Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0005684 (bladder cancer)
 16,431 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have measured the product of the ras oncogene, ras p21, in random un-timed urine samples using an immunoblotting method which relies upon enhanced chemiluminescence for visualisation of the nitrocellulose filter. Urine samples were analysed from groups of patients with prostate (n = 10) or bladder (n = 25) cancer and a control group (n = 30) with no apparent urological disease. The mean concentration of urinary ras p21 in the groups with either bladder or prostate cancer was not significantly higher than that of the control group. The most striking difference between the control and clinical groups was the presence of a previously un-reported ras p21 "doublet" in the electrophoretic patterns obtained from 20% of the bladder cancer group and 10% of the prostate cancer group. This doublet was not present in any of the control samples analysed. This doublet is strongly suggestive of a mutation within the ras oncogene.
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PMID:Measurement of ras p21 in the urine of patients with urological tumours. 777 39

In this study we used the subrenal capsule site of C57BL/6J mice to assess the tumorigenic and metastatic potential of established urothelial cell lines in a syngeneic murine model. High tumor take and subsequent removal of the primary tumor by nephrectomy resulted in the extended lifespan of the animals enabling the formation of secondary tumor growth. To test this model we have used a panel of cell lines expressing constitutively, or following transfection, ras oncogene products. All cell lines constitutively expressing ras oncogenes (K, H, or N-ras) were tumorigenic and metastatic in this assay. One non tumorigenic cell line (BBN3) and one tumorigenic but non-metastatic cell line (SH264), remained non-metastatic following transfection with the pSV2-neo gene but formed micrometastases in the lung when a ras oncogene was introduced in the same manner. Expression of altered ras proteins following transfection in these two cell lines was demonstrated using an H-ras specific antibody in Western blot analysis. This study demonstrates the value of the subrenal capsule site as a metastatic assay for bladder cancer and the potential involvement of ras oncogenes in urothelial cell metastasis.
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PMID:[Urothelial cancer metastases after implantation of tumor cells under the kidney capsule]. 837 44

A central issue in tumor biology is the understanding of the interactions between tumor cells and their environment. Using normal and ras oncogene transfected rat fibroblast cells, we now demonstrate that the transfected cells make altered extracellular matrices (ECM) and that their resulting ECM influence the proliferation and genetic regulation of human bladder cancer EJ cells. Using Western blot analyses, we observed that the ras transfected fibroblast cells lacked the ability to produce extracellular matrix component laminin whereas the normal parental fibroblast cells were able to produce intact laminin. Both transfected and nontransfected fibroblast cells were able to synthesize other extracellular matrix molecules such as type IV collagen and fibronectin. Human bladder tumor EJ cells were grown on ECM derived from normal and transfected rat fibroblast cells, and the proliferation rate and type IV collagen mRNA expression of EJ cells were determined. We observed that EJ cells, when grown on ECM derived from the ras transfected fibroblast cells, had a higher growth rate than when grown on ECM derived from the normal fibroblast cells (P < 0.037). Furthermore, EJ cells grown on ECM derived from transfected fibroblast cells showed up-regulation of type IV collagen mRNA expression when compared with EJ cells grown on ECM derived from nontransfected fibroblast cells. Finally EJ cells grown on purified laminin but not on collagen IV coated flasks showed the same level of type IV collagen mRNA expression as when grown on ECM derived from nontransfected parental fibroblast cells. Haptotactic/motility assays with EJ cells and ECM derived from ras transfected and nontransfected fibroblast cells demonstrated that ECM of ras transfected fibroblast cells, but not the parental fibroblast cells, provided a permissive or fertile soil for EJ tumor cell invasion. Finally, two-dimensional gel electrophoresis of 35S-labeled nuclear matrix proteins of EJ cells cultured on ECM derived from ras transfected fibroblast cells revealed expression of proteins in the molecular weight range of M(r) 35,000-45,000 and isoelectric focusing pH range of 5.5 to 6.0. These proteins were not present in EJ cells cultured on ECM derived from parental nontransfected fibroblast cells. We conclude that extracellular matrices derived from transformed stroma producing cells may influence the proliferation, genetic regulation, and maintenance of the overlying urothelial tumor cells. The mechanism by which the ECM may influence cellular behavior and phenotype may be in their ability to modulate the nuclear matrix proteins of the overlying cell.
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PMID:Altered extracellular matrices influence cellular processes and nuclear matrix organizations of overlying human bladder urothelial cells. 840 87

