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MARS; methionyl-tRNA synthetase (12q13.3)

Gene Summary

Gene:MARS; methionyl-tRNA synthetase
Aliases: MRS, METRS, MTRNS, SPG70
Location:12q13.3
Summary:This gene encodes a member of the class I family of aminoacyl-tRNA synthetases. These enzymes play a critical role in protein biosynthesis by charging tRNAs with their cognate amino acids. The encoded protein is a component of the multi-tRNA synthetase complex and catalyzes the ligation of methionine to tRNA molecules. [provided by RefSeq, Jan 2011]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:methionine--tRNA ligase, cytoplasmic
HPRD
Source:NCBI
Updated:12 December, 2014

Gene
Ontology:

What does this gene/protein do?
Show (10)

Pathways:

What pathways are this gene/protein implicaed in?
- Aminoacyl-tRNA biosynthesis KEGG
- Methionine metabolism KEGG
- Selenoamino acid metabolism KEGG
Data from KEGG and BioCarta [BIOCARTA terms] via CGAP

Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 12 December 2014 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Cell Differentiation
  • Protein-Serine-Threonine Kinases
  • Tumor Suppressor Proteins
  • Ovarian Cancer
  • FISH
  • Genetic Predisposition
  • Gene Expression Regulation
  • Viral Proteins
  • Breast Cancer
  • Matrix Attachment Regions
  • Transcription
  • Cancer DNA
  • DNA-Binding Proteins
  • Patient Satisfaction
  • Chromosome 12
  • RNA
  • Translocation
  • Neoplastic Cell Transformation
  • Molecular Sequence Data
  • Base Sequence
  • Cancer Gene Expression Regulation
  • Genetic Recombination
  • Chromosome Aberrations
  • Mutation
  • Cancer RNA
  • Transcription Factors
  • Adolescents
  • Myeloid Leukemia
  • Nuclear Matrix
  • Lung Cancer
  • Leukaemia
  • Childhood Cancer
  • Nucleic Acid Hybridization
  • Oncogenes
  • Polymerase Chain Reaction
  • Cell Cycle
  • myc Genes
  • Chromosome Mapping
  • DNA
  • Urea
Tag cloud generated 12 December, 2014 using data from PubMed, MeSH and CancerIndex

Notable (4)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Breast CancerMARS and Breast Cancer View Publications10
LeukaemiaMARS and Myeloid Leukemia View Publications5
Lung CancerMARS and Lung Cancer View Publications3
Ovarian CancerMARS and Ovarian Cancer View Publications3

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Related Links

Latest Publications: MARS (cancer-related)

Giordano M, Roncagalli R, Bourdely P, et al.
The tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20) imposes a brake on antitumor activity of CD8 T cells.
Proc Natl Acad Sci U S A. 2014; 111(30):11115-20 [PubMed] Article available free on PMC after 29/01/2015 Related Publications
The transcription factor NF-κB is central to inflammatory signaling and activation of innate and adaptive immune responses. Activation of the NF-κB pathway is tightly controlled by several negative feedback mechanisms, including A20, an ubiquitin-modifying enzyme encoded by the tnfaip3 gene. Mice with selective deletion of A20 in myeloid, dendritic, or B cells recapitulate some human inflammatory pathology. As we observed high expression of A20 transcripts in dysfunctional CD8 T cells in an autochthonous melanoma, we analyzed the role of A20 in regulation of CD8 T-cell functions, using mice in which A20 was selectively deleted in mature conventional T cells. These mice developed lymphadenopathy and some organ infiltration by T cells but no splenomegaly and no detectable pathology. A20-deleted CD8 T cells had increased sensitivity to antigen stimulation with production of large amounts of IL-2 and IFNγ, correlated with sustained nuclear expression of NF-κB components reticuloendotheliosis oncogene c-Rel and p65. Overexpression of A20 by retroviral transduction of CD8 T cells dampened their intratumor accumulation and antitumor activity. In contrast, relief from the A20 brake in NF-κB activation in adoptively transferred antitumor CD8 T cells led to improved control of melanoma growth. Tumor-infiltrating A20-deleted CD8 T cells had enhanced production of IFNγ and TNFα and reduced expression of the inhibitory receptor programmed cell death 1. As manipulation of A20 expression in CD8 T cells did not result in pathologic manifestations in the mice, we propose it as a candidate to be targeted to increase antitumor efficiency of adoptive T-cell immunotherapy.

Related: Interleukin 2 (Aldesleukin) Melanoma TNF


Sarojam S, Raveendran S, Narayanan G, Sreedharan H
Novel t(7;10)(p22;p24) along with NPM1 mutation in patient with relapsed acute myeloid leukemia.
Ann Saudi Med. 2013 Nov-Dec; 33(6):619-22 [PubMed] Related Publications
Chromosomal abnormalities/genetic mutations associated with hematological malignancies alter the structure and function of genes controlling cell proliferation and differentiation through multiple and complex pathways, resulting different clinical outcomes. This is a case study of a lady presented with acute myeloid leukemia (AML M1) at our center who relapsed 10 years after the induction therapy. Cytogenetic and molecular analyses were performed in this case at the time of relapse to find out the chromosomal abnormalities and genetic abnormalities like FMS-like tyrosine kinase (FLT3) and nucleophosmin (NPM1) mutation. The cytogenetic analysis of bone marrow established a novel translocation t(7;10) (p22;q24) in 100% of the cells analyzed. Phytohaemagglutinin (PHA)-stimulated blood culture also revealed the same abnormality. Apart from this, the molecular analysis showed NPM1 exon 12 (hot-spot) mutation in this patient. This was the first report of novel chromosomal translocation in this subset of AML in which a new translocation along with NPM1 mutation was discussed.

Related: Acute Myeloid Leukemia (AML) NPM1 gene FLT3 gene


Zhao X, Qu Z, Tickner J, et al.
The role of SATB2 in skeletogenesis and human disease.
Cytokine Growth Factor Rev. 2014; 25(1):35-44 [PubMed] Related Publications
Since the discovery of SATB2 (special AT-rich sequence binding protein 2) a decade ago, its pivotal roles in development and tissue regeneration have emerged, particularly in craniofacial patterning and development, palate formation, and osteoblast differentiation and maturation. As a member of the special AT-rich binding proteins family that bind to nuclear matrix-attachment regions (MAR), it also displays functional versatility in central nervous development, especially corpus callosum and pons formation, cancer development and prognosis, as well as in immune regulation. At the molecular level, Satb2 gene expression appears to be tissue and stage-specific, and is regulated by several cytokines and growth factors, such as BMP2/4/7, insulin, CNTF, and LIF via ligand receptor signaling pathways. SATB2 mainly performs a twofold role as a transcription regulator by directly binding to AT-rich sequences in MARs to modulate chromatin remodeling, or through association with other transcription factors to modulate the cis-regulation elements and thus to regulate the expression of down-stream target genes and a wide range of biological processes. This contemporary review provides an exploration of the molecular characteristics and function of SATB2; including its expression and cytokine regulation, its involvement in human disease, and its potential roles in skeletogenesis.

