bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chromatin Modification of the Trefoil Factor 1 Gene in Human Breast Cancer Cells by the Ras/Mitogen-Activated Protein Kinase Pathway
Authors: Espino Paula S. , Li Lin , He Shihua , Yu Jenny , Davie James R. 
Published: May 2006

Abstract
Histone H3 phosphorylation is a downstream response to activation of the Ras/mitogen-activated protein kinase (MAPK) pathway. This modification is thought to have a role in chromatin remodeling and in the initiation of gene transcription. In MCF-7 breast cancer cells, we observed that phosphorylated histone H3 (phospho-H3) at Ser10 but not Ser28 increased with phorbol ester (12-O-tetradecanoylphorbol-13-acetate, TPA) treatment. Although phosphorylated extracellular signal-regulated kinase 1/2 levels in these cells cultured under estradiol deplete and replete conditions displayed no change, a significant induction was observed after TPA treatment. Furthermore, whereas both estradiol and TPA increased trefoil factor 1 (TFF1) mRNA levels in these cells, only TPA-induced and not estradiol-induced TFF1 expression was inhibited by the H3 kinase mitogen and stress activated protein kinase (MSK) inhibitor H89 and MAPK kinase inhibitor UO126, showing the involvement of the Ras/MAPK following TPA induction. Mutation of the activator protein 1 (AP-1) binding site abrogated the TPA-induced transcriptional response of the luciferase reporter gene under the control of the TFF1 promoter, showing the requirement for the AP-1 site. In chromatin immunoprecipitation assays, estradiol treatment resulted in the association of the estrogen receptor-α (ERα) and acetylated H3 with the TFF1 promoter. The levels of phospho-H3 and MSK1 associated with the TFF1 promoter were moderately increased. In the presence of TPA, whereas ERα was not bound to the promoter, a strong association of acetylated and/or phospho-H3, MSK1, and c-Jun was observed. These results show that although both stimuli lead to TFF1 gene activation, estradiol and TPA exert their effects on TFF1 gene expression by different mechanisms. (Cancer Res 2006; 66(9): 4610-6)
Nonsteroidal Anti-inflammatory Drugs and the Esophageal Inflammation-Metaplasia-Adenocarcinoma Sequence
Authors: Anderson Lesley A. , Johnston Brian T. , Watson R.G. Peter , Murphy Seamus J. , Ferguson Heather R. , Comber Harry , McGuigan Jim , Reynolds John V. , Murray Liam J. 
Published: May 2006

Abstract
Observational studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of esophageal adenocarcinoma, but it is not known at what stage they may act in the esophageal inflammation-metaplasia-adenocarcinoma sequence. In an all-Ireland case-control study, we investigated the relationship between the use of NSAIDs and risk of reflux esophagitis, Barrett's esophagus, and esophageal adenocarcinoma. Patients with esophageal adenocarcinoma, long-segment Barrett's esophagus and population controls were recruited from throughout Ireland. Esophagitis patients were recruited from Northern Ireland only. Data were collected on known and potential risk factors for esophageal adenocarcinoma and on the use of NSAIDs, including aspirin, at least 1 year before interview. Associations between use of NSAIDs and the stages of the esophageal inflammation-metaplasia-adenocarcinoma sequence were estimated by multiple logistic regression. In total, 230 reflux esophagitis, 224 Barrett's esophagus, and 227 esophageal adenocarcinoma and 260 population controls were recruited. Use of aspirin and NSAIDs was associated with a reduced risk of Barrett's esophagus [odds ratio [OR; 95% confidence interval (95% CI)], 0.53 (0.31-0.90) and 0.40 (0.19-0.81), respectively] and esophageal adenocarcinoma [OR (95% CI), 0.57 (0.36-0.93) and 0.58 (0.31-1.08), respectively]. Barrett's esophagus and esophageal adenocarcinoma patients were less likely than controls to have used NSAIDs. Selection or recall bias may explain these results and the results of previous observational studies indicating a protective effect of NSAIDs against esophageal adenocarcinoma. If NSAIDs have a true protective effect on the esophageal inflammation-metaplasia-adenocarcinoma sequence, they may act early in the sequence. (Cancer Res 2006; 66(9): 4975-82)
Validation of Met as a Therapeutic Target in Alveolar and Embryonal Rhabdomyosarcoma
Authors: Taulli Riccardo , Scuoppo Claudio , Bersani Francesca , Accornero Paolo , Forni Paolo E. , Miretti Silvia , Grinza Alberto , Allegra Paola , Schmitt-Ney Michel , Crepaldi Tiziana , Ponzetto Carola 
Published: May 2006

