Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

As the majority of primary malignant melanomas can be cured by surgical excision, the prognosis of melanomas is dependent on whether tumor cells have disseminated orare capable of doing so at the time of surgery. A prospective and valid detection of this minimal residual disease is not currently possible. The most important known so-called markers of melanoma disease, tyrosinase, S100 and MIA, all are more likely to be present in patients with more advanced disease. A valid prognostic effect has only been shown for S100 in patients with already identified metastatic disease. Further prospective studies are required to determine the potential gain of information by routine determination of these markers in melanoma patients.
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PMID:[Disseminated melanoma cells in blood and bone marrow. Significance and detection by potential tumor markers]. 1138 19

The fermented wheat germ extract with standardized benzoquinone composition has potent tumor propagation inhibitory properties. The authors show that this extract induces profound metabolic changes in cultured MIA pancreatic adenocarcinoma cells when the [1,2-13C2]glucose isotope is used as the single tracer with biologic gas chromatography-mass spectrometry. MIA cells treated with 0.1, 1, and 10 mg/mL wheat germ extract showed a dose-dependent decrease in cell glucose consumption. uptake of isotope into ribosomal RNA (2.4%, 9.4%, and 28.0%), and release of 13CO2. Conversely, direct glucose oxidation and ribose recycling in the pentose cycle showed a dose-dependent increase of 1.2%, 20.7%, and 93.4%. The newly synthesized fraction of cell palmitate and the 13C enrichment of acetyl units were also significantly increased with all doses of wheat germ extract. The fermented wheat germ extract controls tumor propagation primarily by regulating glucose carbon redistribution between cell proliferation-related and cell differentiation-related macromolecules. Wheat germ extract treatment is likely associated with the phosphorylation and transcriptional regulation of metabolic enzymes that are involved in glucose carbon redistribution between cell proliferation-related structural and functional macromolecules (RNA, DNA) and the direct oxidative degradation of glucose, which have devastating consequences for the proliferation and survival of pancreatic adenocarcinoma cells in culture.
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PMID:Wheat germ extract decreases glucose uptake and RNA ribose formation but increases fatty acid synthesis in MIA pancreatic adenocarcinoma cells. 1148 16

Abnormal splicing of primary RNA transcripts of normal genes is a recognized mechanism for the production of some abnormal proteins found in cancer cells. A misspliced form of the cholecystokinin-B/gastrin (CCK-B) receptor recently was reported to be present in colon carcinoma, where it was postulated to play a role in stimulating tumor growth (M. R. Hellmich et al., J. Biol. Chem., 275: 32122-32128, 2000). Here, we report the presence of the same abnormal protein in pancreatic carcinoma and explore the molecular basis for this missplicing event. Reverse transcription-PCR and sequencing were used to demonstrate the presence of a misspliced form of the CCK-B receptor having its fourth intron retained in three pancreatic cancer cell lines and in tumor tissue, but not in surrounding healthy pancreas, from two patients with pancreatic carcinoma. A mini-gene construct representing the region of this gene from its third through its fifth exon and containing the two intervening introns was produced and transiently expressed in the MIA PaCa-2 human pancreatic cancer cell line. Specific reverse transcription-PCR reactions with both vector-derived and receptor-specific primers demonstrated the presence of both correctly fully spliced and selectively misspliced forms of this receptor. Mutagenesis of the mini-gene demonstrated that a suboptimal sequence at the 3'-end of intron 4 contributed to this missplicing. This focused attention on the U2 small nuclear ribonucleoprotein particle auxiliary splicing factors (U2AFs) known to interact specifically with this domain. Indeed, quantitative real-time PCR demonstrated a reduced level of expression of one of these factors, U2AF35, in pancreatic cancer cells compared with healthy pancreas. Furthermore, the relative amount of missplicing of the CCK-B receptor mini-gene in the pancreatic cancer cell line was reversed by transfection of the cells with U2AF35 cDNA. This work describes the presence of an additional abnormal protein in pancreatic cancer and describes a new molecular mechanism for its production, providing additional potential therapeutic targets.
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PMID:A misspliced form of the cholecystokinin-B/gastrin receptor in pancreatic carcinoma: role of reduced sellular U2AF35 and a suboptimal 3'-splicing site leading to retention of the fourth intron. 1183 May 56