Related: Colorectal (Bowel) Cancer Cytokines


Albanus RD, Juliani Siqueira Dalmolin R, Alves Castro MA, et al.
Reverse engineering the neuroblastoma regulatory network uncovers MAX as one of the master regulators of tumor progression.
PLoS One. 2013; 8(12):e82457 [PubMed] Article available free on PMC after 29/01/2015 Related Publications
Neuroblastoma is the most common extracranial tumor and a major cause of infant cancer mortality worldwide. Despite its importance, little is known about its molecular mechanisms. A striking feature of this tumor is its clinical heterogeneity. Possible outcomes range from aggressive invasion to other tissues, causing patient death, to spontaneous disease regression or differentiation into benign ganglioneuromas. Several efforts have been made in order to find tumor progression markers. In this work, we have reconstructed the neuroblastoma regulatory network using an information-theoretic approach in order to find genes involved in tumor progression and that could be used as outcome predictors or as therapeutic targets. We have queried the reconstructed neuroblastoma regulatory network using an aggressive neuroblastoma metastasis gene signature in order to find its master regulators (MRs). MRs expression profiles were then investigated in other neuroblastoma datasets so as to detect possible clinical significance. Our analysis pointed MAX as one of the MRs of neuroblastoma progression. We have found that higher MAX expression correlated with favorable patient outcomes. We have also found that MAX expression and protein levels were increased during neuroblastoma SH-SY5Y cells differentiation. We propose that MAX is involved in neuroblastoma progression, possibly increasing cell differentiation by means of regulating the availability of MYC:MAX heterodimers. This mechanism is consistent with the results found in our SH-SY5Y differentiation protocol, suggesting that MAX has a more central role in these cells differentiation than previously reported. Overexpression of MAX has been identified as anti-tumorigenic in other works, but, to our knowledge, this is the first time that the link between the expression of this gene and malignancy was verified under physiological conditions.

Related: Neuroblastoma Signal Transduction


Fiaschetti G, Abela L, Nonoguchi N, et al.
Epigenetic silencing of miRNA-9 is associated with HES1 oncogenic activity and poor prognosis of medulloblastoma.
Br J Cancer. 2014; 110(3):636-47 [PubMed] Article available free on PMC after 04/02/2015 Related Publications
BACKGROUND: microRNA-9 is a key regulator of neuronal development aberrantly expressed in brain malignancies, including medulloblastoma. The mechanisms by which microRNA-9 contributes to medulloblastoma pathogenesis remain unclear, and factors that regulate this process have not been delineated.
METHODS: Expression and methylation status of microRNA-9 in medulloblastoma cell lines and primary samples were analysed. The association of microRNA-9 expression with medulloblastoma patients' clinical outcome was assessed, and the impact of microRNA-9 restoration was functionally validated in medulloblastoma cells.
RESULTS: microRNA-9 expression is repressed in a large subset of MB samples compared with normal fetal cerebellum. Low microRNA-9 expression correlates significantly with the diagnosis of unfavourable histopathological variants and with poor clinical outcome. microRNA-9 silencing occurs via cancer-specific CpG island hypermethylation. HES1 was identified as a direct target of microRNA-9 in medulloblastoma, and restoration of microRNA-9 was shown to trigger cell cycle arrest, to inhibit clonal growth and to promote medulloblastoma cell differentiation.
CONCLUSIONS: microRNA-9 is a methylation-silenced tumour suppressor that could be a potential candidate predictive marker for poor prognosis of medulloblastoma. Loss of microRNA-9 may confer a proliferative advantage to tumour cells, and it could possibly contribute to disease pathogenesis. Thus, re-expression of microRNA-9 may constitute a novel epigenetic regulation strategy against medulloblastoma.

Related: Childhood Medulloblastoma / PNET


Pisanu ME, Ricci A, Paris L, et al.
Monitoring response to cytostatic cisplatin in a HER2(+) ovary cancer model by MRI and in vitro and in vivo MR spectroscopy.
Br J Cancer. 2014; 110(3):625-35 [PubMed] Article available free on PMC after 04/02/2015 Related Publications
BACKGROUND: Limited knowledge is available on alterations induced by cytostatic drugs on magnetic resonance spectroscopy (MRS) and imaging (MRI) parameters of human cancers, in absence of apoptosis or cytotoxicity. We here investigated the effects of a cytostatic cisplatin (CDDP) treatment on (1)H MRS and MRI of HER2-overexpressing epithelial ovarian cancer (EOC) cells and in vivo xenografts.
METHODS: High-resolution MRS analyses were performed on in vivo passaged SKOV3.ip cells and cell/tissue extracts (16.4 or 9.4 T). In vivo MRI/MRS quantitative analyses (4.7 T) were conducted on xenografts obtained by subcutaneous implantation of SKOV3.ip cells in SCID mice. The apparent diffusion coefficient (ADC) and metabolite levels were measured.
RESULTS: CDDP-induced cytostatic effects were associated with a metabolic shift of cancer cells towards accumulation of MRS-detected neutral lipids, whereas the total choline profile failed to be perturbed in both cultured cells and xenografts. In vivo MRI examinations showed delayed tumour growth in the CDDP-treated group, associated with early reduction of the ADC mean value.
CONCLUSION: This study provides an integrated set of information on cancer metabolism and physiology for monitoring the response of an EOC model to a cytostatic chemotherapy, as a basis for improving the interpretation of non-invasive MR examinations of EOC patients.

Related: Cisplatin Ovarian Cancer


Granata A, Nicoletti R, Tinaglia V, et al.
Choline kinase-alpha by regulating cell aggressiveness and drug sensitivity is a potential druggable target for ovarian cancer.
Br J Cancer. 2014; 110(2):330-40 [PubMed] Article available free on PMC after 21/01/2015 Related Publications
BACKGROUND: Aberrant choline metabolism has been proposed as a novel cancer hallmark. We recently showed that epithelial ovarian cancer (EOC) possesses an altered MRS-choline profile, characterised by increased phosphocholine (PCho) content to which mainly contribute over-expression and activation of choline kinase-alpha (ChoK-alpha).
METHODS: To assess its biological relevance, ChoK-alpha expression was downmodulated by transient RNA interference in EOC in vitro models. Gene expression profiling by microarray analysis and functional analysis was performed to identify the pathway/functions perturbed in ChoK-alpha-silenced cells, then validated by in vitro experiments.
RESULTS: In silenced cells, compared with control, we observed: (I) a significant reduction of both CHKA transcript and ChoK-alpha protein expression; (II) a dramatic, proportional drop in PCho content ranging from 60 to 71%, as revealed by (1)H-magnetic spectroscopy analysis; (III) a 35-36% of cell growth inhibition, with no evidences of apoptosis or modification of the main cellular survival signalling pathways; (IV) 476 differentially expressed genes, including genes related to lipid metabolism. Ingenuity pathway analysis identified cellular functions related to cell death and cellular proliferation and movement as the most perturbed. Accordingly, CHKA-silenced cells displayed a significant delay in wound repair, a reduced migration and invasion capability were also observed. Furthermore, although CHKA silencing did not directly induce cell death, a significant increase of sensitivity to platinum, paclitaxel and doxorubicin was observed even in a drug-resistant context.
CONCLUSION: We showed for the first time in EOC that CHKA downregulation significantly decreased the aggressive EOC cell behaviour also affecting cells' sensitivity to drug treatment. These observations open the way to further analysis for ChoK-alpha validation as a new EOC therapeutic target to be used alone or in combination with conventional drugs.