Abstract
Rhabdomyosarcoma (RMS) is a highly malignant soft-tissue tumor of childhood deriving from skeletal muscle cells. RMS can be classified in two major histologic subtypes: embryonal (ERMS) and alveolar (ARMS), the latter being characterized by the PAX3/7-FKHR translocation. Here we first investigated whether the Met receptor, a transcriptional target of PAX3 and PAX7, has a role in PAX3-FKHR–mediated transformation. Following PAX3-FKHR transduction, Met was up-regulated in mouse embryonal fibroblasts (MEF), NIH 3T3 and C2C12 cells, and they all acquired anchorage independence. This property was lost in low serum but addition of hepatocyte growth factor/scatter factor (HGF/SF) rescued soft-agar growth. Genetic proof that Met is necessary for this PAX3-FKHR–mediated effect was obtained by transducing with PAX3-FKHR MEFs derived from Met mutant (MetD/D) and wild-type (Met+/+) embryos. Only Met+/+ MEFs acquired anchorage-independent growth whereas PAX3-FKHR–transduced MetD/D cells were unable to form colonies in soft agar. To verify if Met had a role in RMS maintenance, we silenced the receptor by transducing ERMS and ARMS cell lines with an inducible lentivirus expressing an anti-Met short hairpin RNA (shRNA). Met down-regulation significantly affected RMS cells proliferation, survival, invasiveness, and anchorage-independent growth. Finally, induction of the Met-directed shRNA promoted a dramatic reduction of tumor mass in a xenograft model of RMS. Our data show that both ARMS- and ERMS-derived cell lines, in spite of the genetic drift which may have occurred in years of culture, seem to have retained an “addiction” to the Met oncogene and suggest that Met may represent a target of choice to develop novel therapeutic strategies for ARMS. (Cancer Res 2006; 66(9): 4742-9)
Combination of a Fusogenic Glycoprotein, Prodrug Activation, and Oncolytic Herpes Simplex Virus for Enhanced Local Tumor Control
Authors: Simpson Guy R. , Han Ziqun , Liu Binlei , Wang Yibing , Campbell Gregor , Coffin Robert S. 
Published: May 2006

AbstractWe have previously developed an oncolytic herpes simplex virus-1 based on a clinical virus isolate, which was deleted for ICP34.5 to provide tumor selected replication and ICP47 to increase antigen presentation as well as tumor selective virus replication. A phase I/II clinical trial using a version of this virus expressing granulocyte macrophage colony-stimulating factor has shown promising results. The work reported here aimed to develop a version of this virus in which local tumor control was further increased through the combined expression of a highly potent prodrug activating gene [yeast cytosine deaminase/uracil phospho-ribosyltransferase fusion (Fcy::Fur)] and the fusogenic glycoprotein from gibbon ape leukemia virus (GALV), which it was hoped would aid the spread of the activated prodrug through the tumor. Viruses expressing the two genes individually or in combination were constructed and tested, showing (a) GALV and/or Fcy::Fur expression did not affect virus growth; (b) GALV expression causes cell fusion and increases the tumor cell killing at least 30-fold in vitro and tumor shrinkage 5- to 10-fold in vivo; (c) additional expression of Fcy::Fur combined with 5-fluorocytosine administration improves tumor shrinkage further. These results indicate, therefore, that the combined expression of the GALV protein and Fcy::Fur provides a highly potent oncolytic virus with improved capabilities for local tumor control. It is intended to enter the GALV/Fcy::Fur expressing virus into clinical development for the treatment of tumor types, such as pancreatic or lung cancer, where local control would be anticipated to be clinically advantageous. (Cancer Res 2006; 66(9): 4835-42)
MET Overexpression Turns Human Primary Osteoblasts into Osteosarcomas
Authors: Patanè Salvatore , Avnet Sofia , Coltella Nadia , Costa Barbara , Sponza Simone , Olivero Martina , Vigna Elisa , Naldini Luigi , Baldini Nicola , Ferracini Riccardo , Corso Simona , Giordano Silvia , Comoglio Paolo M. , Di Renzo Maria Flavia 
Published: May 2006

