Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenovirus type 5 (Ad5) gene therapy vectors require protection against antibodies, complement proteins and blood cells if they are to be delivered intravenously to treat metastatic disease. Such protection can be achieved by chemically modifying Ad5 with polymers based on hydrophilic HPMA. Here, such polymers were designed to include side chains bearing reactive carbonyl thiazolidine-2-thione groups (TTs) to covalently modify available amino groups of the lysine residues in the Ad5 capsid. Furthermore, the inclusion of side chains bearing positively charged quaternary ammonium groups (QAs) was designed to improve electrostatic interaction of the polymers with negatively charged Ad5 hexon protein. Finally, to enable triggered uncoating and reactivation of the Ad5, either the TTs or both the TTs and the QAs were linked to polymer backbone via reductively degradable disulfide bonds. SDS-PAGE demonstrated that these polymers covalently modified Ad5 capsid proteins in a reduction reversible manner. In infection studies, polymers containing QAs prevented binding of coagulation factor X to Ad5. Furthermore, the antibody and complement mediated binding of Ad5 to erythrocytes was reduced by such polymers (>95% without polymer, 25% following coating). These data indicate that coating Ad5 therapeutics with such polymers will improve blood circulation half-life and deposition at disease sites.
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PMID:Coating of adenovirus type 5 with polymers containing quaternary amines prevents binding to blood components. 1916 85

Cell surface membrane proteins are involved in central processes such as cell signaling, cell-cell interactions, ion and solute transport, and they seem to play a pivotal role in several steps of the metastatic process of cancer cells. The low abundance and hydrophobic nature of cell surface membrane proteins complicate their purification and identification by MS. We used two isogenic cell lines with opposite metastatic capabilities in nude mice to optimize cell surface membrane protein purification and to identify potential novel markers of metastatic cancer. The cell surface membrane proteins were isolated by centrifugation/ultracentrifugation steps, followed by membrane separation using a Percoll/sucrose density gradient. The gradient fractions containing the cell surface membrane proteins were identified by enzymatic assays. Stable isotope labeling of the proteome of the metastatic cell line by SILAC followed by mass spectrometry analysis enabled identification and quantification of proteins that were differentially expressed in the two cell lines. Dual stable isotopic labels ((13)C-arginine and (13)C-lysine) instead of a single label ((13)C-arginine) increased the percentage of proteins that could be quantified from 40 to 93%. Repeated LC-MS/MS analyses (3-4 times) of each sample increased the number of identified proteins by 60%. The use of Percoll/sucrose density separation allowed subfractionation of membranes leading to enrichment of membrane proteins (66%) and reduction from 33% to only 16% of protein from other membranous organelles such as endoplasmatic reticulum, Golgi, and mitochondria. In total, our optimized methods resulted in 1919 protein identifications (corresponding to 826 at similarity level 80% (SL80); 1145 (509 at SL80) were identified by two or more peptides of which 622 (300 at SL80) were membrane proteins. The quantitative proteomic analysis identified 16 cell surface proteins as potential markers of the ability of breast cancer cells to form distant metastases.
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PMID:Efficient isolation and quantitative proteomic analysis of cancer cell plasma membrane proteins for identification of metastasis-associated cell surface markers. 1934 Dec 46