Related: Doxorubicin Ovarian Cancer Paclitaxel Signal Transduction


Hemminki O, Immonen R, Närväinen J, et al.
In vivo magnetic resonance imaging and spectroscopy identifies oncolytic adenovirus responders.
Int J Cancer. 2014; 134(12):2878-90 [PubMed] Related Publications
At present, it is not possible to reliably identify patients who will benefit from oncolytic virus treatments. Conventional modalities such as computed tomography (CT), which measure tumor size, are unreliable owing to inflammation-induced tumor swelling. We hypothesized that magnetic resonance imaging (MRI) and spectroscopy (MRS) might be useful in this regard. However, little previous data exist and neither oncolytic adenovirus nor immunocompetent models have been assessed by MRS. Here, we provide evidence that in T2-weighted MRI a hypointense core area, consistent with coagulative necrosis, develops in immunocompetent Syrian hamster carcinomas that respond to oncolytic adenovirus treatment. The same phenomenon was observed in a neuroblastoma patient while he responded to the treatment. With relapse at a later stage, however, the tumor of this patient became moderately hyperintense. We found that MRS of taurine, choline and unsaturated fatty acids can be useful early indicators of response and provide detailed information about tumor growth and degeneration. In hamsters, calprotectin-positive inflammatory cells (heterophils and macrophages) were found in abundance; particularly surrounding necrotic areas in carcinomas and T cells were significantly increased in sarcomas, when these had been treated with a granulocyte-macrophage colony-stimulating factor-producing virus, suggesting a possible link between oncolysis, necrosis (seen as a hypointense core in MRI) and/or immune response. Our study indicates that both MRI and MRS could be useful in the estimation of oncolytic adenovirus efficacy at early time points after treatment.

Related: Neuroblastoma Soft Tissue Sarcomas


Bruggers CS, Moore K
Magnetic resonance imaging spectroscopy in pediatric atypical teratoid rhabdoid tumors of the brain.
J Pediatr Hematol Oncol. 2014; 36(6):e341-5 [PubMed] Related Publications
BACKGROUND: Pediatric central nervous system (CNS) atypical teratoid rhabdoid tumors (ATRT) are highly malignant tumors characterized by SMARCB1 gene abnormalities. Despite chemoradiation responsiveness, most children die of disease. No imaging findings distinguish ATRT from other malignant brain tumors. This study sought to describe magnetic resonance spectroscopy (MRS) of childhood CNS ATRT and identify metabolite patterns for diagnosis and disease status monitoring.
METHODS: Data from 7 children diagnosed with CNS ATRT from 2007 to 2010, whose imaging included MRS, were retrospectively reviewed.
RESULTS: Age at diagnosis ranged from 2.5 to 54 months. Tumors were large with calcium and cysts and avid gadolinium enhancement. All were isointense on T1-weighted imaging and mildly hyperintense on T2-weighted imaging. Short-TE MRS showed prominent lactate+lipid and choline, minimal N-acetyl acetate (NAA), and rarely minimal myoinositol and low creatine peaks. Long TE showed prominent choline, minimal NAA, and rarely low lactate peaks.
CONCLUSIONS: The combination of prominent choline and lactate+lipids peaks, and generally absent NAA and myoinositol peaks by MRS in this panel of ATRT expands existing information and provides a potentially distinct metabolite profile from other malignant pediatric brain tumors, including medulloblastoma. Prospective, comparative quantitative MRS of ATRT with other pediatric CNS tumors is warranted.

Related: Malignant Rhabdoid Tumour


Cappello P, Blaser H, Gorrini C, et al.
Role of Nek2 on centrosome duplication and aneuploidy in breast cancer cells.
Oncogene. 2014; 33(18):2375-84 [PubMed] Related Publications
Breast cancer is the most common solid tumor and the second most common cause of death in women. Despite a large body of literature and progress in breast cancer research, many molecular aspects of this complex disease are still poorly understood, hindering the design of specific and effective therapeutic strategies. To identify the molecules important in breast cancer progression and metastasis, we tested the in vivo effects of inhibiting the functions of various kinases and genes involved in the regulation/modulation of the cytoskeleton by downregulating them in mouse PyMT mammary tumor cells and human breast cancer cell lines. These kinases and cytoskeletal regulators were selected based on their prognostic values for breast cancer patient survival. PyMT tumor cells, in which a selected gene was stably knocked down were injected into the tail veins of mice, and the formation of tumors in the lungs was monitored. One of the several genes found to be important for tumor growth in the lungs was NIMA-related kinases 2 (Nek2), a cell cycle-related protein kinase. Furthermore, Nek2 was also important for tumor growth in the mammary fat pad. In various human breast cancer cell lines, Nek2 knockdown induced aneuploidy and cell cycle arrest that led to cell death. Significantly, the breast cancer cell line most sensitive to Nek2 depletion was of the triple negative breast cancer subtype. Our data indicate that Nek2 has a pivotal role in breast cancer growth at primary and secondary sites, and thus may be an attractive and novel therapeutic target for this disease.

Related: Breast Cancer


Falck Miniotis M, Arunan V, Eykyn TR, et al.
MEK1/2 inhibition decreases lactate in BRAF-driven human cancer cells.
Cancer Res. 2013; 73(13):4039-49 [PubMed] Related Publications
The RAS/BRAF/MEK/ERK signaling pathway is a central driver in cancer with many BRAF and MEK inhibitors being evaluated in clinical trials. Identifying noninvasive biomarkers of early pharmacodynamic responses is important for development of these targeted drugs. As increased aerobic glycolysis is often observed in cancer, we hypothesized that MEK1/2 (MAP2K1/MAP2K2) inhibitors may reduce lactate levels as detected by magnetic resonance spectroscopy (MRS), as a metabolic biomarker for the pharmacodynamic response. MRS was used to monitor intracellular and extracellular levels of lactate in human cancer cells in vitro and in melanoma tumors ex vivo. In addition, we used (1)H MRS and a fluorescent glucose analog to evaluate the effect of MEK inhibition on glucose uptake. MEK1/2 signaling inhibition reduced extracellular lactate levels in BRAF-dependent cells but not BRAF-independent cells. The reduction in extracellular lactate in BRAF-driven melanoma cells was time-dependent and associated with reduced expression of hexokinase-II driven by c-Myc depletion. Taken together, these results reveal how MEK1/2 inhibition affects cancer cell metabolism in the context of BRAF oncogene addiction. Furthermore, they offer a preclinical proof-of-concept for the use of MRS to measure lactate as a noninvasive metabolic biomarker for pharmacodynamic response to MEK1/2 inhibition in BRAF-driven cancers.

