Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Uridine 5'-diphosphate-galactose:glycoprotein galactosyltransferase activity was demonstrated in homogenates of normal ovary and ovarian epithelial adenocarcinomas. The specific activity of the enzyme in ovarian tumors was 3 to 5 times higher than in normal ovaries when the enzyme was assayed under identical conditions. The glycoprotein fetuin, from which terminal sialic acid and penultimate galactose were removed (fetuin minus N-acetylneuraminis acid and galactose), acted as an excellent exogenous acceptor. Galactosyltransferase from normal ovary and ovarian tumor cells had similar properties. Both required Mn2+ and Triton X-100 and had broad pH optima between 5.5 and 7. Galactosyltransferase activity was also measured in serum samples from ovarian cancer patients and normal healthy individuals in the presence of fetuin minus N-acetylneuraminic acid and galactose as exogenous acceptor. The enzyme levels were significantly elevated in the sera of ovarian cancer patients as compared to normal controls. The differences in the levels of this enzyme in the tissues and sera of normal individuals and ovarian cancer patients were not due to differential levels of the degrading enzymes such as uridine 5'-diphosphate-galactose pyrophosphatase or beta-D-galactosidase. Serial determinations were carried out on the sera of 5 ovarian cancer patients over a long period of time. The serum level of galactosyltransferase activity appeared to correlate with tumor volume as well as with the clinical status of the patient, which suggests possible leakage of the tumor enzyme into the host sera. Serial determination of this enzyme level in ovarian cancer patients seems promising in measuring tumor progression or success of therapeutic approaches.
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PMID:Uridine 5'-diphosphate-galactose:glycoprotein galactosyltransferase activity in the ovarian cancer patient. 5 28

Variations in DNA synthesis as measured by tritiated-thymidine autoradiography in mammary carcinoma before and during endocrine therapy were studied in patients treated for inoperable or locally recurrent mammary carcinoma. Tumor cells were collected by aspiration biopsy and immediately expelled into the incubating solution. Cell viability was assessed by staining unfixed cells with trypan blue and fixed cells with orecin. To assess viability tritiated-uridine incorporation was used in some experiments. The same cells were identified by each method. Bilateral oophorectomy was done in 4 patients. In the 1 case in which regression followed, a 5-fold decrease in DNA-synthesis was noted 1 week after oophorectomy but at 2 weeks no cells incoporated thymidine. In the 3 patients with tumor progression the fraction of labeled cells was unchanged. For antiestrogen therapy, Tamoxifen (Nolvadex) was used. Serial needle aspirates were collected from 38 patients who received 20 mg of Tamoxifen twice daily. Complete remission followed in 7, incomplete remission in 8, stationary disease in 7, and progression in 16. DNA synthesis fell to very low values after 1-3 weeks and remained low in the 7 cases with complete regression. Tumors showing partial regression showed diminished fractions of 5-phase cells (tritiated-thymidine-labeled cells) after 1-5 weeks. In 1 instance at 72 weeks the S-phase fraction of cells was higher than initial value. Tumor value remained stationary for 40 weeks and then increased. Antiestrogen therapy was stopped at 82 weeks. In those with progressive tumor growth there was high DNA synthesis. Between 20-30% of the cells were replicating DNA. None showed decrease in the fraction of S-phase cells, and 1 showed increase. For estrogen therapy, estradiol valepianate was given im every 2 weeks. Of the 3 patients who received estrogen therapy, 2 of the tumors responded and the DNA-synthesis rapidly decreased until none was measurable after 4 weeks. S-phase values prior to endocrine therapy showed no correlation with the therapeutic response. Tumors that responded showed a decrease in the proportion of S-phase cells during the first 3 weeks. In tumors responding to encocrine therapy the decrease in tritiated-thymidine incorporation was rapid and preceded reduction in tumor size. Data suggest that 2 aspirates should be studied before therapy and repeated after 2-4 weeks in order to include the minimal proportion of S-phase cells. The patients accepted the needle biopsies well. There were no growths of carcinoma at the puncture sites. About 5 weeks must elapse before tumor response can be assessed. Determining hormone receptors in surgically removed carcinoma specimens gives much more rapid indications as to possible response to endocrine therapy.
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PMID:3H-thymidine incorporation into mammary carcinoma cells obtained by needle aspiration before and during endocrine therapy. 106 73