Abstract
The MET oncogene was causally involved in the pathogenesis of a rare tumor, i.e., the papillary renal cell carcinoma, in which activating mutations, either germline or somatic, were identified. MET activating mutations are rarely found in other human tumors, whereas at higher frequencies, MET is amplified and/or overexpressed in sporadic tumors of specific histotypes, including osteosarcoma. In this work, we provide experimental evidence that overexpression of the MET oncogene causes and sustains the full-blown transformation of osteoblasts. Overexpression of MET, obtained by lentiviral vector–mediated gene transfer, resulted in the conversion of primary human osteoblasts into osteosarcoma cells, displaying the transformed phenotype in vitro and the distinguishing features of human osteosarcomas in vivo. These included atypical nuclei, aberrant mitoses, production of alkaline phosphatase, secretion of osteoid extracellular matrix, and striking neovascularization. Although with a lower tumorigenicity, this phenotype was superimposable to that observed after transfer of the MET gene activated by mutation. Both transformation and tumorigenesis were fully abrogated when MET expression was quenched by short-hairpin RNA or when signaling was impaired by a dominant-negative MET receptor. These data show that MET overexpression is oncogenic and that it is essential for the maintenance of the cancer phenotype. (Cancer Res 2006; 66(9): 4750-7)
Frequent Silencing of the Candidate Tumor Suppressor PCDH20 by Epigenetic Mechanism in Non–Small-Cell Lung Cancers
Authors: Imoto Issei , Izumi Hiroyuki , Yokoi Sana , Hosoda Hiroshi , Shibata Tatsuhiro , Hosoda Fumie , Ohki Misao , Hirohashi Setsuo , Inazawa Johji 
Published: May 2006

Abstract
Protocadherins are a major subfamily of the cadherin superfamily, but little is known about their functions and intracellular signal transduction. We identified a homozygous loss of protocadherin 20 (PCDH20, 13q21.2) in the course of a program to screen a panel of non–small-cell lung cancer (NSCLC) cell lines (1 of 20 lines) for genomic copy number aberrations using an in-house array-based comparative genomic hybridization. PCDH20 mRNA was expressed in normal lung tissue but was not expressed in the majority of NSCLC cell lines without a homozygous deletion of this gene (10 of 19 lines, 52.6%). Expression of PCDH20 mRNA was restored in gene-silenced NSCLC cells after treatment with 5-aza 2′-deoxycytidine. The DNA methylation status of the PCDH20 CpG-rich region correlated inversely with the expression of the gene and a putative target region for methylation showed clear promoter activity in vitro. Methylation of this PCDH20 promoter was frequently observed in primary NSCLC tissues (32 of 59 tumors, 54.2%). Among our primary NSCLC cases, the methylated PCDH20 seemed to be associated with a shorter overall survival (P = 0.0140 and 0.0211 in all and stage I tumors, respectively; log-rank test), and a multivariate analysis showed that the PCDH20 methylation status was an independent prognosticator. Moreover, restoration of PCDH20 expression in NSCLC cells reduced cell numbers in colony formation and anchorage-independent assays. These results suggest that epigenetic silencing by hypermethylation of the CpG-rich promoter region of PCDH20 leads to loss of PCDH20 function, which may be a factor in the carcinogenesis of NSCLC. (Cancer Res 2006; 66(9): 4617-26)
Menin Links Estrogen Receptor Activation to Histone H3K4 Trimethylation
Authors: Dreijerink Koen M.A. , Mulder Klaas W. , Winkler G. Sebastiaan , Höppener Jo W.M. , Lips Cornelis J.M. , Timmers H.Th. Marc 
Published: May 2006

Abstract
The product of the multiple endocrine neoplasia type 1 (MEN1) tumor suppressor gene, menin, is an integral component of MLL1/MLL2 histone methyltransferase complexes specific for Lys4 of histone H3 (H3K4). We show that menin is a transcriptional coactivator of the nuclear receptors for estrogen and vitamin D. Activation of the endogenous estrogen-responsive TFF1 (pS2) gene results in promoter recruitment of menin and in elevated trimethylation of H3K4. Knockdown of menin reduces both activated TFF1 (pS2) transcription and H3K4 trimethylation. In addition, menin can directly interact with the estrogen receptor-α (ERα) in a hormone-dependent manner. The majority of disease-related MEN1 mutations prevent menin-ERα interaction. Importantly, ERα-interacting mutants are also defective in coactivator function. Our results indicate that menin is a critical link between recruitment of histone methyltransferase complexes and nuclear receptor–mediated transcription. (Cancer Res 2006; 66(9): 4929-35)
Cooperative Interactions of p53 Mutation, Telomere Dysfunction, and Chronic Liver Damage in Hepatocellular Carcinoma Progression
Authors: Farazi Paraskevi A. , Glickman Jonathan , Horner James , DePinho Ronald A. 
Published: May 2006