MIA/CD-RAP is a small, soluble protein secreted from malignant melanoma cells and from chondrocytes. Recent evidence has identified MIA/CD-RAP as the prototype of a small family of extracellular proteins adopting an SH3 domain-like fold. It is thought that interaction between MIA/CD-RAP and specific epitopes in extracellular matrix proteins regulates the attachment of tumor cells and chondrocytes. In order to study the consequences of MIA/CD-RAP deficiency in vivo, we generated mice with a targeted gene disruption. The complete absence of MIA/CD-RAP mRNA and protein expression was demonstrated by reverse transcriptase, Western blot analysis, and enzyme-linked immunosorbent assay measurements of whole-embryo extracts. MIA(-/-) mice were viable and developed normally, and histological examination of the organs by means of light microscopy revealed no major abnormalities. In contrast, electron microscopic studies of cartilage composition revealed subtle defects in collagen fiber density, diameter, and arrangement, as well as changes in the number and morphology of chondrocytic microvilli. Taken together, our data indicate that MIA/CD-RAP is essentially required for formation of the highly ordered ultrastructural fiber architecture in cartilage and may have a role in regulating chondrocyte matrix interactions.
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PMID:Ultrastructural cartilage abnormalities in MIA/CD-RAP-deficient mice. 1183 10

Cartilage-derived retinoic acid-sensitive protein (CD-RAP) is a new protein that was isolated from bovine articular chondrocytes and human melanoma cell lines (melanoma inhibitory protein or MIA). In normal tissue its expression is limited to cartilage, and in morbid tissue to melanoma, chondrosarcoma, and breast cancer. Serum levels of CD-RAP/MIA correlate with the progression of malignant melanoma, but there have been no reports on chondrosarcoma. Here, it was first demonstrated by RT-PCR and immunohistological methods that CD-RAP was expressed in tissue from a Swarm rat chondrosarcoma that was used as an experimental model. The course following tumor transplantation and changes in serum CD-RAP after tumor excision were then observed to investigate whether serum CD-RAP could be used as a marker of tumor activity. Consequently, serum CD-RAP in control rats tended to decrease as the animal grew, whereas it rose in proportion to tumor proliferation in rats that had received a tumor graft. Serum CD-RAP levels dropped rapidly following excision of the tumor in a group of tumor-excised rats. In those rats which had a recurrence following excision of the tumor, serum CD-RAP rose prior to the appearance of the tumor. Serum CD-RAP thus sensitively reflected tumor onset and proliferation, so that it appeared to be an effective marker of tumor activity for Swarm rat chondrosarcoma.
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PMID:Serum cartilage-derived retinoic acid-sensitive protein (CD-RAP) levels in swarm rat chondrosarcoma. 1191 21

Inhibitors of ras farnesylation have been extensively studied in the preclinical stage, and some of them are being developed in the clinic. Herein, we describe the antitumor activity of a new farnesyl transferase inhibitor, ER-51785. In vitro, ER-51785 selectively inhibited farnesyl transferase activity (IC50 = 77 nM) compared with geranylgeranyl transferase I activity (IC50 = 4200 nM). In cells, ER-51785 inhibited posttranslational processing of H-ras with IC50 = 28 nM, but not that of rap 1A at concentrations up to 50 microM. This compound also strongly inhibited colony formation of H-ras-transformed NIH 3T3 fibroblasts and EJ-1 bladder carcinoma cells. In vivo, ER-51785 showed potent tumor regression activity against EJ-1 xenografts but only modest activity against MIA PaCa-2 xenografts. Treatment of ER-51785 in combination with paclitaxel exhibited synergistic effects against colony formation and tumor growth of MIA PaCa-2 cells. The results presented herein support the idea that farnesyl transferase inhibitors alone and in combination with other chemotherapeutic agents have the potential to be developed as therapies for tumors expressing H-ras or K-ras oncogenes.
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PMID:Antitumor activity of ER-51785, a new peptidomimetic inhibitor of farnesyl transferase: synergistic effect in combination with paclitaxel. 1193 11