Loss of cell cycle control and acquisition of chromosomal rearrangements such as gene amplification often occur during tumor progression, suggesting that they may be correlated. We show here that the wild-type p53 allele is lost when fibroblasts from patients with the Li-Fraumeni syndrome (LFS) are passaged in vitro. Normal and LFS cells containing wild-type p53 arrested in G1 when challenged with the uridine biosynthesis inhibitor PALA and did not undergo PALA-selected gene amplification. The converse occurred in cells lacking wild-type p53 expression. Expression of wild-type p53 in transformants of immortal and tumor cells containing mutant p53 alleles restored G1 control and reduced the frequency of gene amplification to undetectable levels. These studies reveal that p53 contributes to a metabolically regulated G1 check-point, and they provide a model for understanding how abnormal cell cycle progression leads to the genetic rearrangements involved in tumor progression.
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PMID:Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles. 152 30

The effects of a single application of 1.8 nmol 12-O-tetradecanoylphorbol-13-acetate (TPA) on precursor incorporation into RNA, DNA and protein in the epidermis, dermis and subcutis from 3-methylcholanthrene (MCA) injected precancerous mouse skin were studied at various time points between 3 and 96 h. In the precancerous tissues, the rates of incorporation of [3H]uridine into RNA did not alter appreciably from those in the control tissues; while the rates of [3H]methylthymidine incorporation into DNA were elevated with peaks appearing between 6 and 12 h, at 24 h and at 72 h in epidermis, dermis and subcutis. The rate of incorporation of [14C]leucine into protein was markedly elevated in all the three tissues which showed 3-4 sharp peaks. The maximum stimulation ranged between 14 and 20 times that of the control. A single application of TPA to the precancerous mouse skin induced early stimulation of precursor incorporation into all the three macromolecules in epidermis, dermis and subcutis. The increased stimulation was maintained for 36-72 h. The patterns of incorporation of [3H]methylthymidine into DNA gave rise to 2-3 peaks of elevated uptake in each tissue up to 36-48 h. A lowered rate of DNA synthesis between 48 and 60 h was followed by a peak at 72 h. In each group, epidermal mitotic activity correlated well with spurts of precursor incorporation into cellular DNA. The observations indicate that TPA recruits more cells into the DNA synthetic phase and accelerates selective growth of preneoplastic cells during tumor progression.
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PMID:Effects of 12-O-tetradecanoylphorbol-13-acetate on the incorporation of labelled precursors into RNA, DNA and protein in epidermis, dermis and subcutis from precancerous mouse skin with reference to enhanced tumorigenesis. 669 31

The aim of this study was to evaluate whether food intake modulates experimental tumour growth by acute alterations in the energy state and blood flow of the tumour, and if so whether such changes are related to alterations in the enzyme ornithinedecarboxylase (ODC) and DNA synthesis. Inbred mice (C57BL/J) bearing a syngeneic undifferentiated and rapidly growing tumour were used. The tumour levels of high energy phosphates were measured in vivo by 31-P-NMR spectroscopy and biochemically following tissue extraction. DNA synthesis was estimated by measuring the incorporation of bromodeoxy-uridine into tumour DNA. Difluoro-methylornithine (DFMO) was used to inhibit ODC-activity. Tumour blood flow was estimated by a 132Xe local clearance technique. Tumour progression was associated with a significant decrease in tumour tissue high energy phosphates. Acute starvation decreased DNA-synthesis and tumour energy charge as well as its PCr/Pi which were rapidly normalised during subsequent refeeding. These changes were related to similar alterations in tumour blood flow. The inorganic phosphate (Pi) resonance and the resonances in the phosphomonoester (PME) region were considerably increased in tumour tissue. Inhibition of ODC-activity by DFMO decreased DNA-synthesis, which was associated with a secondary increase in tumour high energy phosphates probably due to a lowered energy demand for tumour cell division. The results demonstrate that host undernutrition was translated into retarded tumour growth associated with a decrease in the energy state and blood flow of the tumour. The results have bearing for the evaluation and planning of all treatment protocols with potential influence on food intake in experimental tumour-bearing animals.
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PMID:Energetics of nutrition and polyamine-related tumor growth alterations in experimental cancer. 839 89

