Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0007138 (transitional cell carcinoma)
 3,949 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this investigation the profile of p53 and epidermal growth factor receptor (EGFR) expression in tumour tissue biopsies of transitional cell carcinoma of bladder (TCC) and of oral-pharyngeal carcinoma (OP) were compared using an immunocytochemical staining method. In addition, various techniques including sodium dodecyl sulphate-polyacrylamide gel elecrophoresis (SDS-PAGE), colorimetric assay and gene transfection were used to investigate the influence of p53 on the behaviour of human tumour cell lines in vitro. The results showed that: (a) p53 was detectable in more than 45% of cases in both tumour types, although the profile and intensity of expression differed. (b) Concomitant strong expression of EGFR and p53 for TCC and OP was 21% and 38% (P>0.05%), respectively. (c) Treatment of tumour cells by either gamma radiation or by cisplatin resulted in the induction of p53 independent of the origin of the tumour. (d) Susceptibility of two cell lines, one with and one without constitutive expression of p53 showed that the expressing cells were more sensitive to gamma radiation (the percentage inhibition at 250 cGy was 57% versus -15%, P<0.01), and also cisplatin (the percentage inhibition at 1 microgram/ml was 71.0+/-6.0 versus 2.6+/-7.0, P<0.001). (e) Transfection of wild-type TP53 gene into a bladder tumour cell line resulted in a rapid cell apoptosis (by as much as 90%) whereas cells receiving mutated TP53 survived. A similar frequency of TP53 mutation in TCCs and OPs was observed. In addition, the pattern of p53 expression within the squamous type of TCC was similar to that in OPs. If the data from the in vitro studies could be translated into an in vivo setting, one could envisage a situation where the introduction of wild-type TP53 gene by gene transfection into tumour cells (independent of their TP53 gene mutational status), would prove to be beneficial. If the cellular TP53 gene is mutated, then an introduction of the normal TP53 gene would induce cells to undergo apoptosis. Alternatively, if TP53 is wild-type, then the increased levels of p53 expression would enable the cells to become more susceptible to DNA damaging treatments such as cisplatin or gamma radiation.
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PMID:Profile of p53 expression in bladder and oral tumours. Effects of in vitro manipulations of p53 on the behaviour of established human tumour cell lines. 1097 34

Transitional cell carcinoma (TCC), a neoplasm of urinary bladder urothelial cells, generally appears in either of two forms, papillary non-invasive or invasive TCC, although intermediate forms can occur. Each has a distinctive morphology and clinical course. Altered expression of the p53 and pRb genes has been associated with the more serious invasive TCC, suggesting that the loss of activity of these tumor suppressor proteins may have a causal role in this disease. To test this hypothesis directly, transgenic mice were developed that expressed the simian virus 40 large T antigen (TAg) in urothelial cells under the control of the cytokeratin 19 gene (CK19) regulatory elements. In one CK19-TAg lineage, all transgenic mice developed highly invasive bladder neoplasms that resembled invasive human bladder TCCs. Stages of disease progression included development of carcinoma in situ, stromal invasion, muscle invasion, rapid growth, and, in 20% of affected mice, intravascular lung metastasis. Papillary lesions never were observed. Western blot analysis indicated that TAg was bound to both p53 and pRb, which has been shown to cause inactivation of these proteins. Our findings support suggestions that (i) inactivation of p53 and/or pRb constitutes a causal step in the etiology of invasive TCC, (ii) papillary and invasive TCC may have different molecular causes, and (iii) carcinoma in situ can represent an early stage in the progression to invasive TCC.
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PMID:Highly invasive transitional cell carcinoma of the bladder in a simian virus 40 T-antigen transgenic mouse model. 1098 Jan 20