Abstract
Hepatocellular carcinoma is among the most common and lethal cancers in humans. Hepatocellular carcinoma is commonly associated with physical or functional inactivation of the p53 tumor suppressor, high levels of chromosomal instability, and disease conditions causing chronic cycles of hepatocyte death and regeneration. Mounting evidence has implicated regeneration-induced telomere erosion as a potential mechanism fueling genome instability. In mouse models of hepatocellular carcinoma, telomere dysfunction has been shown to enhance initiation of hepatic neoplasias yet constrain full malignant progression of these neoplasms possibly due to activation of a p53-dependent checkpoint and/or intolerable levels of genomic instability. Here, in a hepatocellular carcinoma–prone model brought about through toxin-induced hepatocyte injury and regeneration, we sought to determine the cooperative interactions of germ line p53 mutation and telomere dysfunction [produced by telomerase reverse transcriptase (mTERT) gene knockout]. In the setting of intact telomeres, p53 mutation had no effect on hepatocarcinogenesis, whereas in the setting of telomere dysfunction, p53 mutation enabled advanced hepatocellular carcinoma disease. Notably, there was no evidence of deletion or mutation of the wild-type p53 allele in the late generation mTert−/−p53+/− mice, suggesting that reduced levels of p53 potently enable hepatocellular carcinoma progression in the setting of telomere dysfunction. Thus, this study supports a model that, in the face of chronic liver damage, attenuated p53 function and telomere-induced chromosomal instability play critical and cooperative roles in the progression of hepatocellular carcinoma. (Cancer Res 2006; 66(9): 4766-73)
IMC-EB10, an Anti-FLT3 Monoclonal Antibody, Prolongs Survival and Reduces Nonobese Diabetic/Severe Combined Immunodeficient Engraftment of Some Acute Lymphoblastic Leukemia Cell Lines and Primary Leukemic Samples
Authors: Piloto Obdulio , Nguyen Bao , Huso David , Kim Kyu-Tae , Li Yiwen , Witte Larry , Hicklin Daniel J. , Brown Patrick , Small Donald 
Published: May 2006

AbstractThe class III receptor tyrosine kinase FLT3 is expressed on the blasts of &gt;90% of patients with B-lineage acute lymphoblastic leukemias (ALL). In addition, it is expressed at extremely high levels in ALL patients with mixed lineage leukemia rearrangements or hyperdiploidy and is sometimes mutated in these same patients. In this report, we investigate the effects of treating ALL cell lines and primary samples with human anti-FLT3 monoclonal antibodies (mAb) capable of preventing binding of FLT3 ligand. In vitro studies, examining the ability of two anti-FLT3 mAbs (IMC-EB10 and IMC-NC7) to affect FLT3 activation and downstream signaling in ALL cell lines and primary blasts, yielded variable results. FLT3 phosphorylation was consistently inhibited by IMC-NC7 treatment, but in some cell lines, IMC-EB10 actually stimulated FLT3 activation, possibly as a result of antibody-mediated receptor dimerization. Through antibody-dependent, cell-mediated cytotoxicity, such an antibody could still prove efficacious against leukemia cells in vivo. In fact, IMC-EB10 treatment significantly prolonged survival and/or reduced engraftment of several ALL cell lines and primary ALL samples in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. This occurred even when IMC-EB10 treatment resulted in FLT3 activation in vitro. Moreover, fluorescence-activated cell sorting and PCR analysis of IMC-EB10-treated NOD/SCID mice surviving 150 days post-leukemic cell injection revealed that FLT3 immunotherapy reduced leukemic engraftment below the level of detection in these assays (&lt;0.001%). Furthermore, in vivo IMC-EB10 treatment did not select for resistant cells, because cells surviving IMC-EB10 treatment remain sensitive to IMC-EB10 cytotoxicity upon retransplantation. In vivo studies involving either partial depletion or activation of natural killer (NK) cells show that most of the cytotoxic effect of IMC-EB10 is mediated through NK cells. Therefore, such an antibody, either naked or conjugated to radioactive isotopes or cytotoxic agents, may prove useful in the therapy of infant ALL as well as childhood and adult ALL patients whose blasts typically express FLT3. (Cancer Res 2006; 66(9): 4843-51)
Meeting Report: Exploiting the Tumor Microenvironment for Therapeutics
Authors: Melillo Giovanni , Semenza Gregg L. 
Published: May 2006