Related: Melanoma BRAF gene


Ward CS, Eriksson P, Izquierdo-Garcia JL, et al.
HDAC inhibition induces increased choline uptake and elevated phosphocholine levels in MCF7 breast cancer cells.
PLoS One. 2013; 8(4):e62610 [PubMed] Article available free on PMC after 21/01/2015 Related Publications
Histone deacetylase (HDAC) inhibitors have emerged as effective antineoplastic agents in the clinic. Studies from our lab and others have reported that magnetic resonance spectroscopy (MRS)-detectable phosphocholine (PC) is elevated following SAHA treatment, providing a potential noninvasive biomarker of response. Typically, elevated PC is associated with cancer while a decrease in PC accompanies response to antineoplastic treatment. The goal of this study was therefore to elucidate the underlying biochemical mechanism by which HDAC inhibition leads to elevated PC. We investigated the effect of SAHA on MCF-7 breast cancer cells using (13)C MRS to monitor [1,2-(13)C] choline uptake and phosphorylation to PC. We found that PC synthesis was significantly higher in treated cells, representing 154±19% of control. This was within standard deviation of the increase in total PC levels detected by (31)P MRS (129±7% of control). Furthermore, cellular choline kinase activity was elevated (177±31%), while cytidylyltransferase activity was unchanged. Expression of the intermediate-affinity choline transporter SLC44A1 and choline kinase α increased (144% and 161%, respectively) relative to control, as determined by mRNA microarray analysis with protein-level confirmation by Western blotting. Taken together, our findings indicate that the increase in PC levels following SAHA treatment results from its elevated synthesis. Additionally, the concentration of glycerophosphocholine (GPC) increased significantly with treatment to 210±45%. This is likely due to the upregulated expression of several phospholipase A2 (PLA2) isoforms, resulting in increased PLA2 activity (162±18%) in SAHA-treated cells. Importantly, the levels of total choline (tCho)-containing metabolites, comprised of choline, PC and GPC, are readily detectable clinically using (1)H MRS. Our findings thus provide an important step in validating clinically translatable non-invasive imaging methods for follow-up diagnostics of HDAC inhibitor treatment.

Related: Breast Cancer


Crisi G, Orsingher L, Filice S
Lipid and macromolecules quantitation in differentiating glioblastoma from solitary metastasis: a short-echo time single-voxel magnetic resonance spectroscopy study at 3 T.
J Comput Assist Tomogr. 2013 Mar-Apr; 37(2):265-71 [PubMed] Related Publications
OBJECTIVE: The differentiation between solitary metastasis (MET) and glioblastoma (GBM) is difficult using only magnetic resonance imaging techniques. Magnetic resonance spectroscopy (MRS) lipid signal indicates cellular necrosis both in GBMs and METs. The purpose of this prospective study was to determine whether a class of lipids and/or macromolecules (MMs), able to efficiently discriminate between these two types of lesions, exists.
METHODS: Forty-one patients with solitary brain tumor (23 GBMs and 18 METs) underwent magnetic resonance imaging and single-voxel MRS. Short-echo time point resolved spectroscopy sequence acquisition with water suppression technique was used. Spectra were analyzed using LCModel. Absolute quantification was performed with "water-scaling" procedure. The analysis was focused on sums of lipid and macromolecular (LM) components at 0.9 and 1.3 ppm.
RESULTS: The LM13 absolute concentration was statistically different (P < 0.0001) between GBMs and METs. With a cutoff of 81 mM in LM13 absolute concentration, METs and GBMs can be distinguished with a 78% of specificity and an 81% of sensitivity. The presence of the MM12 peak, related to the fucose II complex, in tumors harboring a K-ras gene mutation has been investigated.
CONCLUSIONS: We exploited the performance of a clinically easily implementable method, such as short-echo time single-voxel MRS, for the differentiation between brain metastasis and primary brain tumors. The study showed that MRS absolute lipid and macromolecular signals could be helpful in differentiating GBM from metastasis. LM13 class was found to be a discriminant parameter with an accuracy of 85%. Detection of the MM12-fucose peak may also have a role in understanding molecular biology of brain metastasis and should be further investigated to address specific metabolic phenotypes.


Sakowicz-Burkiewicz M, Kitowska A, Grden M, et al.
Differential effect of adenosine receptors on growth of human colon cancer HCT 116 and HT-29 cell lines.
Arch Biochem Biophys. 2013; 533(1-2):47-54 [PubMed] Related Publications
The study aimed to evaluate the impact of adenosine receptors (ARs) on human colon tumor cells (HCT 116, HT-29) growth and sensitivity to 5-Fluorouracil (5-FU) an anticancer chemotherapeutic drug. The exposure of cancer cells to a selective A(3)-AR agonist (IB-MECA) resulted in an increase in HT-29 cells number, whereas the number of HCT 116 cells decreased significantly. In the presence of IB-MECA (1 μM) the percentage of apoptotic HT-29 cells significantly decreased, whereas the number of apoptotic and necrotic HCT 116 cells increased by 3- and 2,5-fold, respectively. The application of a selective A(2A)-AR agonist resulted in the increased survival of HCT 116 cells, but not HT-29 cells. The blockade of A(2A)-AR with ZM 241385 (0.1 μM) significantly increased the cytotoxicity of 5-FU (1 μM) in HCT 116 cells but not in HT-29 cells. The suppression of A(3)-AR with MRS 1523 (1 μM) increased the sensitivity of HT-29 cells to 5-FU while response of HCT 116 cells to 5-FU decreased. The growth promoting effect of IB-MECA in HT-29 cells was associated with the decreased intracellular cAMP level, whereas IB-MECA growth inhibitory effect in HCT 116 cells was abolished by okadaic acid (2 nM) indicating the involvement of protein phosphatase PP2A.

