bluuebunny/crossref_metadata_2025_split huggingface dataset:
Telomerase-Independent Telomere Length Maintenance in the Absence of Alternative Lengthening of Telomeres–Associated Promyelocytic Leukemia Bodies
Authors: Fasching Clare L. , Bower Kylie , Reddel Roger R. 
Published: September 2005

Abstract
Immortal tumor cells and cell lines employ a telomere maintenance mechanism that allows them to escape the normal limits on proliferative potential. In the absence of telomerase, telomere length may be maintained by an alternative lengthening of telomeres (ALT) mechanism. All human ALT cell lines described thus far have nuclear domains of unknown function, termed ALT-associated promyelocytic leukemia bodies (APB), containing promyelocytic leukemia protein, telomeric DNA and telomere binding proteins. Here we describe telomerase-negative human cells with telomeres that contain a substantial proportion of nontelomeric DNA sequences (like telomerase-null Saccharomyces cerevisiae survivor type I cells) and that are maintained in the absence of APBs. In other respects, they resemble typical ALT cell lines: the telomeres are highly heterogeneous in length (ranging from very short to very long) and undergo rapid changes in length. In addition, these cells are capable of copying a targeted DNA tag from one telomere into other telomeres. These data show that APBs are not always essential for ALT-mediated telomere maintenance.
Integrated Array-Comparative Genomic Hybridization and Expression Array Profiles Identify Clinically Relevant Molecular Subtypes of Glioblastoma
Authors: Nigro Janice M. , Misra Anjan , Zhang Li , Smirnov Ivan , Colman Howard , Griffin Chandi , Ozburn Natalie , Chen Mingang , Pan Edward , Koul Dimpy , Yung W.K. Alfred , Feuerstein Burt G. , Aldape Kenneth D. 
Published: September 2005

Abstract
Glioblastoma, the most aggressive primary brain tumor in humans, exhibits a large degree of molecular heterogeneity. Understanding the molecular pathology of a tumor and its linkage to behavior is an important foundation for developing and evaluating approaches to clinical management. Here we integrate array-comparative genomic hybridization and array-based gene expression profiles to identify relationships between DNA copy number aberrations, gene expression alterations, and survival in 34 patients with glioblastoma. Unsupervised clustering on either profile resulted in similar groups of patients, and groups defined by either method were associated with survival. The high concordance between these separate molecular classifications suggested a strong association between alterations on the DNA and RNA levels. We therefore investigated relationships between DNA copy number and gene expression changes. Loss of chromosome 10, a predominant genetic change, was associated not only with changes in the expression of genes located on chromosome 10 but also with genome-wide differences in gene expression. We found that CHI3L1/YKL-40 was significantly associated with both chromosome 10 copy number loss and poorer survival. Immortalized human astrocytes stably transfected with CHI3L1/YKL-40 exhibited changes in gene expression similar to patterns observed in human tumors and conferred radioresistance and increased invasion in vitro. Taken together, the results indicate that integrating DNA and mRNA-based tumor profiles offers the potential for a clinically relevant classification more robust than either method alone and provides a basis for identifying genes important in glioma pathogenesis.
Valproic Acid Stimulates Proliferation and Self-renewal of Hematopoietic Stem Cells
Authors: Bug Gesine , Gül Hilal , Schwarz Kerstin , Pfeifer Heike , Kampfmann Manuela , Zheng Xiaomin , Beissert Tim , Boehrer Simone , Hoelzer Dieter , Ottmann Oliver Gerhard , Ruthardt Martin 
Published: September 2005