The neurofibromatosis type 1 (NF1) gene is considered a tumor-suppressor gene whose product acts upstream of ras. The ras gene is an oncogene very commonly detected in human cancers and consists of three families, H-ras, K-ras and N-ras. These genes are converted to active oncogenes by point mutations in codon 12, 13, or 61. Examination was made of the mutations of these genes in 39 urothelial malignant tumors (31 bladder cancer, 6 renal pelvic tumor, and 2 ureter tumors) using polymerase chain reaction single-stranded conformation polymorphism and direct sequencing methods. Three of 39 (7.7%) cases showed mobility shifts in the ras family gene but no point mutations in NF1 and N-ras genes could be detected. Mutations were found in 1 case in H-ras at codon 13 (GGT-GTT/GGT) and K-ras at codon 12 in 2 cases (GGT-GCT/GGT, GGT-GTT/GGT). All 3 cases had progressed far beyond grade 2 and stage pT2. It follows from the above that NF1 and ras gene mutations are infrequent in the pathogenesis of urothelial tumors.
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PMID:Infrequent involvement of mutations on neurofibromatosis type 1, H-ras, K-ras and N-ras in urothelial tumors. 853 97

The multistage model of carcinogenesis during tumor progression requires that there should be consecutive genetic abnormalities of both oncogenes and tumor suppressor genes. As is true of the protein products of oncogenes, tumor suppressor proteins are found to have various cellular functions. They are involved in the regulation of adhesion, cell-cell interaction, and cytoplasmic signal transducers as well as nuclear transcription factors. The recently identified hMSH2 (human MutS homolog 2) gene in colorectal carcinomas possesses sequence homologies to DNA mismatch repair genes in bacteria and yeast. An accumulation of evidence exists to indicate the tumor suppressive functions of actin-regulatory proteins. We have shown that both mutant gelsolin His321 and human authentic gelsolin, if expressed at increased levels, may have a suppressive potential against the tumorigenicity of mouse ras-transformed cells (EJ-NIH/3T3). His321 inhibited phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis by phospholipase C gamma 1 more strongly in vitro than did wild-type gelsolin because of its higher binding capacity to phosphoinositide. We have also demonstrated that the production of gelsolin was either lost or notably reduced in human gastric carcinomas and urinary bladder cancers. The cDNAs encoding mouse or human authentic gelsolins were transfected into a urinary bladder cancer cell line. The urinary bladder transfectant lost their tumorigenicity in nude mice. All these and the facts that vinculin, alpha-actinin, erythrocyte band 4.1 family and gelsolin have both tumor-suppressive and phosphoinositides-binding activities in common suggest that these actin-regulatory proteins are a new family of effective tumor suppressors.
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PMID:[Progress of research on tumor suppressor genes]. 864 69

The refractoriness of prostate cancer to androgen suppression is the landmark of clinically aggressive disease. In this study, the androgen-dependent LNCaP prostate cancer cells were transfected with the mutated c-Ha-ras gene from the T24 human bladder cancer. The derivative clone overexpressing T24-ras (LNCaP(T24-ras)) proliferated in androgen-depleted medium and showed increased growth. Protein isoprenylation and p21ras farnesylation in LNCaP(T24-ras) cells were tested in the presence of phenylacetate to document a possible relationship with the drug-induced inhibition of cell proliferation. Phenylacetate is a differentiation inducer that down-regulates in vitro the expression of the myc oncogene and activates the human peroxisome proliferator-activated nuclear receptor involved in cell growth regulation. The drug inhibited protein isoprenylation and p21ras farnesylation in LNCaP(T24-ras) cells; IC50 values were 3.1 and 3.3 mM, respectively, compared with controls. The drug reduced the cellular levels of endogenous farnesyl-PP (mean IC50 = 3.5 mM) and inhibited activation of the p21ras downstream target, p42(MAPK)/ERK2. LNCaP(T24-ras) was more sensitive than the parental line to both growth inhibition (mean IC50 = 3.01 and 7.1 mM, respectively) and apoptosis by phenylacetate. Exogenous farnesyl- and geranylgeranyl-PP indeed reduced the effects of the drug on proliferation and apoptosis in LNCaP(T24-ras) cells. In conclusion, the inhibition of protein isoprenylation and p21ras farnesylation by phenylacetate resulted in increased chemosensitivity of the androgen-independent LNCaP(T24-ras) cells compared with LNCaP, and this effect might contribute to the pharmacological activity of the drug.
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PMID:Phenylacetate inhibits protein isoprenylation and growth of the androgen-independent LNCaP prostate cancer cells transfected with the T24 Ha-ras oncogene. 864 57