Related: Fluorouracil Signal Transduction


Yu W, Smil D, Li F, et al.
Bromo-deaza-SAH: a potent and selective DOT1L inhibitor.
Bioorg Med Chem. 2013; 21(7):1787-94 [PubMed] Related Publications
Chemical inhibition of proteins involved in chromatin-mediated signaling is an emerging strategy to control chromatin compaction with the aim to reprogram expression networks to alter disease states. Protein methyltransferases constitute one of the protein families that participate in epigenetic control of gene expression, and represent a novel therapeutic target class. Recruitment of the protein lysine methyltransferase DOT1L at aberrant loci is a frequent mechanism driving acute lymphoid and myeloid leukemias, particularly in infants, and pharmacological inhibition of DOT1L extends survival in a mouse model of mixed lineage leukemia. A better understanding of the structural chemistry of DOT1L inhibition would accelerate the development of improved compounds. Here, we report that the addition of a single halogen atom at a critical position in the cofactor product S-adenosylhomocysteine (SAH, an inhibitor of SAM-dependent methyltransferases) results in an 8-fold increase in potency against DOT1L, and reduced activities against other protein and non-protein methyltransferases. We solved the crystal structure of DOT1L in complex with Bromo-deaza-SAH and rationalized the observed effects. This discovery reveals a simple strategy to engineer selectivity and potency towards DOT1L into the adenosine scaffold of the cofactor shared by all methyltransferases, and can be exploited towards the development of clinical candidates against mixed lineage leukemia.

Related: Leukemia


Mamessier E, Pradel LC, Thibult ML, et al.
Peripheral blood NK cells from breast cancer patients are tumor-induced composite subsets.
J Immunol. 2013; 190(5):2424-36 [PubMed] Related Publications
Human NK lymphocytes are involved in antitumor immunity. The therapeutic potential of this population against cancers has stimulated their study and led to the discovery of several NK cell subsets, each of which is endowed with different immunoregulatory functions. We have previously reported that NK cell functions are profoundly altered in advanced breast cancer patients. In this study, we show that these tumor-mediated alterations also variably affect NK cell subsets. We found that in addition to the known human CD56(dim)CD16(+), CD56(bright)CD16(-), and CD56(-)CD16(+) NK cell subsets, two additional subsets, namely the CD56(bright)CD16(+) and CD56(dim)CD16(-) subsets, were increased in the peripheral blood of patients with advanced invasive breast cancers. These subsets corresponded to the main two subsets found at the tumor site. The extensive phenotype of these subsets revealed an "à la carte" pattern of expression for the various NK receptors, functional molecules, adhesion molecules, and chemokine receptors, depending on the subset. We next compared these subsets to known NK cell populations endowed with specific phenotypic characteristics, but also with functional properties. Our data show that advanced breast cancer patients have an increased proportion of more immature and noncytotoxic NK cell subsets in their peripheral blood, which might account for at least part of the low cytotoxic functions observed in these patients. They reveal a major heterogeneity and plasticity of the NK cell compartment, which are both tightly linked to the microenvironment. The identification of NK cell subsets endowed with particular functional capabilities might help monitor residual antitumor NK cell-mediated responses in breast cancer patients.

Related: Breast Cancer


Kindt N, Preillon J, Kaltner H, et al.
Macrophage migration inhibitory factor in head and neck squamous cell carcinoma: clinical and experimental studies.
J Cancer Res Clin Oncol. 2013; 139(5):727-37 [PubMed] Related Publications
PURPOSE: The present in vivo/in vitro study was undertaken in order to evaluate the importance of macrophage migration inhibitory factor (MIF) in the progression of head and neck squamous cell carcinoma (HNSCC).
METHODS: Tumor tissue expression (MIF immunostaining) and plasma levels (ELISA) of MIF were determined in HNSCC patients and correlated with tumor recurrence and metastasis, and overall survival. Furthermore, the impact of MIF expression on cell proliferation and anticancer drug sensitivity was examined in murine squamous carcinoma cell line SCCVII after MIF knockdown (MIF-KD).
RESULTS: As revealed by quantitative analysis of MIF immunostaining, tumor progression was accompanied by an increase in mean optical density (MOD) and labeling index (LI). Likewise, an elevation of MIF serum levels was noted in HNSCC patients (n = 66) versus healthy individuals (n = 16). Interestingly, comparison of laryngeal carcinoma patients on the basis of MIF tissue expression (high expression, LI ≥ 47, versus low expression, LI < 47) disclosed a significant difference between disease-free survival curves for local and nodal recurrence, and overall survival curve. In vitro, MIF knockdown in murine SCCVII cells resulted in reduced cell proliferation and a decrease in cell motility. In mice inoculated with SCCVII cells, MIF-KD tumors grew more slowly and also appeared more sensitive to chemotherapy.
CONCLUSIONS: Both clinical observations and experimental data suggest that MIF plays a pivotal role in the progression of HNSCC.

Related: Head and Neck Cancers Head and Neck Cancers - Molecular Biology


Lazovic J, Soto H, Piccioni D, et al.
Detection of 2-hydroxyglutaric acid in vivo by proton magnetic resonance spectroscopy in U87 glioma cells overexpressing isocitrate dehydrogenase-1 mutation.
Neuro Oncol. 2012; 14(12):1465-72 [PubMed] Article available free on PMC after 21/01/2015 Related Publications
The arginine 132 (R132) mutation of isocitrate dehydrogenase -1 (IDH1(R132)) results in production of 2-hydroxyglutarate (2-HG) and is associated with a better prognosis compared with wild-type (WT) in glioma patients. The majority of lower-grade gliomas express IDH1(R132), whereas this mutation is rare in grade IV gliomas. The aim of this study was to noninvasively investigate metabolic and physiologic changes associated with the IDH1 mutation in a mouse glioma model. Using a 7T magnet, we compared MRI and proton magnetic resonance spectroscopy (MRS) in U87 glioma cells overexpressing either the mutated IDH1(R132) or IDH1 wild-type (IDH1(WT)) gene in a mouse flank xenograft model. Flank tumors overexpressing IDH1(R132) showed a resonance at 2.25 ppm corresponding to the 2-HG peak described for human IDH1(R132) gliomas. WT tumors lacked this peak in all cases. IDH1 mutant tumors demonstrated significantly reduced glutamate by in vivo MRS. There were no significant differences in T(2), apparent diffusion coefficient (ADC), or perfusion values between the mutant and IDH1(WT) tumors. The IDH1(R132) mutation results in 2-HG resonance at 2.25 ppm and a reduction of glutamate levels as determined by MRS. Our results establish a model system where 2-HG can be monitored noninvasively, which should be helpful in validating 2-HG levels as a prognostic and/or predictive biomarker in glioma.


Borozan I, Wilson S, Blanchette P, et al.
CaPSID: a bioinformatics platform for computational pathogen sequence identification in human genomes and transcriptomes.
BMC Bioinformatics. 2012; 13:206 [PubMed] Article available free on PMC after 21/01/2015 Related Publications
BACKGROUND: It is now well established that nearly 20% of human cancers are caused by infectious agents, and the list of human oncogenic pathogens will grow in the future for a variety of cancer types. Whole tumor transcriptome and genome sequencing by next-generation sequencing technologies presents an unparalleled opportunity for pathogen detection and discovery in human tissues but requires development of new genome-wide bioinformatics tools.
RESULTS: Here we present CaPSID (Computational Pathogen Sequence IDentification), a comprehensive bioinformatics platform for identifying, querying and visualizing both exogenous and endogenous pathogen nucleotide sequences in tumor genomes and transcriptomes. CaPSID includes a scalable, high performance database for data storage and a web application that integrates the genome browser JBrowse. CaPSID also provides useful metrics for sequence analysis of pre-aligned BAM files, such as gene and genome coverage, and is optimized to run efficiently on multiprocessor computers with low memory usage.
CONCLUSIONS: To demonstrate the usefulness and efficiency of CaPSID, we carried out a comprehensive analysis of both a simulated dataset and transcriptome samples from ovarian cancer. CaPSID correctly identified all of the human and pathogen sequences in the simulated dataset, while in the ovarian dataset CaPSID's predictions were successfully validated in vitro.