Abstract
Histone deacetylase inhibitors have attracted considerable attention because of their ability to overcome the differentiation block in leukemic blasts, an effect achieved either alone or in combination with differentiating agents, such as all-trans retinoic acid. We have previously reported favorable effects of the potent histone deacetylase inhibitor valproic acid in combination with all-trans retinoic acid in patients with advanced acute myeloid leukemia leading to blast cell reduction and improvement of hemoglobin. These effects were accompanied by hypergranulocytosis most likely due to an enhancement of nonleukemic myelopoiesis and the suppression of malignant hematopoiesis rather than enforced differentiation of the leukemic cells. These data prompted us to investigate the effect of valproic acid on normal hematopoietic stem cells (HSC). Here we show that valproic acid increases both proliferation and self-renewal of HSC. It accelerates cell cycle progression of HSC accompanied by a down-regulation of p21cip-1/waf-1. Furthermore, valproic acid inhibits GSK3β by phosphorylation on Ser9 accompanied by an activation of the Wnt signaling pathway as well as by an up-regulation of HoxB4, a target gene of Wnt signaling. Both are known to directly stimulate the proliferation of HSC and to expand the HSC pool. In summary, we here show that valproic acid, known to induce differentiation or apoptosis in leukemic blasts, stimulates the proliferation of normal HSC, an effect with a potential effect on its future role in the treatment of acute myeloid leukemia.
Peroxisome Proliferator-Activated Receptor γ Inhibition Prevents Adhesion to the Extracellular Matrix and Induces Anoikis in Hepatocellular Carcinoma Cells
Authors: Schaefer Katherine L. , Wada Koichiro , Takahashi Hirokazu , Matsuhashi Nobuyuki , Ohnishi Shin , Wolfe M. Michael , Turner Jerrold R. , Nakajima Atsushi , Borkan Steven C. , Saubermann Lawrence J. 
Published: September 2005

Abstract
Activation of the nuclear transcription factor peroxisome proliferator-activated receptor γ (PPARγ) inhibits growth and survival of hepatocellular carcinoma (HCC) cell lines. To further investigate the function of PPARγ in HCC, PPARγ expression patterns in primary tumors were examined, and the responses of two HCC cell lines to PPARγ activation and inhibition were compared. PPARγ expression was increased in HCC and benign-appearing peritumoral hepatocytes compared with remote benign hepatocytes. Both compound PPARγ inhibitors and PPARγ small interfering RNAs prevented HCC cell lines from adhering to the extracellular matrix. Loss of adhesion was followed by caspase-dependent apoptosis (anoikis). PPARγ inhibitors had no effect on initial β1 integrin-mediated adhesion, or on total focal adhesion kinase levels but did reduce focal adhesion kinase phosphorylation. The PPARγ inhibitor T0070907 was significantly more efficient at causing cancer cell death than the activators troglitazone and rosiglitazone. T0070907 caused cell death by reducing adhesion and inducing anoikis, whereas the activators had no direct effect on adhesion and caused cell death at much higher concentrations. In conclusion, PPARγ overexpression is present in HCC. Inhibition of PPARγ function causes HCC cell death by preventing adhesion and inducing anoikis-mediated apoptosis. PPARγ inhibitors represent a potential novel treatment approach to HCC.
The RhoGAP Protein DLC-1 Functions as a Metastasis Suppressor in Breast Cancer Cells
Authors: Goodison Steve , Yuan Jing , Sloan Derek , Kim Ryung , Li Cheng , Popescu Nicholas C. , Urquidi Virginia 
Published: September 2005

Abstract
The identification of molecular signatures characteristic of tumor cells that are capable of metastatic spread is required for the development of therapeutic interventions to abrogate this lethal process. To facilitate this, we have previously characterized an experimental system in which the role of candidate metastasis-related genes can be screened and tested. Monoclonal cell lines M4A4 and NM2C5 are spontaneously occurring sublines of the MDA-MB-435 cell breast tumor cell line that exhibit phenotypic differences in growth, invasion, and metastatic efficiency in athymic mice. In this study, transcriptional profiles of these cell lines were created using oligonucleotide microarrays representing over 12,000 genes. Intensity modeling and hierarchical clustering analysis identified a 171-gene expression signature that correlated with metastatic phenotype and highlighted several GTPase signaling components. Restoration of one of these GTPases, deleted in liver cancer-1 (DLC-1), in metastatic M4A4 cells to levels observed in the nonmetastatic NM2C5 cell line resulted in the inhibition of migration and invasion in vitro and a significant reduction in the ability of these cells to form pulmonary metastases in athymic mice. These studies show the utility of expression profiling, in an appropriate experimental system, to identify genetic determinants of metastatic sufficiency. The finding that DLC-1 can act as a metastasis-suppressor gene supports an influential role for GTPase signaling in tumor progression.
p73β-Mediated Apoptosis Requires p57kip2 Induction and IEX-1 Inhibition
Authors: Gonzalez Susana , Perez-Perez Manuel M. , Hernando Eva , Serrano Manuel , Cordon-Cardo Carlos 
Published: September 2005