Biological markers that are predictive of recurrence and progression of superficial bladder tumors must provide additional information to that provided by multiplicity, size and grade. Field anomalies in normal appearing urothelium of patients with papillary superficial transitional cell carcinoma have been associated with tumor antigens and chromosome 9 deletions. Also, primary tumors with chromosome 9 deletions are associated with a higher risk of recurrence. Abnormal expression of p53, p21 and Ki-67 cell cycle markers have little predictive value for recurrence. However, p53 overexpression or mutation and decreased expression of p27 are associated with cancer progression and survival. New markers, such as mutations in the fibroblast growth factor receptor 3 gene (found in 30% of tumors), anomalies of the PTEN gene and vascular endothelial growth factor expression, may have potential and require further evaluation. Molecular fingerprints of superficial tumors with distinct clinical behavior are being rapidly unravelled. Large-scale clinical studies are urgently needed to provide supportive evidence for their incorporation in clinical management.
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PMID:Can biological markers predict recurrence and progression of superficial bladder cancer? 1100 49

A very small quantity of DNA was extracted from paraffin sections of 25 bladder and 2 ureteral cancer cases, and exons 5-8 of the p53 gene were amplified by the polymerase chain reaction. Mutations were detected by direct sequencing, and their relationships to clinicopathological factors were assessed. Point mutations of the p53 gene were observed in 2 of 27 specimens of transitional cell carcinoma. One was a novel nonsense mutation. The prognosis of patients with p53 gene mutations was poorer than those of patients without mutations. Analysis of the data showed that assessment of the potential malignancy of bladder cancer, combined with a conventional pathological diagnosis, allows a more precise prognosis. Direct sequencing of tissue specimens enables swift prognostic evaluation and prompt decisions concerning treatment.
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PMID:Mutation analysis of the p53 tumor suppressor gene using paraffin-embedded specimens of human transitional cell carcinomas by the direct sequencing method. 1112 10

The global genomic repair of DNA adducts was examined in human papillary transitional cell carcinoma (TCC) cell lines after exposure to N:-hydroxy-4-acetylaminobiphenyl (N-OH-AABP), the proximate carcinogenic metabolite of the human bladder carcinogen 4-aminobiphenyl (ABP). (32)P-post-labeling analysis of TCC cultures exposed to N-OH-AABP revealed a major adduct, identified as the 3',5'-bisphosphate derivative of N-(deoxyguanosin-8-yl)-4-aminobiphenyl (dG-C8-ABP). The amount of adduct formation in TCC10 was dependent upon the dose and the duration of exposure and ranged between 1 and 5 adducts/10(7) nucleotides. To test if p53 regulates repair of the dG-C8-ABP adduct in genomic DNA, an isogeneic set of cell lines was obtained by infection of the TCC10 cultures with a retroviral construct expressing a trans-dominant mutant of p53, namely a Val-->Ala mutation at codon 143. The TDM143-TCC10 line expressing the mutant form of p53 was selected. The rate of repair of dG-C8-ABP was compared between TCC10 and TDM143-TCC10 cultures after treatment with 15 microM N-OH-AABP. The rate of disappearance of the adduct was monitored over a period of time after chemical treatment. (32)P-post-labeling analysis of dG-C8-ABP in parental TCC10 showed its rapid removal, the majority of adducts disappearing within 48 h. In contrast to TCC10, TDM143-TCC10 was relatively slower in removal of dG-C8-ABP. After 24 h DNA repair TDM143-TCC10 showed an approximately 3-fold greater amount of dG-C8-ABP compared with TCC10. These results imply that p53 plays a role in the repair of ABP adducts and that in p53 null cells the unrepaired DNA damage could cause accumulation of mutations, which might contribute to increased genomic instability and neoplastic progression.
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PMID:Role of TP53 in repair of N-(deoxyguanosin-8-yl)-4-aminobiphenyl adducts in human transitional cell carcinoma of the urinary bladder. 1115 53