Xenopus wnt-8 (Xwnt-8) is one of the most potent Wnts to activate the WNT - beta-catenin - TCF signaling pathway. We have previously cloned and characterized WNT8A and WNT8B, two human homologues of Xwnt-8. Here, we investigated expression and regulation of WNT8A and WNT8B mRNAs in human tumor cell lines by using cDNA-PCR. WNT8A mRNA was undetectable in 7 pancreatic cancer cell lines, but WNT8B mRNA was detected in pancreatic cancer cell lines PSN-1, BxPC-3, MIA PaCa-2. Both WNT8A and WNT8B mRNAs were undetectable in 7 brain tumor cell lines. Although WNT8A mRNA was undetectable in 3 breast cancer cell lines, WNT8B mRNA was detected in the breast cancer cell line MCF-7. WNT8B mRNA, but not WNT8A mRNA, was significantly up-regulated by beta-estradiol in MCF-7 cells. WNT8A mRNA was detected in embryonal tumor cell lines NEC-14, NCC-IT, and NT2, while WNT8B mRNA was detected in embryonal tumor cell lines NEC-8, NEC-14, and NT2. Because NT2 cells differentiate into neuronal cells after all-trans retinoic-acid treatment, effects of all-trans retinoic acid on mRNA expression of WNT8A and WNT8B were next investigated. WNT8A and WNT8B mRNAs were down-regulated together in NT2 cells after all-trans retinoic-acid treatment. WNT8A and WNT8B might play key roles in embryonal tumors and embryonic stem cells through synergistic activation of the beta-catenin - TCF signaling pathway.
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PMID:Expression and regulation of WNT8A and WNT8B mRNAs in human tumor cell lines: up-regulation of WNT8B mRNA by beta-estradiol in MCF-7 cells, and down-regulation of WNT8A and WNT8B mRNAs by retinoic acid in NT2 cells. 1195 96

Pancreatic ductal adenocarcinomas (PDACs) overexpress various cell-surface tyrosine kinase receptors, including the type I high-affinity fibroblast growth factor receptor (FGFR-1). The purpose of this study was to determine whether FGFR-targeted gene therapy is feasible in this disorder. Accordingly, the effects of a conjugate consisting of fibroblast growth factor (FGF)-2 linked to a Fab' fragment against the adenovirus knob region were evaluated in human pancreatic cancer cell lines treated with an adenoviral vector containing the herpes simplex virus thymidine kinase (AdTK) gene. An adenoviral vector containing the firefly luciferase reporter gene (AdLuc) served to assess infection efficiency, and was initially tested in L6 rat myoblasts. In parental L6 cells that express exceedingly low levels of high-affinity FGFRs, transduction with AdLuc was enhanced 7- to 10-fold with the FGF2-Fab' conjugate, whereas in L6 cells transfected to express FGFR-1, it was enhanced 39- to 52-fold. The pancreatic cancer cell lines expressed variable levels of the four high-affinity FGF receptors, and exhibited 2- to 34-fold increases in gene transduction in the presence of the FGF2-Fab' conjugate. In the absence of FGF2-Fab' there was no correlation between surface binding of FGF2 and AdLuc transduction efficiency, whereas in the presence of FGF2-Fab', enhanced AdLuc transduction efficiency correlated with greater surface binding of FGF2. In the absence of AdTK, all the cell lines were insensitive to ganciclovir, whereas after AdTK transduction, only ASPC-1 and PANC-1 cells were resistant to ganciclovir even in the presence of FGF2-Fab'. Ganciclovir-mediated inhibition was dependent on the conjugate in CAPAN-1 and COLO-357 cells, but was independent of the conjugate in T3M4 and MIA-PaCa-2 cells. Real-time quantitative PCR of laser-captured cancer cells revealed high levels of various FGFR mRNA species in six of seven PDAC tumor samples. These findings indicate that transduction efficiency with FGF2-Fab' in pancreatic cancer cells is independent of native adenoviral transduction efficiency and is greatest in cells that exhibit concomitant expression of various high-affinity FGFRs. In view of the overexpression of high-affinity FGFRs in the cancer cells in PDAC, our findings also suggest that the combined use of AdTK, ganciclovir, and FGF2-Fab' may ultimately be a promising therapeutic approach in a subgroup of patients with PDAC.
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PMID:Targeting of suicide gene delivery in pancreatic cancer cells via FGF receptors. 1203 63