Abstract
Similarly to p53, p73α and p73β induce growth arrest and/or apoptosis in response to DNA damage or when exogenously expressed. However, how they trigger apoptosis remains unresolved. After stable transduction of either p73α or p73β, a greater apoptotic response was observed for p73β in both primary and tumor cells. Consistently, blocking ectopic and endogenous p73β expression by specific shRNA significantly decreased apoptotic levels after DNA damage. We found that p73β targets the apoptotic program at multiple levels: (i) facilitating caspase activation through p53-dependent signals and (ii) inducing p57KIP2, while down-regulating c-IPA1 and IEX1 through a p53-independent mechanism. p73β-mediated apoptosis was considerably reduced after inhibition of p57KIP2 by small interfering RNA, IEX-1 overexpression, and in mouse embryo fibroblasts derived from p57−/− mice. Data from this study offer evidence for the apoptotic activity exclusive of p73β. In the clinical context, these results might have potential therapeutic implications, because p73β could induce alternative apoptotic responses in tumors harboring p53 mutations.
Progesterone Receptor in Non–Small Cell Lung Cancer—A Potent Prognostic Factor and Possible Target for Endocrine Therapy
Authors: Ishibashi Hironori , Suzuki Takashi , Suzuki Satoshi , Niikawa Hiromichi , Lu Liangying , Miki Yasuhiro , Moriya Takuya , Hayashi Shin-ichi , Handa Masashi , Kondo Takashi , Sasano Hironobu 
Published: September 2005

Abstract
A possible involvement of gender-dependent factors has been postulated in development of human non–small-cell lung cancers (NSCLC), but its details remain unclear. In this study, we examined biological significance of progesterone receptor in NSCLCs. Progesterone receptor immunoreactivity was detected in 106 of 228 NSCLCs (46.5%). Progesterone receptor–positive NSCLC was frequently detected in female and adenocarcinoma, and was inversely associated with tumor-node-metastasis stage and histologic differentiation. Progesterone receptor status was also associated with better clinical outcome of the patients, and a multivariate analysis revealed progesterone receptor status as an independent prognostic factor. Progesterone-synthesizing enzymes were detected in NSCLCs, and tissue concentration of progesterone was higher in these cases (n = 42). Immunoblotting analyses showed the presence of progesterone receptor in three NSCLC cell lines (A549, LCSC#2, and 1-87), but not in RERF-LC-OK or PC3. Transcriptional activities of progesterone receptor were increased by progesterone in these three progesterone receptor–positive NSCLC cells by luciferase assays. Cell proliferation was inhibited by progesterone in these progesterone receptor–positive NSCLC cells in a dose-dependent manner, which was inhibited by progesterone receptor blocker. Proliferation of these tumor cells injected into nude mice was also dose-dependently inhibited by progesterone, with a concomitant increase of p21 and p27 and a decrease of cyclin A, cyclin E, and Ki67. Results of our present study suggested that progesterone receptor was a potent prognostic factor in NSCLCs and progesterone inhibited growth of progesterone receptor–positive NSCLC cells. Therefore, progesterone therapy may be clinically effective in suppressing development of progesterone receptor–positive NSCLC patients.
Virus-Associated RNA I–Deleted Adenovirus, a Potential Oncolytic Agent Targeting EBV-Associated Tumors
Authors: Wang Yaohe , Xue Shao-An , Hallden Gunnel , Francis Jennelle , Yuan Ming , Griffin Beverly E. , Lemoine Nick R. 
Published: September 2005