Although we have identified two putative targets, ATF3 and CENPF, for a frequently gained/amplified region around 1q32-q41 in esophageal squamous cell carcinoma (ESCC), it is possible that other amplification targets remain to be identified. In this study, we tested whether SET and MYND domain-containing protein 2 (SMYD2), located between those two genes and encoding a lysine methyltransferase for histone H3K36 and p53K370 that regulates transcription and inhibits transactivation activity, respectively, acts as a cancer-promoting gene through activation/overexpression in ESCC. Frequent overexpression of SMYD2 messenger RNA and protein was observed in KYSE150 cells with remarkable amplification at 1q32-41.1 and other ESCC cell lines (11/43 lines, 25.6%). Overexpression of SMYD2 protein was frequently detected in primary tumor samples of ESCC (117/153 cases, 76.5%) as well and significantly correlated with gender, venous invasion, the pT category in the tumor-lymph node-metastases classification and status of recurrence. Patients with SMYD2-overexpressing tumors had a worse overall rate of survival than those with non-expressing tumors, and SMYD2 positivity was independently associated with a worse outcome in the multivariate analysis. Knockdown of SMYD2 expression inhibited and ectopic overexpression of SMYD2 promoted the proliferation of ESCC cells in a TP53 mutation-independent but SMYD2 expression-dependent manner. These findings suggest that SMYD2 plays an important role in tumor cell proliferation through its activation/overexpression and highlight its usefulness as a prognosticator and potential therapeutic target in ESCC.
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PMID:Overexpression of SMYD2 relates to tumor cell proliferation and malignant outcome of esophageal squamous cell carcinoma. 1942 49

Head and neck squamous cell carcinomas (HNSCCs) are known for their aggressive growth and propensity to metastasize. The authors investigated the effect of a novel nutrient mixture (NM) containing ascorbic acid, lysine, proline, and green tea extract on human HNSCC cell line FaDu in vivo and in vitro. Athymic male nude mice (n = 12) were inoculated with 3 x 10(6) FaDu cells subcutaneously and randomly divided into 2 groups: group A was fed a regular diet and group B a regular diet supplemented with 0.5% NM. Four weeks later, the mice were sacrificed and their tumors were excised, weighted, and processed for histology. In vitro, FaDu cells were cultured in Dulbecco's modified Eagle's medium and exposed to NM at 0 to 1000 microg/mL in triplicate. Cell proliferation was assessed by MTT assay, matrix metalloproteinase (MMP) secretion by gelatinase zymography, invasion through Matrigel, apoptosis by live-green caspases, and cell morphology by hematoxylin-eosin staining. NM inhibited the growth of tumors by 55% (P = .0002) and exhibited dose-dependent toxicity on FaDu cells in vitro, with 53% (P = .0003) at 1000 microg/mL NM. Zymography revealed MMP-2 and phorbol 12-myristate 13-acetate-induced MMP-9 secretion. NM inhibited secretion of both MMPs in a dose-dependent manner, with virtual total inhibition at 1000 microg/mL. NM significantly inhibited FaDu invasion through Matrigel with total block at 1000 microg/mL. NM induced dose-dependent apoptosis. In conclusion, NM has therapeutic potential in the treatment of HNSCC by significantly suppressing tumor growth and significantly inhibiting MMP secretion and invasion of HNSCC cells in vitro.
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PMID:Marked inhibition of growth and invasive parameters of head and neck squamous carcinoma FaDu by a nutrient mixture. 1967 26

Non-invasive detection of prostate cancer or metastases still remains a challenge in the field of molecular imaging. In our recent work of screening arginine- or lysine-rich peptides for intracellular delivery of a therapeutic agent into prostate cancer cells, an arginine-rich cell permeable peptide (NH(2)GR(11)) was found with an unexpectedly preferential uptake in prostate cancer cell lines. The goal of this work was to develop this peptide as a positron emission tomography (PET) imaging probe for specific detection of distant prostate cancer metastases. The optimal length of arginine-rich peptides was evaluated by the cell uptake efficiency of three fluorescein isothiocyanate (FITC)-tagged oligoarginines (NHGR(9), NHGR(11), and NHGR(13)) in four human prostate cell lines (LNCaP, PZ-HPV-7, DU145, and PC3). Of the three oligoarginines, NH(2)GR(11) showed the highest cell uptake and internalization efficiency with its subcellular localization in cytosol. The biodistribution of FITC-NHGR(9), FITC-NHGR(11), and FITC-NHGR(13) performed in control nude mice displayed the unique preferential accumulation of FITC-NHGR(11) in the prostate tissue. Further in vivo evaluation of FITC-NHGR(11) in PC3 tumor-bearing nude mice revealed elevated uptake of this peptide in tumors as compared to other organs. In vivo pharmacokinetics evaluated with (64)Cu-labeled NH(2)GR(11) showed that the peptide was rapidly cleared from the blood (t(1/2) = 10.7 min) and its elimination half-life was 17.2 h. The PET imaging specificity of (64)Cu-labled NH(2)GR(11) was demonstrated for the detection of prostate cancer in a comparative imaging experiment using two different human cancer xenograft models.
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PMID:A cell permeable peptide analog as a potential-specific PET imaging probe for prostate cancer detection. 2022 50

