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Query: UMLS:C0005684 (bladder cancer)
 16,431 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This report concerns the study of Ha-ras gene mutations and ras p21 expression in primary tumors of the urinary bladder. Polymerase chain reaction-based techniques and computerized image analysis were used. The data obtained were related to tumor grade, DNA ploidy, and tumor invasion. A point mutation (G-->T) at Ha-ras codon 12 was found in 30 of 67 tumors. The mutation frequency was greater in grade III (65%) than in grade II (44%) tumors; no mutations were observed in grade I tumors. The mutation was observed more often in aneuploid (58%) than in diploid (28%) tumors. No other substitution at codon 12 was seen and no codon 61 mutation was detected. The tumors were also tested for the A-->G mutation at position 2719 of Ha-ras intron D. Concurrent codon 12 and intron D mutations were identified in seven high-grade aneuploid tumors; six were invasive. The levels of the ras gene product p21 were approximately 10 times higher in tumors with intron D mutation than in those without. These findings confirm on human bladder tumors the observations of the effect of synchronous exon-intron mutations reported on the bladder cancer cell line T24. Our results are the first demonstration of Ha-ras intron D alterations in human tumor tissues and suggest that concurrent mutations at codon 12 and intron D of this gene within the same tumor may contribute to the aggressive behavior of human bladder carcinomas.
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PMID:Concurrent mutations of coding and regulatory sequences of the Ha-ras gene in urinary bladder carcinomas. 142 48

This paper represents the first report of a codon 59 mutation in Ki-ras from a spontaneous human transitional cell carcinoma of the bladder. Point mutations have the potential to activate the ras genes if they occur in critical coding regions. These include the sequences of codons 12, 13, 59, 61 and 63. Mutations in codons 12, 13 and 61 have been reported in a wide variety of human cancers, including transitional cell carcinoma of the bladder. However mutations in codon 59 have been reported only in retroviral Ki-ras and as a result of in vitro mutagenesis experiments. We have used the polymerase chain reaction and direct sequencing to detect mutations of Ki-ras, and allele-specific restriction analysis to detect mutations of N-ras in xenografts and continuous cell lines established from bladder cancer biopsies of ten different patients as well as in direct biopsy specimens from five human bladder tumours. For studies of Ki-ras, a 139 bp fragment which spanned the critical codons 12 and 13 and a 128 bp fragment that spanned the sequences of codon 59, 61 and 63 were enzymatically amplified and then sequenced. No N-ras mutations were detected. A heterozygous mutation of Ki-ras at codon 59 GCA----G/ACA was detected in one line. This mutation is being expressed and appears stable as it was detected over several xenograft passages and was present in paraffin-embedded tissue from the primary tumour of the patient. The biological significance of the mutation in bladder cancer is currently under study.
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PMID:Detection of a rare point mutation in Ki-ras of a human bladder cancer xenograft by polymerase chain reaction and direct sequencing. 155 89

Recent studies have provided the first clues as to the molecular mechanisms responsible for bladder carcinogenesis. Cytogenetic and molecular studies have demonstrated nonrandom changes of chromosomes 1, 5, 7, 9, 11, and 17. The finding of monosomy of chromosome 9 in early noninvasive lesions has initiated a search for a bladder-specific gene responsible for bladder oncogenesis. Activation of ras and erbB oncogenes has been reported, although the role that these changes play in bladder cancer is not yet understood. Inactivation of two well-characterized tumor suppressor genes, p53 and Rb, also appears to be important in the pathogenesis of bladder cancer, and evidence suggests that inactivation of p53 correlates with the acquisition by bladder cancer cells of the invasive phenotype. Although the picture is far from complete, it is clear that for the first time an understanding of the molecular events responsible for bladder cancer is possible, and that this information will have clinical impact on patients in the near future.
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PMID:Molecular biology of bladder cancer. 155 51