Abstract
Given the growing number of tumor types recognizably associated with EBV infection, it is critically important that therapeutic strategies are developed to treat such tumors. Replication-selective oncolytic adenoviruses represent a promising new platform for anticancer therapy. Virus-associated I (VAI) RNAs of adenoviruses are required for efficient translation of viral mRNAs. When the VAI gene is deleted, adenovirus replication is impeded in most cells (including HEK 293 cells). EBV-encoded small RNA1 is uniformly expressed in most EBV-associated human tumors and can functionally substitute for the VAI RNAs of adenovirus. It enables replication to proceed through complementation of VAI-deletion mutants. We hypothesized that VAI-deleted adenovirus would selectively replicate in EBV-positive tumor cells due to the presence of EBV-encoded small RNA1 with no (or poor) replication in normal or EBV-negative tumor cells. In this report, we show that high levels of replication occurred in the VAI-deleted mutant in the EBV-positive tumor cells compared with low (or negligible) levels in EBV-negative and normal human primary cells. Correspondingly, high toxicity levels were observed in EBV-positive tumor cells but not in EBV-negative tumor or normal human primary cells. In vivo, VAI-deleted adenovirus showed superior antitumoral efficacy to wild-type adenovirus in EBV-positive tumor xenografts, with lower hepatotoxicity than wild-type adenovirus. Our data suggest that VAI-deleted adenovirus is a promising replication-selective oncolytic virus with targeting specificity for EBV-associated tumors.
Disruption of Rb/E2F Pathway Results in Increased Cyclooxygenase-2 Expression and Activity in Prostate Epithelial Cells
Authors: Davis Joanne N. , McCabe Michael T. , Hayward Simon W. , Park John M. , Day Mark L. 
Published: September 2005

Abstract
The loss of the retinoblastoma tumor suppressor gene (RB) is common in many human cancers, including prostate. We previously reported that engineered deletion of RB in prostate epithelial cells results in sustained cell growth in serum-free media, a predisposition to develop hyperplasia and dysplasia in prostate tissue recombinant grafts, and sensitization to hormonal carcinogenesis. Examining the molecular consequence of RB loss in this system, we show that cyclooxygenase-2 (COX-2) is significantly up-regulated following RB deletion in prostate tissue recombinants. To study the effect of RB deletion on COX-2 regulation, we generated wild-type (PrE) and Rb−/− (Rb−/−PrE) prostate epithelial cell lines rescued by tissue recombination. We show elevated COX-2 mRNA and protein expression in Rb−/−PrE cell lines with increased prostaglandin synthesis. We also find that loss of Rb leads to deregulated E2F activity, with increased expression of E2F target genes, and that exogenous expression of E2F1 results in elevated COX-2 mRNA and protein levels. COX-2 promoter studies reveal that E2F1 transcriptionally activates COX-2, which is dependent on the transactivation and DNA-binding domains of E2F1. Further analysis revealed that the E2F1 target gene, c-myb, is elevated in Rb−/−PrE cells and E2F1-overexpressing cells, whereas ectopic overexpression of c-myb activates the COX-2 promoter in prostate epithelial cells. Additionally, cotransfection with E2F1 and a dominant-negative c-myb inhibited E2F1 activation of the COX-2 promoter. Taken together, these results suggest activation of a transcriptional cascade by which E2F1 regulates COX-2 expression through the c-myb oncogene. This study reports a novel finding describing that deregulation of the Rb/E2F complex results in increased COX-2 expression and activity.
Dominant-Negative Notch3 Receptor Inhibits Mitogen-Activated Protein Kinase Pathway and the Growth of Human Lung Cancers
Authors: Haruki Nobuhiro , Kawaguchi Keiko S. , Eichenberger Shannon , Massion Pierre P. , Olson Sandra , Gonzalez Adriana , Carbone David P. , Dang Thao P. 
Published: September 2005

Abstract
Notch3 is a member of an evolutionarily conserved family of cell surface receptors important in cell-fate determination in both vertebrates and invertebrates. Significant data support the role of Notch pathway in cancer development, although the conflicting role of Notch signaling pathways in tumorigenesis suggests that its action is highly context-dependent. Furthermore, although Notch receptors signal primarily through the regulation of hairy enhancer of split (HES) and HES-related (HRT) genes, they are known to crosstalk with other signaling pathways, including the epidermal growth factor (EGF) and the mitogen-activated protein kinase pathways. Whereas much is known about the role of Notch1 in human cancer, the role of Notch3 in epithelial tumors, such as lung carcinomas, has not been well established. In this study, we show that Notch3 is expressed in 80 of 207 (39%) resected human lung tumors and that its expression is positively correlated with EGF receptor expression. Inhibition of the Notch3 pathway using a dominant-negative receptor dramatically reduces growth in soft agar and increases growth factor dependence. We also find that Notch inhibition increases sensitivity to EGF receptor tyrosine kinase inhibition and decrease in phosphorylation of the mitogen-activated protein kinase. These observations support a role for Notch3 signaling in lung cancer, and one potential mechanism of maintaining the neoplastic phenotype is through the modulation of the EGF pathway.
Antitumor Activity of the Insulin-Like Growth Factor-I Receptor Kinase Inhibitor NVP-AEW541 in Musculoskeletal Tumors
Authors: Scotlandi Katia , Manara Maria Cristina , Nicoletti Giordano , Lollini Pier-Luigi , Lukas Stella , Benini Stefania , Croci Stefania , Perdichizzi Stefania , Zambelli Diana , Serra Massimo , García-Echeverría Carlos , Hofmann Francesco , Picci Piero 
Published: September 2005