Recent evidence has emphasized the importance of programmed cell death, or apoptosis, in the maintenance of tissue homeostasis and pathogenesis of tumors. This study analyzed the significance of apoptosis in relation to the expression of p53 and bcl-2 proteins, tissue proliferation defined by Ki-67 expression, and tissue histology in thyroid tissue. Extent of apoptosis was defined by morphological criteria and the terminal deoxynucleotidyl transferase-mediated deoxy uridine triphosphate (dUTP) biotin nick end labeling (TUNEL) assay. Immunocytochemistry was performed for p53, bcl-2, and Ki-67 expression. There was good correlation between TUNEL-reactive cells and morphological evaluation criteria for apoptosis. The extent of apoptosis was significantly associated with the type of thyroid lesion (r = 0.66990, p = 0.000012), both proliferative (namely multinodular goiter) and neoplastic (benign and malignant). A higher extent of apoptosis was evident in medullary and anaplastic carcinomas. Apoptosis also correlated to p53 protein accumulation (r = 0.485, p = 0.00041) and Ki-67 immunoreactivity (r = 0.435, p = 0.001). An inverse correlation was observed between bcl-2 expression and the extent of apoptosis (r = -0.33369, p = 0.01912). A direct correlation was also observed between p53 expression and Ki-67 immunoreactivity (r = 0.623, p = 0.0002). By inhibiting apoptosis, bcl-2, may cause a shift in tissue kinetics toward the preservation of genetically aberrant cells, thereby facilitating tumor progression. These results imply that rapidly proliferating tumors appear to have a high cell turnover state in which there may be increased chance of apoptosis among the proliferating cells. The ability of apoptosis to occur in the presence of a possibly mutant p53 protein suggest the existence of at least two p53 dependent apoptotic pathways, one requiring activation of specific target genes and the other independent of it. However, keeping in mind the limited number of subjects studied in each subgroup and the rather low correlation coefficients, these possibilities would have to be substantiated in a larger study population.
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PMID:In situ apoptosis in the thyroid. 1071 47

Tumors of the central nervous system (CNS) often have sustained expression of labile genes, including angiogenic growth factors and immunosuppressive cytokines, which promote tumor progression. Stabilization of the RNA transcripts for these genes, such as vascular endothelial growth factor (VEGF), is an important molecular pathway for this up-regulation. HuR, a member of the Elav family of RNA-binding proteins, has been implicated in this pathway through its binding to adenine and uridine (AU)-rich stability elements (ARE) located in the 3' untranslated regions (3'-UTRs) of the mRNA. Whereas three of the Elav family members (Hel-N1, HuC, and HuD) are restricted to young and mature neurons, HuR is more broadly expressed, including proliferating cells of the developing CNS. Because RNA stabilization of labile genes may promote tumor growth, we analyzed and compared the expression pattern of HuR in 35 freshly resected and cultured CNS tumors to determine whether there was any correlation with tumor grade or histological type. We found that HuR mRNA was consistently expressed in all of the tumors, regardless of cell origin or degree of malignancy. Using a novel HuR-specific polyclonal antibody, we found that strong HuR protein expression was limited to high-grade malignancies (glioblastoma multiforme and medulloblastoma). Within the glioblastoma multiforme, prominent HuR expression was also detected in perinecrotic areas in which angiogenic growth factors are up-regulated. To further define its role as a potential RNA stabilizer, we analyzed whether HuR could bind to the stability motifs within the 3'-UTRs of cytokines and growth factors linked to brain tumor progression. We used a novel ELISA-based RNA binding assay and focused on the 3'-UTRs of angiogenic factors VEGF, COX-2, and (interleukin) IL-8 as well as the immunomodulating factors IL-6, transforming growth factor (TGF)-beta and tumor necrosis factor (TNF)-alpha as potential RNA ligands. Our results indicated overall a very high binding affinity to these RNA targets. A comparison of these ligands revealed a hierarchy of binding affinities with the angiogenic factors, and TGF-beta showing the highest (Kd of 1.8-3.4 nM), and TNF-alpha the lowest (Kd of 18.3 nM). The expression pattern of HuR, coupled with the RNA binding data, strongly suggests a role for this protein in the posttranscriptional regulation of these genes in CNS tumors.
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PMID:HuR, a RNA stability factor, is expressed in malignant brain tumors and binds to adenine- and uridine-rich elements within the 3' untranslated regions of cytokine and angiogenic factor mRNAs. 1128 Jul 80