Normal cell proliferation is closely regulated by proteins called cyclins. One of these, cyclin D1, in combination with its corresponding cyclin-dependent kinase (cdk), is essential for G(1)/S phase transition. Cyclin/cdk complexes are generally inhibited by cyclin-dependent kinase inhibitors(ckis), some of which are induced by wild-type p53. The aims of this study were: to investigate levels of cyclin D1 expression in transitional cell carcinoma (TCC) of the bladder; to correlate these results with data concerning the expression of p53, waf1, pRb and Ki67; and to determine whether cyclin D1 expression could predict clinical outcome. Paraffin-sections from 150 newly diagnosed bladder tumours (Ta/T1 = 97; T2-T4 = 53) were stained for cyclin D1 using immunohistochemistry and a cyclin D1 index assigned. These results were correlated with data relating to the expression of p53 and waf1 by the same tumours. A representative subset of 54 tumours (Ta/T1 = 28; T2-T4 = 26) was also stained for Ki67 and 55 were stained for pRb. The clinical course of each patient was recorded and multivariate analyses of risk factors for tumour recurrence, stage progression and overall survival were performed. Positive staining for cyclin D1 was found in 83% of tumours. The staining pattern varied between tumours with nuclear, cytoplasmic or a combination of the two evident in different tumours. 89% of Ta/T1 and 74% of T2-T4 tumours showed nuclear staining with or without cytoplasmic staining. The median value for cyclin D1 staining was significantly higher in Ta/T1 tumours (41%) compared with T2-T4 tumours (8%, P< 0.005) with 26% of muscle-invasive tumours demonstrating absent staining. In addition, the median value for cyclin D1 staining was significantly higher in G1/G2 tumours (43%) compared with G3 tumours (14%, P< 0.005). There was a significant positive correlation between expression of cyclin D1 and waf1 expression (P< 0.0001) as well as pRb expression but not between cyclin D1 expression and expression of p53. Ki67 expression was significantly associated with increasing tumour stage (P< 0.005) and histological grade (P< 0.05) but did not correlate with cyclin D1 expression. A cyclin D1 index > or = 8% was associated with significantly better survival in those patients with muscle-invasive disease (T2-T4). In addition, there was a significantly higher progression rate for those patients with Ta/T1 disease whose tumours demonstrated cytoplasmic cyclin D1 staining. These results indicate that cyclin D1 expression is significantly higher in low-stage, well differentiated bladder tumours and strongly correlates with waf1 expression. In a multivariate analysis, cyclin D1 expression is an independent prognostic indicator of survival in those patients with muscle-invasive disease.
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PMID:Cyclin D1 expression in transitional cell carcinoma of the bladder: correlation with p53, waf1, pRb and Ki67. 1116 87

The expression of p27(Kip1), a negative regulator of the cell cycle, has been reported to correlate with the biological behavior and prognosis of several tumors. However, its prognostic importance in transitional cell carcinoma of the upper urinary tract (TCC-UUT) has not previously been investigated. We investigated p27(Kip1) protein expression using immunohistochemistry in 132 cases of TCC-UUT and also its relation to proliferating cell nuclear antigen (PCNA) immunoreactivity, p53 oncoprotein immunoreactivity, clinicopathologic parameters, and clinical outcome. A positive expression of p27(Kip1) protein was recognized in 94.7% of the samples and was apparent within tumor nuclei. In the normal urothelium, its expression was identified in all cell layers. A positive expression of p53 oncoprotein was recognized in 27.2% of the patients. The PCNA index was 7.4 to 93.1% (mean, 66.4%). Examination of the relationships between the expression of p27(Kip1) protein and clinicopathologic findings, PCNA index, and the expression of p53 oncoprotein revealed that the expression of p27(Kip1) protein decreased significantly with stage and grade. In a univariate analysis of disease-free and overall survival rates, no correlation was found between the expression of p27(Kip1) protein and prognosis. The expression of p27(Kip1) protein appears to be of little or no value in informing the prognosis in TCC-UUT.
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PMID:Expression of p27(Kip1) protein in transitional cell carcinoma of the upper urinary tract. 1135 44