Large intervening non-coding RNAs (lincRNAs) are pervasively transcribed in the genome yet their potential involvement in human disease is not well understood. Recent studies of dosage compensation, imprinting, and homeotic gene expression suggest that individual lincRNAs can function as the interface between DNA and specific chromatin remodelling activities. Here we show that lincRNAs in the HOX loci become systematically dysregulated during breast cancer progression. The lincRNA termed HOTAIR is increased in expression in primary breast tumours and metastases, and HOTAIR expression level in primary tumours is a powerful predictor of eventual metastasis and death. Enforced expression of HOTAIR in epithelial cancer cells induced genome-wide re-targeting of Polycomb repressive complex 2 (PRC2) to an occupancy pattern more resembling embryonic fibroblasts, leading to altered histone H3 lysine 27 methylation, gene expression, and increased cancer invasiveness and metastasis in a manner dependent on PRC2. Conversely, loss of HOTAIR can inhibit cancer invasiveness, particularly in cells that possess excessive PRC2 activity. These findings indicate that lincRNAs have active roles in modulating the cancer epigenome and may be important targets for cancer diagnosis and therapy.
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PMID:Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. 2039 66

Consumption of a plant-based diet has been associated with prevention of the development and progression of cancer. We have developed strategies to inhibit cancer development and its spread by targeting common mechanisms used by all types of cancer cells that decrease stability and integrity of connective tissue. Strengthening of collagen and connective tissue can be achieved naturally through the synergistic effects of selected nutrients, such as lysine, proline, ascorbic acid and green tea extract (NM). This micronutrient mixture has exhibited a potent anticancer activity in vivo and in vitro in a few dozen cancer cell lines. Its anti-cancer effects include inhibition of metastasis, tumor growth, matrix metalloproteinase (MMP) secretion, invasion, angiogenesis, and cell growth as well as induction of apoptosis. Many cancers are often diagnosed at later stages, when metastasis has occurred, which standard treatment has been unable to control. Our studies on NM effects on hepatic and pulmonary metastasis demonstrated profound, significant suppression of metastasis in a murine model. Evaluation of effects of NM on xenografts in murine models demonstrated significant reduction in tumor size and tumor burden in all human cancer cell lines tested. In vitro studies demonstrated that NM was very effective in inhibition of cell proliferation (by MTT assay), MMP secretion (by gelatinase zymography), cell invasion (through Matrigel), cell migration (by scratch test), induction of apoptosis (by live green caspase) and induction of pro-apoptotic genes in many diverse cancer cell lines. Furthermore, in vivo and in vitro studies of effects of individual micronutrients compared to their specific combination demonstrated synergistic effects resulting in improved anticancer potency.
Cancer Metastasis Rev 2010 Sep
PMID:Micronutrient synergy--a new tool in effective control of metastasis and other key mechanisms of cancer. 2071 5