Abstract
Recent progress in understanding the role of the tumor microenvironment in cancer progression was the subject of the 2nd International Tumor Metabolism Summit entitled “Exploiting the Tumor Microenvironment for Therapeutics,” a meeting held at Palazzo Ducale in Genoa, Italy, October 7 to 8, 2005. One of the major conceptual advances in oncology over the last decade has been the appreciation that all major aspects of cancer biology are influenced by the tumor microenvironment. Two important means by which cancer cells adapt to their microenvironment are by reprogramming cellular glucose/energy metabolism to use pathways that generate ATP in the absence of O2 and by stimulating angiogenesis to increase O2 delivery. These responses are principally mediated at the transcriptional level by hypoxia-inducible factor-1. This meeting emphasized the complexity of the tumor microenvironment and opportunities for therapeutic intervention by targeting transcriptional and metabolic pathways that are activated during cancer progression. A better understanding of the crosstalk between signaling pathways and metabolic alterations that contribute to the cancer phenotype may provide insights leading to the development of novel therapeutic strategies. (Cancer Res 2006; 66(9): 4558-60)
Dysregulated Human Myeloid Nuclear Differentiation Antigen Expression in Myelodysplastic Syndromes: Evidence for a Role in Apoptosis
Authors: Briggs Robert C. , Shults Keith E. , Flye Leanne A. , McClintock-Treep Sara A. , Jagasia Madan H. , Goodman Stacey A. , Boulos Fouad I. , Jacobberger James W. , Stelzer Greg T. , Head David R. 
Published: May 2006

Abstract
Reduced levels of human myeloid nuclear differentiation antigen (MNDA) gene transcripts have been detected in both familial and sporadic cases of myelodysplastic syndromes (MDS). Numerous reports implicate elevated apoptosis/programmed cell death and death ligands and their receptors in the pathogenesis of MDS. MNDA and related proteins contain the pyrin domain that functions in signaling associated with programmed cell death and inflammation. We tested the hypothesis that MNDA is involved in the regulation of programmed cell death in human myeloid hematopoietic cells. Clones of K562 cells (MNDA-null) that expressed ectopic MNDA protein were established using retroviral transduction. MNDA-expressing K562 clones were resistant to tumor necrosis factor-related apoptosis inducing ligand (TRAIL)–induced apoptosis, but were not protected from programmed cell death induced with genotoxic agents or H2O2. MNDA protein expression assessed in control and intermediate and high-grade MDS marrows showed several patterns of aberrant reduced MNDA. These variable patterns of dysregulated MNDA expression may relate to the variable pathophysiology of MDS. We propose that MNDA has a role regulating programmed cell death in myeloid progenitor cells, and that its down-regulation in MDS is related to granulocyte-macrophage progenitor cell sensitivity to TRAIL-induced programmed cell death. (Cancer Res 2006; 66(9): 4645-51)
When bad things happen to good fish: the loss of hemoglobin and myoglobin expression in Antarctic icefishes
Authors: Sidell Bruce D. , O'Brien Kristin M. 
Published: May 2006

SUMMARYThe Antarctic icefishes (Family Channichthyidae) provide excellent examples of unique traits that can arise in a chronically cold and isolated environment. Their loss of hemoglobin (Hb) expression, and in some cases, loss of myoglobin (Mb) expression, has taught us much about the function of these proteins. Although absences of the proteins are fixed traits in icefishes, the losses do not appear to be of adaptive value. Contrary to some suggestions,loss of Hb has led to higher energetic costs for circulating blood, and losses of Mb have reduced cardiac performance. Moreover, losses of Hb and Mb have resulted in extensive modifications to the cardiovascular system to ensure adequate oxygen delivery to working muscles. Recent studies suggest that losses of Hb and Mb, and their associated nitric oxide (NO)-oxygenase activities, may have accelerated the development and evolution of these cardiovascular modifications. The high levels of NO that should occur in the absence of Hb and Mb have been shown in other animal groups to lead to an increase in tissue vascularization, an increase in the lumenal diameter of blood vessels, and an increase in mitochondrial densities. These characteristics are all hallmark traits of Antarctic icefishes. Homeostatic feedback mechanisms thus may have accelerated evolution of the pronounced cardiovascular traits of Antarctic icefishes.