dose-reflective of daily exposure levels in the hamster model of nephrocarcinogenicity, 12% of the dose is recovered within 5 h as a combination of GSH conjugates of 2- and 4-hydroxy-17beta-estradiol and 2- and 4-hydroxyestrone. In summary, oxidation of catechol estrogens, followed by GSH conjugation, occurs in vivo and 17beta-estradiol is a mild nephrotoxicant in a manner dependent on the activity of gamma-GT.
Carcinogenesis 1997 Mar
PMID:Formation of catechol estrogen glutathione conjugates and gamma-glutamyl transpeptidase-dependent nephrotoxicity of 17beta-estradiol in the golden Syrian hamster. 906 57

Renal cell carcinomas (RCC) develop as a consequence of somatic mutations of the von Hippel-Lindau (VHL) tumour suppressor gene. Recent epidemiological studies show that high and prolonged occupational exposures to trichloroethene (TRI) are associated with an increased incidence of RCC. Tumour tissues from 23 RCC patients with occupational histories of very high TRI exposure were analysed for somatic mutations within the VHL gene. DNA was isolated from microdissected tumour cells, amplified by polymerase chain reaction (PCR), and analysed in single strand conformation polymorphism (SSCP) and sequencing. RCC tissues of all 23 TRI exposed persons analysed thus far showed aberrations of the VHL gene, with 30% having aberrations in exon 1, 44% in exon 2, and 26% in exon 3. By comparison to much lower reported VHL mutation frequencies of 33-55% in TRI-unexposed RCC patients, these results indicate a specifically high mutation frequency at the VHL gene in TRI-exposed RCC patients; four of these aberrations have thus far been confirmed as VHL mutations by sequence analysis. This finding indicates the VHL gene being a susceptible and specific target in TRI induced renal carcinogenesis. Furthermore, the frequent involvement of exon 2 identifies potential 'hot spots' for this carcinogen. In addition to the available epidemiological studies the results are now further proof for human renal carcinogenicity induced by high occupational exposures to TRI.
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PMID:Renal cell carcinomas in trichloroethene (TRI) exposed persons are associated with somatic mutations in the von Hippel-Lindau (VHL) tumour suppressor gene. 913 12

The proto-oncogene c-met encodes a transmembrane tyrosine kinase receptor for hepatocyte growth factor and is expressed in normal kidney tissue. This receptor may be involved in the carcinogenesis of various organs. The aim of this study was to investigate the relationship between c-met immunohistochemical expression and pathological tumor variables in human renal cell carcinomas (RCCs) and adenomas (RAs). Formalin fixed, paraffin embedded tissues from 35 RCCs, 16 RAs and 17 normal kidneys were immunostained (Strept. ABC/HRP) with a polyclonal antibody against c-met protein (Santa Cruz, Clone C-12). The statistical analysis was performed using the linear trend in proportions and Fisher's exact test. C-met protein was detected in the cytoplasm and the plasma membranes of neoplastic cells in 19/35 RCCs (54%), 10/16 adenomas (63%) (p = 0.41) and in 17/17 controls in the epithelial cells of distal renal tubules and collecting ducts. C-met protein expression was not related with gender (p = 0.45), age (p = 0.18), tumor size (p = 0.99), cell type (p = 0.26), grade (p = 0.86) and stage (p = 0.33). Moreover, c-met immunopositive tumor cell percentage and intensity were increased in stage [RCCs, but these results were not statistically significant. Apart from glandular differentiation, c-met protein expression was not related to other histopathological features (i.e. to the type of cells or to any selective overexpression in tumor cells). C-met product may be involved in the malignant transformation of tubular epithelial cells as an early event in RCC carcinogenesis. C-met expression does not seem to have any prognostic significance for RCCs, as it was not associated with any pathological prognosticator.
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PMID:Immunodetection of c-met-oncogene's protein product in renal cell neoplasia. 925 56

The FHIT (fragile histidine triad) gene has been isolated from the chromosome region 3p14.2, which includes the fragile site locus FRA3B and the breakpoint of the t(3;8) of familial renal carcinoma. FHIT has been suggested to be a candidate tumor suppressor gene for digestive tract carcinomas. To evaluate the significance of FHIT gene abnormalities in gastric carcinogenesis, we examined the allelic status and transcripts of the gene in 23 primary gastric carcinomas as well as 7 gastric carcinoma cell lines. Four of the seven (57%) cell lines exhibited homozygous deletions of variable sizes at 3p14.2 all of which included D3S1300, which is located close to, or within, FRA3B. However, only 2 of 16 (13%) informative cases showed loss of heterozygosity at D3S1300 in the primary tumors. Direct analysis by reverse transcriptase polymerase chain reaction failed to reveal abnormal transcripts, including exon skipping and sequence changes, in the primary tumors or in the cell lines without homozygous deletions. These results suggest that FHIT gene abnormalities are infrequent in primary gastric carcinomas and that the frequent homozygous deletions seen in cell lines might simply reflect the plasticity of the genome at FRA3B under culture conditions.
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PMID:Analysis of the fragile histidine triad gene in primary gastric carcinomas and gastric carcinoma cell lines. 929 Sep 61

The aim of this study was to investigate the relationship between chromosome aberrations detected by fluorescence in situ hybridization (FISH) and tumor grade, stage, venous involvement, and DNA ploidy status in 18 renal tumors. Using FISH with chromosome-specific DNA probes, the copy number of pericentromeric sequences on chromosomes 3, 7, 9, and 17 was detected within interphase nuclei in touch preparations from tumor specimens. Monosomy for chromosome 3 was detected in seven of 9 DNA diploid tumors, whereas all DNA aneuploid tumors demonstrated trisomy or tetrasomy for chromosome 7. Moreover, monosomy for chromosome 3 was more frequently shown in the diploid and low-stage tumors than in the aneuploid and high-stage tumors. The percentage of hyperdiploid cells significantly correlated with DNA ploidy status in the case of chromosomes 3 and 7 (p = 0.030, p = 0.007, respectively). The percentage of hyperdiploid cells for chromosome 3 had borderline significance with tumor stage. On the other hand, the percentage of diploid cells for chromosome 17 was significantly correlated with DNA ploidy status and tumor stage (p = 0.030, p = 0.027, respectively). Moreover, the percentage of diploid cells for chromosome 7 in renal cell carcinoma (RCC) with venous involvement was significantly lower than those without venous involvement (p = 0.023). These results suggest that the incidence of chromosomal aberrations detected by FISH is more frequent than the chromosomal aneuploidy reported previously by conventional cytogenetics. Therefore, loss of chromosome 3 may be associated with an early event in RCC carcinogenesis. Gain of chromosomes 3 and 7 is correlated with tumor progression as well as gain and loss of chromosome 17. Study of the chromosomal aberrations may provide a greater understanding of tumor carcinogenesis and progression in RCC.
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PMID:Chromosome aberrations in renal tumors detected by fluorescence in situ hybridization. 935 94


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