Related: Ovarian Cancer


Valles I, Pajares MJ, Segura V, et al.
Identification of novel deregulated RNA metabolism-related genes in non-small cell lung cancer.
PLoS One. 2012; 7(8):e42086 [PubMed] Article available free on PMC after 21/01/2015 Related Publications
Lung cancer is a leading cause of cancer death worldwide. Several alterations in RNA metabolism have been found in lung cancer cells; this suggests that RNA metabolism-related molecules are involved in the development of this pathology. In this study, we searched for RNA metabolism-related genes that exhibit different expression levels between normal and tumor lung tissues. We identified eight genes differentially expressed in lung adenocarcinoma microarray datasets. Of these, seven were up-regulated whereas one was down-regulated. Interestingly, most of these genes had not previously been associated with lung cancer. These genes play diverse roles in mRNA metabolism: three are associated with the spliceosome (ASCL3L1, SNRPB and SNRPE), whereas others participate in RNA-related processes such as translation (MARS and MRPL3), mRNA stability (PCBPC1), mRNA transport (RAE), or mRNA editing (ADAR2, also known as ADARB1). Moreover, we found a high incidence of loss of heterozygosity at chromosome 21q22.3, where the ADAR2 locus is located, in NSCLC cell lines and primary tissues, suggesting that the downregulation of ADAR2 in lung cancer is associated with specific genetic losses. Finally, in a series of adenocarcinoma patients, the expression of five of the deregulated genes (ADAR2, MARS, RAE, SNRPB and SNRPE) correlated with prognosis. Taken together, these results support the hypothesis that changes in RNA metabolism are involved in the pathogenesis of lung cancer, and identify new potential targets for the treatment of this disease.

Related: Non-Small Cell Lung Cancer Lung Cancer


Hundt W, Steinbach S, O'Connell-Rodwell CE, et al.
In vivo monitoring of antiangiogenic therapy by magnetic resonance and bioluminescence imaging in an M21 tumor model through activation of an hsp70 promoter-luciferase reporter construct.
Contrast Media Mol Imaging. 2012 Sep-Oct; 7(5):450-9 [PubMed] Related Publications
We have investigated the effect of targeted gene therapy on the melanoma cell line M21, using a combination of bioluminescence imaging (BLI) and magnetic resonance imaging (MRI). M21 cells transfected with a plasmid containing either an hsp70 (Hspa1b) or a CMV promoter fragment, along with the luciferase reporter gene, were grown to a tumor size of 900 mm(3) . Five mice in each group were intravenously treated every 72 h with a complex consisting of a nanoparticle, an Arg-Gly-Asp-peptide, and a dominant negative mutant protein kinase inhibitor gene. BLI and MRI were performed at specific time intervals. The MRI scan protocol included T(1) -weighted-spin-echo ± contrast medium, T(2) -weighted-fast-spin-echo, dynamic contrast-enhanced MRI (DCE-MRI), and diffusion-weighted-stimulated-echo-acquisition-mode-sequence. The T(2) times were obtained using a 1.5 T GE MRI scanner. The size of the treated M21 tumors remained almost constant during the treatment phase (837.8 ± 133.4 vs 914.8 ± 134.4 mm(3) ). BLI showed that, if transcription was controlled by the CMV promoter, the luciferase activity decreased to 51.1 ± 8.3%. After transcription was controlled by the hsp70 promoter, the highest luciferase activity (4.4 ± 0.3 fold) was seen after 24 h. The signal-to-noise ratio (SNR; T(2) -weighted images) of the tumors was 36.7 ± 0.6 and subsequently dropped to 31.2 ± 4.4 (p=0.004). DCE-MRI showed a reduction of the slope and the Ak(ep) of 67.8% ± 4.3 and 64.8% ± 3.3%, respectively, compared with the baseline. The SNR value (T(1) -weighted images) of the tumors was 42.3 ± 1.9 immediately following contrast medium application and subsequently dropped to 28.5 ± 3.0 (p<0.001). In the treatment group, the diffusion coefficient increased significantly under therapy (0.66 ± 0.05 vs the pretreatment value of 0.54 ± 0.009 p<0.01). Thus, we observed that targeted antiangiogenic therapy can induce activation of the hsp70 promoter through a heat shock/luciferase reporter system. Moreover, MRI showed a significant reduction of the contrast medium uptake parameters and an increase in the diffusion coefficient of the tumors.

Related: Melanoma


Milan E, Lazzari C, Anand S, et al.
SAA1 is over-expressed in plasma of non small cell lung cancer patients with poor outcome after treatment with epidermal growth factor receptor tyrosine-kinase inhibitors.
J Proteomics. 2012; 76 Spec No.:91-101 [PubMed] Related Publications
It has been shown that a proteomic algorithm based on 8 MALDI TOF MS signals obtained from plasma of NSCLC patients treated with EGFR TKIs, is able to predict patients' clinical outcome. In the current study, we identified the proteins originating 4 out of 8 mass signals in the classification algorithm. Plasma samples collected before the beginning of gefitinib therapy were analyzed by MALDI TOF MS and classified according to the proteomic algorithm in good and poor profiles. Two pools of good and poor classified samples were prepared using MARS and ProteoMiner Protein Enrichment kit before 2DE analysis. Proteins differentially expressed between good and poor 2DE samples were excised from gels and analyzed with MALDI TOF MS and LC MS/MS. The identified proteins were validated by Immunodepletion and Western blot analyses. serum amyloid A protein 1 (SAA1), together with its two truncated forms, was over-expressed in plasma of poor classified patients, and was identified as the protein that generates 4 out of the 8 mass signals composing the proteomic algorithm VeriStrat. SAA levels measured by ELISA in 97 NSCLC patients treated with gefitinib correlated with the clinical outcome of the patients. This article is part of a Special Issue entitled: Integrated omics.