We have analyzed the bladder biopsies of six bladder cancer patients exposed to high levels of 2-naphthylamine and benzidine, 11 unexposed bladder cancer patients, six subjects with benign conditions of the bladder, and 16 healthy subjects. Immunohistochemical analysis of the p21 and p185 protein products, for overexpression of ras and c-erbB-2 oncogenes, was performed. Overexpression of ras was found in four of six exposed cancer patients, 3 of 11 unexposed cancer patients, zero of six benign disease patients, and zero of 16 healthy subjects. The odds ratio for ras overexpression, comparing exposed with unexposed cases, was 5.3 (90% confidence interval 0.6 to 64). Overexpression of c-erB-2 was apparently not associated with occupational exposure.
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PMID:Exposure to aromatic amines and ras and c-erbB-2 overexpression in bladder cancer. 892 23

In this study we demonstrate the involvement of ras oncogenes in bladder cancer at the level of RNA overexpression. We examined 26 bladder specimens, consisting of paired tumor and adjacent normal tissue and found that H-ras transcripts were overexpressed in 39% of the specimens while K-ras and N-ras in 58% of total specimens. Each tumor specimen had a unique pattern of overexpression for the three ras genes. A competitive-RT-PCR was employed for H-ras and a beta-actin control gene was co-amplified with K-ras or N-ras genes. These results indicate that the involvement of ras oncogenes in bladder cancer could be relative to overexpression of these genes.
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PMID:Transcriptional activation of H-ras, K-ras and N-ras proto-oncogenes in human bladder tumors. 894 20

We examined the expression of gelsolin in a murine ras tumor and a number of human stomach, colon, bladder, and lung cancer cell lines and tissues. In most of the cell lines and tumor tissues, gelsolin expression was undetectable or extremely low in comparison with its expression in normal epithelial cells. Upon the introduction of the exogenous human wild-type gelsolin cDNA into human cancer cell lines, the gelsolin transfectants had greatly reduced colony-forming ability and tumorigenicity in vivo. After UVC irradiation, the gelsolin-overexpressing bladder cancer cells demonstrated increased accumulation and/or protracted delay in G2 phase as compared to neotransfected cells. UVC-induced production of diacylglycerol was reduced in gelsolin-overexpressed UMUC-2 cells as compared to neo-transfected UMUC-2 cells. Levels of cyclin B in the synchronized and gelsolin-overexpressing UMUC-2 cells remained low during the G2 delay. To investigate the in vivo efficacy of gene therapy with the gelsolin tumor suppressor, we treated human urinary bladder cancers (UMUC-2 and DAB-1), inoculated in nude mice, with recombinant retrovirus packaging cells containing the human gelsolin cDNA. This gene therapy resulted in remarkable tumor growth inhibition, and prolonged survival time in the majority of animals. These observations suggest that gelsolin plays a key role as a tumor suppressor by regulating a G2 checkpoint function of cancer cells through phosphoinositol lipid metabolism, and demonstrate the potential of using the gelsolin tumor suppressor in human urinary bladder carcinoma.
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PMID:[Tumor suppressive function of gelsolin]. 930 38

The usual course of drug discovery begins with the demonstration of compound activity in cells and, usually, a lower level of activity in animals. Successive rounds of drug design may result in a compound with sufficient activity in animals to justify clinical trials. The basic endpoints of therapeutic oligonucleotide experiments include target antigen reduction, target messenger reduction and inhibition of transformed cell proliferation or viral replication. However, one should expect oligonucleotides to exhibit pleiotropic behaviour, as do all other drugs. In an animal oligonucleotides will necessarily bind to and dissociate from all macromolecules encountered in the blood, in tissues, on cell surfaces and within cellular compartments. Contrary to expectations, oligonucleotides designed to be complementary to certain transcripts have sometimes been found moderately effective in cell-free extracts, more effective in cell culture and most effective in animal models. If greater potency against standard endpoints is reported in mouse models than was observed in cell culture, critical examination must consider alternate modes of action in animals that may not apply in cell culture. This counterintuitive paradox will be examined, based on studies of Ha-ras expression in bladder cancer, Ki-ras expression in pancreatic cancer, erbB2 expression in ovarian cancer and c-myc expression in B cell lymphoma.
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PMID:Differential oligonucleotide activity in cell culture versus mouse models. 938 73


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