The prognosis of hepatocellular carcinoma (HCC) still remains dismal, although many advances in its clinical study have been made. It is important for tumor control to identify the factors that predispose patients to death. With new discoveries in cancer biology, the pathological and biological prognostic factors of HCC have been studied quite extensively. Analyzing molecular markers (biomarkers) with prognostic significance is a complementary method. A large number of molecular factors have been shown to associate with the invasiveness of HCC, and have potential prognostic significance. One important aspect is the analysis of molecular markers for the cellular malignancy phenotype. These include alterations in DNA ploidy, cellular proliferation markers (PCNA, Ki-67, Mcm2, MIB1, MIA, and CSE1L/CAS protein), nuclear morphology, the p53 gene and its related molecule MD M2, other cell cycle regulators (cyclin A, cyclin D, cyclin E, cdc2, p27, p73), oncogenes and their receptors (such as ras, c-myc, c-fms, HGF, c-met, and erb-B receptor family members), apoptosis related factors (Fas and FasL), as well as telomerase activity. Another important aspect is the analysis of molecular markers involved in the process of cancer invasion and metastasis. Adhesion molecules (E-cadherin, catenins, serum intercellular adhesion molecule-1, CD44 variants), proteinases involved in the degradation of extracellular matrix (MMP-2, MMP-9, uPA, uPAR, PAI), as well as other molecules have been regarded as biomarkers for the malignant phenotype of HCC, and are related to prognosis and therapeutic outcomes. Tumor angiogenesis is critical to both the growth and metastasis of cancers including HCC, and has drawn much attention in recent years. Many angiogenesis-related markers, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived endothelial cell growth factor (PD-ECGF), thrombospondin (TSP), angiogenin, pleiotrophin, and endostatin (ES) levels, as well as intratumor microvessel density (MVD) have been evaluated and found to be of prognostic significance. Body fluid (particularly blood and urinary) testing for biomarkers is easily accessible and useful in clinical patients. The prognostic significance of circulating DNA in plasma or serum, and its genetic alterations in HCC are other important trends. More attention should be paid to these two areas in future. As the progress of the human genome project advances, so does a clearer understanding of tumor biology, and more and more new prognostic markers with high sensitivity and specificity will be found and used in clinical assays. However, the combination of some items, i.e., the pathological features and some biomarkers mentioned above, seems to be more practical for now.
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PMID:The prognostic molecular markers in hepatocellular carcinoma. 1204 56

Pancreatic cancer is often resistant to conventional chemotherapy. In this study, we examined the role of adenovirus-mediated overexpression of E2F-1 in inducing apoptosis and increasing the sensitivity of pancreatic cancer cells to chemotherapeutic agents. MIA PaCa-2 pancreatic head exocrine adenocarcinoma cells (mutant p53) were treated by mock infection or adenoviruses expressing beta-galactosidase or E2F-1 (Ad-E2F-1) alone or in combination with sublethal concentrations of each chemotherapeutic drug. Cell growth and viability were assessed at selected time points. Apoptosis was evaluated by flow cytometry, characteristic changes in cell morphology and poly (ADP-ribose) polymerase (PARP) cleavage. Western blot analysis was used to examine the expression of E2F-1 and Bcl-2 family member proteins and PARP cleavage. Western blot analysis revealed marked overexpression of E2F-1 at a multiplicity of infection (MOI) of 20 and 70. By 3 days after infection, Ad-E2F-1 treatment at an MOI of 70 resulted in approximately a 20-fold reduction in cell growth and 60% reduction in cell viability as compared to mock-infected cells. Cell cycle analysis, PARP cleavage and changes in cell morphology supported apoptosis as the mechanism of cell death in response to E2F-1. In order to test the efficacy of treatment with a combination of gene therapy and chemotherapy, we utilized concentrations of Ad-E2F-1 which reduced viability to 50% in combination with each chemotherapeutic agent. Cotreatment of the cells with E2F-1 virus and roscovitine (ROS) or etoposide resulted in an additive effect on cell growth inhibition and induction of apoptosis. Interestingly, 5-fluorouracil did not cooperate with Ad-E2F-1 in the mediation of tumor death or inhibition of cell growth. Immunoblotting for Bcl-2 family members revealed no significant changes in the expression levels of Bcl-2, Bcl X(L), Bax or Bak following gene or 'chemogene' therapy with E2F-1. However, a Bax cleavage product was noted which was substantially increased by cotreatment with ROS or etoposide. E2F-1 overexpression initiates apoptosis and suppresses growth in pancreatic MIA PaCa-2 cells in vitro. E2F-1-mediated apoptosis was not associated with significant changes in the expression of Bcl-2 family member proteins in these pancreatic cancer cells. ROS and etoposide, when combined with E2F-1 overexpression, induce apoptosis in an additive manner. This chemogene combination may provide a potentially useful therapeutic strategy for advanced pancreatic cancer.
Tumour Biol
PMID:E2F-1 gene therapy induces apoptosis and increases chemosensitivity in human pancreatic carcinoma cells. 1206 45


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