Malignant gliomas are highly aggressive tumors of the central nervous system that rely on production of growth factors for tumor progression. Vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), and tumor necrosis factor-alpha, for example, are up-regulated in these tumors to promote angiogenesis and proliferation. RNA stability, mediated through adenine and uridine-rich elements (ARE) in the 3' untranslated region, is a critical control point for regulating these growth factors. RNA half-life is predominantly governed by a balance between stabilizing and destabilizing factors that bind to ARE. We have previously shown that the stabilizing factor HuR is overexpressed in malignant gliomas and linked to RNA stabilization of angiogenic growth factors. Here, we report that the destabilizing factor tristetraprolin (TTP) is also ubiquitously expressed in primary malignant glioma tissues and cell lines. In contrast to benign astrogliotic tissues, however, the protein was hyperphosphorylated, with evidence implicating the p38/mitogen-activated protein kinase (MAPK) pathway. Conditional overexpression of TTP as a transgene in malignant glioma cells led to RNA destabilization of IL-8 and VEGF and down-regulation of protein production. Analysis of in vivo RNA binding indicated a shift of mRNA toward ectopic TTP and away from endogenous HuR. This biochemical phenotype was associated with a decrease in cell proliferation, loss of cell viability, and apoptosis. We postulate that hyperphosphorylation of TTP via p38/MAPK promotes progression of malignant gliomas by negatively regulating its RNA destabilizing function.
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PMID:Tristetraprolin down-regulates interleukin-8 and vascular endothelial growth factor in malignant glioma cells. 1824 66

Hypoxia, a common feature of solid tumors, plays a significant role in determining tumor phenotype and tumor progression. In this study, using an in-house PCR-array, we investigated phenotypic changes and differentially expressed hypoxia related genes in the KKU-M213 CCA cell line, cultured under hypoxic (1% O2) condition. Trefoil factor-1 (TFF1), a disintegrin, and metalloprotease 12 (ADAM12), integrin-alpha 5 (ITGA5) and baculoviral IAP repeat-containing 5 (BIRC5/survivin), proteins involved with cell proliferation, metastasis and apoptosis resistance, were up-regulated whereas uridine 5'-monophosphate synthase (UMPS) and S100 calcium binding protein P (S100P), involved with chemosensitivity and cell adhesion, were down-regulated. Growth arrest, apoptosis resistance to UV-irradiation and chemotherapeutic drugs (5- flourouracil, cisplatin, doxorubicin) as well as cell adhesion were thus significantly enhanced upon exposure to hypoxic condition. These findings emphasize the significance of a hypoxic state in the induction of an aggressive phenotype and suggest the potential of targeting hypoxia regulated genes to enhance the sensitivity of chemotherapeutic drug against CCA.
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PMID:Hypoxia enhances aggressiveness of cholangiocarcinoma cells. 2348 Jul 65

Malignant gliomas rely on the production of certain critical growth factors including VEGF, interleukin (IL)-6 and IL-8, to fuel rapid tumor growth, angiogenesis, and treatment resistance. Post-transcriptional regulation through adenine and uridine-rich elements of the 3' untranslated region is one mechanism for upregulating these and other growth factors. In glioma cells, we have shown that the post-transcriptional machinery is optimized for growth factor upregulation secondary to overexpression of the mRNA stabilizer, HuR. The negative regulator, tristetraprolin (TTP), on the other hand, may be suppressed because of extensive phosphorylation. Here we test that possibility by analyzing the phenotypic effects of a mutated form of TTP (mt-TTP) in which 8 phosphoserine residues were converted to alanines. We observed a significantly enhanced negative effect on growth factor expression in glioma cells at the post-transcriptional and transcriptional levels. The protein became stabilized and displayed significantly increased antiproliferative effects compared to wild-type TTP. Macroautophagy was induced with both forms of TTP, but inhibition of autophagy did not affect cell viability. We conclude that glioma cells suppress TTP function through phosphorylation of critical serine residues which in turn contributes to growth factor upregulation and tumor progression.
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PMID:Mutant tristetraprolin: a potent inhibitor of malignant glioma cell growth. 2352 47


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