Farnesylation is a key maturation step involved in the ras-dependent transformation of cells. This acylation step is catalyzed by protein: farnesyltransferase, a soluble enzyme. The present work describes the use of a new HPLC method of measurement of this enzymatic activity using the K-ras-derived CVIM tetrapeptide as substrate. The method is used to check the activity catalyzed by cytosols issued from various types of cancer cells. J82, a human bladder cancer cell line was retained for measurement of the inhibitory potency of a few peptide sequences and will be used as starting biological material for the purification of the enzyme. This HPLC method presented herein has the main advantages over other published methods of being automatisable and versatile, because it can be used with a wide spectrum of peptide substrates. Results presented herein are only first studies and need some more structural observations. The obtention of the cancer cell line-derived, partially purified farnesyltransferase will hopefully lead us to the discovery of specific inhibitors with potential non-cytotoxic anti-cancer activities.
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PMID:[Farnesyltransferase as target for non-cytotoxic anti-cancer agents: first steps]. 180 89

Recent studies have shown that orthotopic (transurethral) transplantation of human bladder cancer cell lines into nude mice permits tumor growth that more accurately reflects their clinical malignant status in the original host. We have previously demonstrated that transfection and overexpression of normal or mutated c-Ha-ras genes into a noninvasive human papillary transitional cell carcinoma cell line confer upon these cells an invasive phenotype in vivo with behavior remarkably similar to the clinical behavior of high grade bladder carcinomas. Since elevated expression levels of the epidermal growth factor receptor (EGF-R), in addition to that of c-Ha-ras, have been correlated with transitional cell carcinoma progression, we sought to determine whether up-regulation of the EGF-R had occurred in the invasive high ras expressors and if so, what functional significance this might have. Our results show that invasive cell lines which overexpress the c-Ha-ras gene also have increased epidermal EGF-R expression. This was found to occur at both the protein and mRNA levels, and analysis of the EGF-R promoter/enhancer sequences has revealed a putative AP-1 site which may possibly enhancer sequences has revealed a putative AP-1 site which may possibly serve as a ras response element. In addition, we found that the cells overexpressing the EGF-R had acquired a positive sensitivity to the stimulatory mitogenic effects of EGF. Hence, the results obtained suggest a role for either a normal or a mutated overexpressing Ha-ras in up-regulating the surface EGF-R, possibly through an AP-1 site during human bladder carcinoma progression; they also highlight the potential that EGF may have in cooperating with this EGF-R up-regulation to help mediate enhanced tumor growth.
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PMID:Ha-ras induction of the invasive phenotype results in up-regulation of epidermal growth factor receptors and altered responsiveness to epidermal growth factor in human papillary transitional cell carcinoma cells. 186 71

Point mutations of c-ras genes at codons 12, 13 and 61 were analyzed in 26 cases of bladder cancer and 16 cases of kidney cancer. DNA prepared from either frozen tissues or 10% formalin-fixed, paraffin-embedded tissues were amplified by means of polymerase chain reaction methods, and mutations were analyzed by dot blot hybridization assays with oligonucleotide probes. In three cases of bladder cancer c-ras mutations were found, at codons 13 and 61 of c-Ha-ras and at codon 61 of c-Ki-ras, while no mutation was found in kidney cancer. No mutation was found in normal bladder epithelial tissues from the same patients. Our findings, taken together, may indicate relative scarcity of c-ras mutations in these types of human cancer. The results of dot blot hybridization assays and DNA sequencing showed a G-to-C transition of the first nucleotide at codon 13 c-Ha-ras. This is the first time that such a point mutation has been detected in human cancer tissues.
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PMID:Point mutations of c-ras genes in human bladder cancer and kidney cancer. 210 44

Over the past several years, many tumor markers, including cell surface antigens, T-antigen, ras p55, and ras p52 proteins, have been studied as potential tumor markers of bladder cancer. The lack of specificity and inconsistency of these markers led us to develop a new method for studying the urinary excretion of autocrine motility factor (uAMF) and tumor cell collagenase stimulating factor (TCSF) in 24-hour and first morning voided specimens. AMF is a glycoprotein secreted by the malignant cells and is responsible for cell locomotion, a key event in invasion and metastases of the malignant cells. TCSF is a membrane bound glycoprotein of tumor cells that stimulates fibroblast collagenase production. We have utilized an enzyme-linked immunoabsorption assay to detect the levels of uAMF and TCSF in urine samples collected from normal volunteers, patients with benign diseases, and patients with bladder cancer. Our data indicate that urinary concentrations of uAMF and TCSF are elevated in patients with bladder cancer. Furthermore, the levels of uAMF and TCSF are more elevated in invasive tumors as compared with benign counterparts. We have localized uAMF and TCSF in bladder cancer cells, utilizing immunohistologic techniques.
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PMID:A new method for evaluation of urinary autocrine motility factor and tumor cell collagenase stimulating factor as markers for urinary tract cancers. 212 27