Abstract
Identification of new drugs is strongly needed for sarcomas. Insulin-like growth factor-I receptor (IGF-IR) was found to provide a major contribution to the malignant behavior of these tumors, therefore representing a very promising therapeutic target. In this study, we analyzed the therapeutic potential of a novel kinase inhibitor of IGF-IR, NVP-AEW541, in Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma, the three most frequent solid tumors in children and adolescents. NVP-AEW541 inhibits IGF-I-mediated receptor activation and downstream signaling. Ewing's sarcoma cells were generally found to be more sensitive to the effects of this drug compared with rhabdomyosarcoma and osteosarcoma, in agreement with the high dependency of this neoplasm to IGF-IR signaling. NVP-AEW541 induced a G1 cell cycle block in all cells tested, whereas apoptosis was observed only in those cells that show a high level of sensitivity. Concurrent exposure of cells to NVP-AEW541 and other chemotherapeutic agents resulted in positive interactions with vincristine, actinomycin D, and ifosfamide and subadditive effects with doxorubicin and cisplatin. Accordingly, combined treatment with NVP-AEW541 and vincristine significantly inhibited tumor growth of Ewing's sarcoma xenografts in nude mice. Therefore, results encourage inclusion of this drug especially in the treatment of patients with Ewing's sarcoma. For the broadest applicability and best efficacy in sarcomas, NVP-AEW541 may be combined with vincristine, actinomycin D, and ifosfamide, three major drugs in the treatment of sarcomas.
Real-time Detection of Gene Expression in Cancer Cells Using Molecular Beacon Imaging: New Strategies for Cancer Research
Authors: Peng Xiang-Hong , Cao Ze-Hong , Xia Jin-Tang , Carlson Grant W. , Lewis Melinda M. , Wood William C. , Yang Lily 
Published: September 2005

Abstract
Development of novel approaches for quantitative analysis of gene expression in intact tumor cells should provide new means for cancer detection and for studying the response of cancer cells to biological and therapeutic reagents. We developed procedures for detecting the levels of expression of multiple genes in fixed as well as viable cells using molecular beacon imaging technology. We found that simultaneous delivery of molecular beacons targeting survivin and cyclin D1 mRNAs produced strong fluorescence in breast cancer but not in normal breast cells. Importantly, fluorescence intensity correlated well with the level of gene expression in the cells detected by real-time reverse transcription–PCR or Western blot analysis. We further show that molecular beacons can detect changes of survivin gene expression in viable cancer cells following epidermal growth factor stimulation, docetaxel treatment, and overexpression of p53 gene. Thus, molecular beacon imaging is a simple and specific method for detecting gene expression in cancer cells. It has great potential for cancer detection and drug development.
Targeted Replacement of Hypoxia-Inducible Factor-1α by a Hypoxia-Inducible Factor-2α Knock-in Allele Promotes Tumor Growth
Authors: Covello Kelly L. , Simon M. Celeste , Keith Brian 
Published: September 2005

Abstract
Hypoxia-inducible factors (HIF) are essential transcriptional regulators that mediate adaptation to hypoxic stress in rapidly growing tissues such as tumors. HIF activity is regulated by hypoxic stabilization of the related HIF-1α and HIF-2α subunits, which are frequently overexpressed in cancer cells. To assess the relative tumor-promoting functions of HIF-1α and HIF-2α directly, we replaced HIF-1α expression with HIF-2α by creating a novel “knock-in” allele at the Hif-1α locus through homologous recombination in primary murine embryonic stem cells. Compared with controls, s.c. teratomas derived from knock-in embryonic stem cells were larger and more proliferative, had increased microvessel density, and exhibited increased expression of vascular endothelial growth factor, transforming growth factor-α, and cyclin D1. These and other data indicate that HIF-2α promotes tumor growth more effectively than HIF-1α in multiple contexts.