Altered p53 expression has been demonstrated in the majority of advanced transitional cell carcinoma (TCC) of the bladder tumors. The objective of this investigation was to examine the effect of the introduction of a p53 or p21((WAF1/CIP1)) adenovirus on the proliferation and apoptosis of various human TCC cell lines in vitro and in vivo. Proliferation was measured by 3H-thymidine incorporation. Apoptosis was measured by DNA fragmentation and bax expression. We also examined the effect of ex vivo introduction of the p21((WAF1/CIP1)) or the p53 gene on growth of the T24 TCC cells and UMUC-3 TCC cells introduced subcutaneously into athymic nude mice. We found that although the effect of the p21-adenovirus on the proliferation of various TCC lines varied with each individual cell line, there was a substantial growth inhibition observed (greater than 80% growth inhibition) in seven of the eight TCC cell lines at the highest viral dosage. In contrast, after 24 h, the highest dosage of the p53-adenovirus produced only a heterogeneous decrease in proliferation compared to the highest dose of the p21((WAF1/CIP1))-adenovirus (40-90%). In ex vivo experiments, no tumors were found in nude mice injected subcutaneously with either TCC cell line exposed in vitro to the AdSCMV-p21((WAF1/CIP1)) or AdSCMV-p53 viruses before three weeks. There was a threefold decrease in tumor square area at week 5 in the Ad5CMV-p21((WAF1/CIP1)) or Ad5CMV-p53 TCC cells injected mice (p<0.001, p<0.009) compared to either mock or Ad5CMVLacZ TCC bladder tumor cells. These data suggest that significant portion of the effect of altered p53 on TCC phenotype may be mediated through the p21((WAF1/CIP1)) pathway. Thus, the restoration of p21((WAF1/CIP1)) function in this tumor system may be a beneficial therapeutic strategy.
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PMID:Growth inhibitory effect of p21 and p53 containing adenoviruses on transitional cell carcinoma cell lines in vitro and in vivo. 1141 22

The transformation of a normal into a malignant cell is a multistep mechanism, which involves various alterations on the molecular and genetic level. These molecular alterations occur spontaneously or are induced by carcinogens (e.g. naphthylamine--a component of cigarette smoke and one of the most important carcinogens leading to bladder tumor carcinogenesis). This report summarizes some of the most important molecular and genetic alterations in bladder cancer. As in most other malignancies the generation of bladder cancer is caused by the accumulation of various molecular changes. The expression of oncogenes (ras, erbB-2 and EGF receptor), tumor-suppressor genes (Rb, p53), cell-cycle genes (p15, p16) and DNA-repair genes is altered mostly by mutation or chromosomal aberration. Loss of heterozygosity of chromosome 9p and 9q has been shown to be a crucial event in the transition of normal urothelium to papillary transitional cell carcinoma while p53 is primarily involved in the development of carcinoma in situ.
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PMID:Bladder cancer. I. Molecular and genetic basis of carcinogenesis. 1146 28

Nephrourete-rectomy with excision of a bladder cuff has been the standard treatment of the upper urinary tract transitional cell carcinoma. The very indolent behavior (GI, II, Ta, T1) of more than 50% and up to 82% of the upper urinary tract tumors treated with nephroureterectomy in different series in conjunction with the advent of sophisticated endourological techniques have permitted in certain cases alternative treatments using a conservative approach with either ureteropyeloscopy or percutaneous access. Ureteroscopy is reserved for ureteral tumors and small, simple tumors of the renal pelvis (< 1.5 cm) while large or multiple tumors of the renal pelvis are approached in a percutaneous way. During 14 years 64 patients with transitional cell carcinoma of the upper urinary tract were treated percutaneously at our department at Long Island Jewish Medical Center, 15 (23.5%) with grade I, 26 (40.6%) with grade II and 23 (35.9%) with grade III and IV. After a mean follow-up of 51 months, percutaneously treated patients had a tumor specific survival of 85.6%, being 100% for GI tumors, 96.1% for GII and 60.8% for GIII. Recurrence of grade I tumors were observed in 20%, 26.9% for grade II and 56.5% for Grade III. In conclusion, with a rigorous follow-up transitional cell carcinoma of the upper tract with low and moderate grades (GI, GII, Ta, T1) can be treated endorologically even in the presence of a normal contralateral kidney with low morbility and a long term efficiency comparable to a nephroureterectomy. An elective endorologic management for GIII tumors is not recommended. Endoscopic conservative surgery can be offered when the criteria of good prognosis are found for Ta (such as absence of carcinoma in situ, presence of diploidy, low p53 expression and a single tumor) and in the cases of a solitary kidney or chronic renal insufficiency or for poor surgical candidates for T1. Patients with stage T2-T3 should be offered a nephroureterectomy.
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PMID:[Endourologic treatment of transitional cell carcinoma of the upper urinary tract]. 1151 26


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