Related: Non-Small Cell Lung Cancer Lung Cancer EGFR Gefitinib (Iressa)


Otsuki T, Kanno T, Fujita Y, et al.
A3 adenosine receptor-mediated p53-dependent apoptosis in Lu-65 human lung cancer cells.
Cell Physiol Biochem. 2012; 30(1):210-20 [PubMed] Related Publications
BACKGROUND/AIMS: A(3) adenosine receptor mediates apoptosis in cancer cells via diverse signaling pathways. The present study examined A(3) adenosine receptor-mediated apoptosis in Lu-65 cells, a human giant cell lung carcinoma cell line.
METHODS: MTT assay, TUNEL staining, real-time RT-PCR, Western blotting, and assay of caspase-3, -8, and -9 activities were carried out in Lu-65 cells, and A(3) adenosine receptor or p53 was knocked-down by transfecting each siRNA into cells.
RESULTS: Extracellular adenosine induces Lu-65 cell apoptosis in a concentration (0.01-10 mM)-dependent manner, and the effect was inhibited by the A(3) adenosine receptor inhibitor MRS1191 or by knocking-down A(3) adenosine receptor or p53. Like adenosine, the A(3) adenosine receptor agonist 2-Cl-IB-MECA also induced Lu-65 cell apoptosis. Adenosine upregulated expression of p53 and Noxa mRNAs and activated caspase-3 and -9, but not caspase-8. Those adenosine effects were still inhibited by knocking-down A(3) adenosine receptor or p53.
CONCLUSION: The results of the present study show that adenosine upregulates p53 expression via A(3) adenosine receptor, to promote p53-dependent Noxa gene transcription, causing activation of caspase-9 and the effector caspase-3 to induce Lu-65 cell apoptosis.

Related: Apoptosis Lung Cancer Risk Factors and Prevention of Lung Cancer TP53


Cross NC, White HE, Müller MC, et al.
Standardized definitions of molecular response in chronic myeloid leukemia.
Leukemia. 2012; 26(10):2172-5 [PubMed] Related Publications
The International Randomized Study of Interferon and STI571 (IRIS) demonstrated long-term cytogenetic responses in patients with chronic-phase chronic myeloid leukemia (CML-CP) treated with the tyrosine kinase inhibitor (TKI) imatinib. However, deep molecular responses (MRs), as measured by reductions in BCR-ABL transcript levels below the threshold of major MR, were achieved only by a small proportion of patients. With the advent of the second-generation TKIs nilotinib and dasatinib for the treatment of patients with newly diagnosed CML-CP, the proportion of patients who achieve the deepest levels of MR is likely to increase significantly. With these changes, the potential for patient eligibility in TKI cessations studies is becoming a more widely discussed topic and area for research. These developments highlight the need for robust, standardized and workable definitions of deep MRs. Specifically, it is critical that the measurement of MR is standardized in a manner to withstand both intra- and inter-laboratory variability, as well as new methodological developments. This review summarizes the relevant clinical background and proposes a framework within which standardization of MR can be taken forward.

Related: ABL1 Chronic Myeloid Leukemia (CML) CML - Molecular Biology


Cao MD, Döpkens M, Krishnamachary B, et al.
Glycerophosphodiester phosphodiesterase domain containing 5 (GDPD5) expression correlates with malignant choline phospholipid metabolite profiles in human breast cancer.
NMR Biomed. 2012; 25(9):1033-42 [PubMed] Article available free on PMC after 21/01/2015 Related Publications
Altered choline phospholipid metabolism is a hallmark of cancer, leading to malignant choline metabolite profiles consisting of low glycerophosphocholine (GPC) and high phosphocholine (PC) in human breast cancers. Glycerophosphocholine phosphodiesterase (GPC-PDE) catalyzes the degradation of GPC to free choline and glycerol-3-phosphate. The gene(s) encoding for the GPC-PDE(s) responsible for GPC degradation in breast cancers have not yet been identified. Here, we demonstrate for the first time that the GPC-PDE encoded by glycerophosphodiester phosphodiesterase domain containing 5 (GDPD5) is associated with breast cancer malignancy. Two human breast cancer cell lines (n = 8 and n = 10) and primary human breast tumor samples (n = 19) were studied with combined MRS and quantitative reverse transcription-polymerase chain reaction to investigate several isoforms of GDPD expression with respect to choline phospholipid metabolite levels. Of the five GDPDs tested, GDPD5 was found to be significantly overexpressed in highly malignant estrogen receptor negative (ER(-)) compared with weakly malignant estrogen receptor positive (ER(+)) human breast cancer cells (p = 0.027) and breast tumors from patients (p = 0.015). GDPD5 showed significantly positive correlations with PC (p < 0.001), total choline (tCho) (p = 0.007) and PC/GPC (p < 0.001) levels in human breast tumors. GDPD5 showed a trend towards a negative correlation with GPC levels (p = 0.130). Human breast cancers with malignant choline metabolite profiles consisting of low GPC and high PC levels highly co-expressed GDPD5, choline kinase alpha (CHKA) and phosphatidylcholine-specific phospholipase D1 (PLD1), whereas cancers containing high GPC and relatively low PC levels displayed low co-expression of GDPD5, CHKA and PLD1. GDPD5, CHKA and PLD1 were significantly overexpressed in highly malignant ER(-) tumors in our patient cohort. Our study identified GDPD5 as a GPC-PDE that probably participates in the regulation of choline phospholipid metabolism in breast cancer, which possibly occurs in cooperation with CHKA and PLD1.

Related: Breast Cancer


Andronesi OC, Kim GS, Gerstner E, et al.
Detection of 2-hydroxyglutarate in IDH-mutated glioma patients by in vivo spectral-editing and 2D correlation magnetic resonance spectroscopy.
Sci Transl Med. 2012; 4(116):116ra4 [PubMed] Article available free on PMC after 21/01/2015 Related Publications
Mutations in the gene isocitrate dehydrogenase 1 (IDH1) are present in up to 86% of grade II and III gliomas and secondary glioblastoma. Arginine 132 (R132) mutations in the enzyme IDH1 result in excess production of the metabolite 2-hydroxyglutarate (2HG), which could be used as a biomarker for this subset of gliomas. Here, we use optimized in vivo spectral-editing and two-dimensional (2D) correlation magnetic resonance spectroscopy (MRS) methods to unambiguously detect 2HG noninvasively in glioma patients with IDH1 mutations. By comparison, fitting of conventional 1D MR spectra can provide false-positive readouts owing to spectral overlap of 2HG and chemically similar brain metabolites, such as glutamate and glutamine. 2HG was also detected using 2D high-resolution magic angle spinning MRS performed ex vivo on a separate set of glioma biopsy samples. 2HG detection by in vivo or ex vivo MRS enabled detailed molecular characterization of a clinically important subset of human gliomas. This has implications for diagnosis as well as monitoring of treatments targeting mutated IDH1.