N-Myc downstream-regulated gene 1 (NDRG1) plays vital roles in tumor metastasis suppression and is frequently silenced in metastatic colon cancers. NDRG1 is silenced in a highly metastatic colon cancer cell line SW620. The objective of this study was to investigate the potential mechanisms involved in silencing of the NDRG1 gene. SW480 and SW620 are two colon cancer cell lines established from the same patient with different metastatic potentials, making them an ideal model for investigation of metastatic mechanisms. Knockdown of NDRG1 in SW480 to a level that is similar to that in SW620 also modulated cell cycle and proliferation in SW480 towards the status of the highly metastatic SW620. Epigenetic mechanisms of the transcriptional control of NDRG1 were investigated. The silencing of NDRG1 in SW620 was not due to promoter hyper-methylation as bisulfite sequencing of the NDRG1 promoter showed minimal DNA methylation in both cell lines. On the other hand, chromatin immunoprecipitation showed a significantly higher level of RNA polymerase II (Pol II) association with the NDRG1 promoter in SW480 compared to SW620, in agreement with its gene expression level. The low Pol II binding at the NDRG1 promoter in SW620 was associated with gene-wide decrease in histone H4 acetylation and increase in histone H3 serine 10 phosphorylation. Meanwhile, the NDRG1 coding region showed much higher histone H3 lysine 4 methylation in SW480. In conclusion we observed unique histone modifications in two colon cancer cell lines with different metastatic potentials, indicating possible mechanisms for the down-regulation of NDRG1 in metastatic SW620.
Clin Exp Metastasis 2011 Feb
PMID:Transcriptional silencing of N-Myc downstream-regulated gene 1 (NDRG1) in metastatic colon cancer cell line SW620. 2118 44

Control of gene expression is exerted at a number of different levels, one of which is the accessibility of genes and their controlling elements to the transcriptional machinery. Accessibility is dictated broadly by the degree of chromatin compaction, which is influenced in part by polycomb group proteins. EZH2, together with SUZ12 and EED, forms the polycomb repressive complex 2 (PRC2), which catalyzes trimethylation of histone H3 lysine 27 (H3K27me3). PRC2 may recruit other polycomb complexes, DNA methyltransferases, and histone deacetylases, resulting in additional transcriptional repressive marks and chromatin compaction at key developmental loci. Overexpression of EZH2 is a marker of advanced and metastatic disease in many solid tumors, including prostate and breast cancer. Mutation of EZH2 Y641 is described in lymphoma and results in enhanced activity, whereas inactivating mutations are seen in poor prognosis myeloid neoplasms. No histone demethylating agents are currently available for treatment of patients, but 3-deazaneplanocin (DZNep) reduces EZH2 levels and H3K27 trimethylation, resulting in reduced cell proliferation in breast and prostate cancer cells in vitro. Furthermore, synergistic effects are seen for combined treatment with DNA demethylating agents and histone deacetylation inhibitors, opening up the possibility of refined epigenetic treatments in the future.
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PMID:Aberrations of EZH2 in cancer. 2136 48

MMSET (WHSC1/NSD2) is a SET domain-containing histone lysine methyltransferase the expression of which is deregulated in a subgroup of multiple myelomas with the t(4;14)(p16;q32) translocation associated with poor prognosis. Recent studies have shown that MMSET mRNA levels are increased in other tumor types as well. We have carried out immunohistochemical staining of tissue microarrays and found that MMSET protein is frequently and highly expressed in neuroblastoma (MMSET positive in 75% of neuroblastomas, n = 164). The expression level of MMSET in neuroblastomas was significantly associated with poor survival, negative prognostic factors, and metastatic disease. Moreover, a subset of neuroblastomas for which pre- and postchemotherapy biopsies were available displayed a strong decrease in MMSET protein levels after chemotherapy. In agreement with neuroblastomas becoming more differentiated after treatment, we show that retinoic acid-induced differentiation of human neuroblastoma cells in vitro also leads to a strong decrease in MMSET levels. Furthermore, we show that the high levels of MMSET in normal neural progenitor cells are strongly downregulated during differentiation. Importantly, we show that MMSET is required for proliferation of neuroblastoma cells and brain-derived neural stem cells. Taken together, our results suggest that MMSET is implicated in neuroblastomagenesis possibly by supporting proliferation of progenitor cells and negatively regulating their differentiation. In this respect, MMSET might be a strong candidate therapeutic target in a subset of neuroblastomas with unfavorable prognosis.
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PMID:MMSET is highly expressed and associated with aggressiveness in neuroblastoma. 2152 57


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