Numerous studies have shown that intact cancer cells and cell extracts have the capacity to lyse erythrocytes in vitro. The transformation of NIH-3T3 fibroblasts by ras oncogenes has recently been demonstrated to result in tumour cells releasing a haemolytic factor. The purpose of this study has been to purify and further characterise the soluble tumour haemolytic factor (sTHF) produced by mouse fibroblasts transformed by T24 human bladder cancer DNA and by the cloned Harvey murine sarcoma viral oncogene. To this end, transformed fibroblasts were cultivated in serum-free medium. The cell-free supernatant was treated with ammonium sulphate and the precipitate achieved at 60-100% saturation was dialysed and applied to a gel filtration column. A haemolytic factor was eluted with an Mr between 65,000 and 75,000. Zinc chelate and strong anion exchange column chromatography resulted in greater than 3,000-fold enrichment of sTHF. SDS-PAGE of sTHF resulted in a single protein band of 66,000 Da. Soluble THF had no immunological cross-reactivity with known cytokines produced by lymphocytes and macrophages. The pathophysiological role of sTHF in cancer remains to be determined.
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PMID:Purification and characterisation of soluble tumour haemolytic factor isolated from oncogene transformed fibroblasts. 220 21

Clinical studies of human bladder cancer cells with mouse monoclonal antibodies (mAbs) have revealed two surface glycoproteins (T43 and T138) expressed by aggressive cancers and not by normal cells and a differentiation antigen (T16) expressed by normal and tumor cells of urothelial origin (Y. Fradet et al., Proc. Natl. Acad. Sci. USA, 81: 224-228, 1984; Y. Fradet et al. Cancer Res., 46: 5183-5188, 1986). To investigate further the possible association of these antigenic phenotypes with growth advantage of tumor cells, their expression, according to phases of the cell cycle and growth states (exponential and plateau phase) was studied in the human bladder carcinoma cell line T24. Expression of the p21 ras oncogene product, the Thomsen-Friedenreich antigen and the HLA class I antigen were also studied with mAbs. Multiparameter flow cytometry was used to determine antigen expression and DNA content of cells stained with mAbs and propidium iodide. Two antigens, T16 and T43, showed marked variations of their expression according to the growth status of the cells, although with an inverse profile. T16 was expressed on resting cells up to 12.5 times more than on exponentially growing cells. Conversely, T43 expression increased by a factor of 4.5 on actively proliferating cells. However, there was no preferential expression of either antigen in any one phase of the cell cycle. None of the other antigens studied, including the p21 protein, showed any density variation with either cell cycle or growth states. The results of these studies suggest that T43 may be associated with a growth advantage of tumor cells and that T16 has the characteristics of a differentiation antigen whose expression is induced on resting cells. These findings may have implications for the potential clinical use of these mAbs.
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PMID:Growth-regulated surface glycoproteins of human bladder cancer. 240 38

We examined the effect of 60Co irradiation on the clonogenic survival of rat NRK cells, NRK cells carrying a temperature-sensitive viral K-ras oncogene (tsK-NRK), mouse NIH 3T3 cells, and NIH 3T3 cells transformed with the human bladder cancer (T24) H-ras oncogene (PAP2). We tested the hypothesis that ras oncogene expression renders cells more resistant to radiation, but found in both systems that ras-transformed cells were more, not less, sensitive to radiation. We also found indications of altered repair of sublethal radiation damage. PAP2 cells were more sensitive to radiation than NIH 3T3 cells. Increased sensitivity was reflected in a decreased shoulder region of the survival curve with little effect on its slope (D0). TsK-NRK cells were also slightly more sensitive to radiation than NRK and exhibited decreased repair of sublethal damage at both the permissive and nonpermissive temperatures. Thus, we found that expression of ras oncogenes is not always associated with increased radiation resistance. In summary, our results suggest that (1) ras oncogene expression in some cells may be associated with increased, rather than decreased, radiation sensitivity, and (2) ras oncogene expression may alter the shoulder region of the dose response curve, suggesting changes in the repair of sublethal radiation damage.
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PMID:Some ras-transformed cells have increased radiosensitivity and decreased repair of sublethal radiation damage. 240 58


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