Related: IDH1 gene


Pope WB, Prins RM, Albert Thomas M, et al.
Non-invasive detection of 2-hydroxyglutarate and other metabolites in IDH1 mutant glioma patients using magnetic resonance spectroscopy.
J Neurooncol. 2012; 107(1):197-205 [PubMed] Article available free on PMC after 21/01/2015 Related Publications
Mutations of the isocitrate dehydrogenase 1 and 2 genes (IDH1 and IDH2) are commonly found in primary brain cancers. We previously reported that a novel enzymatic activity of these mutations results in the production of the putative oncometabolite, R(-)-2-hydroxyglutarate (2-HG). Here we investigated the ability of magnetic resonance spectroscopy (MRS) to detect 2-HG production in order to non-invasively identify patients with IDH1 mutant brain tumors. Patients with intrinsic glial brain tumors (n = 27) underwent structural and spectroscopic magnetic resonance imaging prior to surgery. 2-HG levels from MRS data were quantified using LC-Model software, based upon a simulated spectrum obtained from a GAMMA library added to the existing prior knowledge database. The resected tumors were then analyzed for IDH1 mutational status by genomic DNA sequencing, Ki-67 proliferation index by immunohistochemistry, and concentrations of 2-HG and other metabolites by liquid chromatography-mass spectrometry (LC-MS). MRS detected elevated 2-HG levels in gliomas with IDH1 mutations compared to those with wild-type IDH1 (P = 0.003). The 2-HG levels measured in vivo with MRS were significantly correlated with those measured ex vivo from the corresponding tumor samples using LC-MS (r (2) = 0.56; P = 0.0001). Compared with wild-type tumors, those with IDH1 mutations had elevated choline (P = 0.01) and decreased glutathione (P = 0.03) on MRS. Among the IDH1 mutated gliomas, quantitative 2-HG values were correlated with the Ki-67 proliferation index of the tumors (r ( 2 ) = 0.59; P = 0.026). In conclusion, water-suppressed proton ((1)H) MRS provides a non-invasive measure of 2-HG in gliomas, and may serve as a potential biomarker for patients with IDH1 mutant brain tumors. In addition to 2-HG, alterations in several other metabolites measured by MRS correlate with IDH1 mutation status.

Related: IDH1 gene


Shah T, Stasinopoulos I, Wildes F, et al.
Noninvasive imaging identifies new roles for cyclooxygenase-2 in choline and lipid metabolism of human breast cancer cells.
NMR Biomed. 2012; 25(5):746-54 [PubMed] Related Publications
The expression of cyclooxygenase-2 (COX-2) is observed in approximately 40% of breast cancers. A major product of the COX-2-catalyzed reaction, prostaglandin E(2), is an inflammatory mediator that participates in several biological processes, and influences invasion, vascularization and metastasis. Using noninvasive MRI and MRS, we determined the effect of COX-2 downregulation on the metabolism and invasion of intact poorly differentiated MDA-MB-231 human breast cancer cells stably expressing COX-2 short hairpin RNA. Dynamic tracking of invasion, extracellular matrix degradation and metabolism was performed with an MRI- and MRS-compatible cell perfusion assay under controlled conditions of pH, temperature and oxygenation over the course of 48  h. COX-2-silenced cells exhibited a significant decrease in invasion relative to parental cells that was consistent with the reduced expression of invasion-associated matrix metalloproteinase genes and an increased level of the tissue inhibitor of metalloproteinase-1. We identified, for the first time, a role for COX-2 in mediating changes in choline phospholipid metabolism, and established that choline kinase expression is partly dependent on COX-2 function. COX-2 silencing resulted in a significant decrease in phosphocholine and total choline that was detected by MRS. In addition, a significant increase in lipids, as well as lipid droplet formation, was observed. COX-2 silencing transformed parental cell metabolite patterns to those characteristic of less aggressive cancer cells. These new functional roles of COX-2 may identify new biomarkers and new targets for use in combination with COX-2 targeting to prevent invasion and metastasis.

Related: Breast Cancer COX2 (PTGS2)


Mamessier E, Sylvain A, Bertucci F, et al.
Human breast tumor cells induce self-tolerance mechanisms to avoid NKG2D-mediated and DNAM-mediated NK cell recognition.
Cancer Res. 2011; 71(21):6621-32 [PubMed] Related Publications
Breast cancer is the leading cause of death for women between the ages of 35 to 65. This is mostly due to intertumor heterogeneity and the lack of specific therapies for all subtypes. However, some breast cancers with an unexpected good prognosis are associated with enhanced antitumor immunity in situ. We studied whether breast cancer subtypes might have different susceptibilities to natural killer (NK) cells' antitumor immunity. We collected a large public set of microarray data for primary breast tumors and determined NK cell ligand expression. We found that despite heterogeneous levels of inhibitory HLA members, NKG2D ligands and DNAM ligands are expressed in virtually all breast tumor subtypes. Functional experiments in breast cancer subtypes expressing various levels of NK cell ligands showed that NK-mediated cytotoxicity is mainly HLA, NKG2D, and DNAM dependent. In parallel, we showed that cell lines and primary breast tumor cells secrete soluble inhibitory factors that alter NK cell functions. Finally, we showed that these mechanisms of escape occur in vivo in the MMTV-Neu model of spontaneous murine breast cancer. Our study shows that breast cancer cells, independent of the subtype, have developed different mechanisms to escape from NK cells' antitumor immunity. These results emphasize the role of NK cells in breast tumor clearance and underlie the importance of devising future therapy aiming at enhancing NK cell-mediated recognition in parallel with the prevention of the tumor-editing process.

Related: Breast Cancer


Darpolor MM, Yen YF, Chua MS, et al.
In vivo MRSI of hyperpolarized [1-(13)C]pyruvate metabolism in rat hepatocellular carcinoma.
NMR Biomed. 2011; 24(5):506-13 [PubMed] Article available free on PMC after 21/01/2015 Related Publications
Hepatocellular carcinoma (HCC), the primary form of human adult liver malignancy, is a highly aggressive tumor with average survival rates that are currently less than 1 year following diagnosis. Most patients with HCC are diagnosed at an advanced stage, and no efficient marker exists for the prediction of prognosis and/or response(s) to therapy. We have reported previously a high level of [1-(13)C]alanine in an orthotopic HCC using single-voxel hyperpolarized [1-(13)C]pyruvate MRS. In the present study, we implemented a three-dimensional MRSI sequence to investigate this potential hallmark of cellular metabolism in rat livers bearing HCC (n = 7 buffalo rats). In addition, quantitative real-time polymerase chain reaction was used to determine the mRNA levels of lactate dehydrogenase A, nicotinamide adenine (phosphate) dinucleotide dehydrogenase quinone 1 and alanine transaminase. The enzyme levels were significantly higher in tumor than in normal liver tissues within each rat, and were associated with the in vivo MRSI signal of [1-(13)C]alanine and [1-(13)C]lactate after a bolus intravenous injection of [1-(13)C]pyruvate. Histopathological analysis of these tumors confirmed the successful growth of HCC as a nodule in buffalo rat livers, revealing malignancy and hypervascular architecture. More importantly, the results demonstrated that the metabolic fate of [1-(13)C]pyruvate conversion to [1-(13)C]alanine significantly superseded that of [1-(13)C]pyruvate conversion to [1-(13)C]lactate, potentially serving as a marker of HCC tumors.

Related: Liver Cancer


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