bluuebunny/crossref_metadata_2025_split huggingface dataset:
c-Jun NH2-Terminal Kinase-Mediated Up-regulation of Death Receptor 5 Contributes to Induction of Apoptosis by the Novel Synthetic Triterpenoid Methyl-2-Cyano-3,12-Dioxooleana-1, 9-Dien-28-Oate in Human Lung Cancer Cells
Authors: Zou Wei , Liu Xiangguo , Yue Ping , Zhou Zhongmei , Sporn Michael B. , Lotan Reuben , Khuri Fadlo R. , Sun Shi-Yong 
Published: September 2005

Abstract
Death receptor (DR) 4 or 5, on binding to its ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), triggers apoptosis via activating the caspase-8–mediated caspase cascade. Certain anticancer drugs up-regulate the expression of these receptors and thereby induce apoptosis or enhance TRAIL-induced apoptosis. In this study, we explored the ability of methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate (CDDO-Me) to activate the extrinsic DR-mediated apoptotic pathway in human lung cancer cells. We found that CDDO-Me not only activated caspase-8 but also induced expression of DRs, particularly DR5, in a p53-independent mechanism. Correspondingly, CDDO-Me augmented TRAIL-induced apoptosis in these cells regardless of p53 status as evidenced by enhanced DNA fragmentation and activation of caspase cascades, suggesting that CDDO-Me–induced DRs are functionally active. Moreover, silencing of DR5 expression using small interfering RNA suppressed apoptosis induced by CDDO-Me alone or by combination of CDDO-Me and TRAIL, indicating that DR5 up-regulation is required for induction of apoptosis by CDDO-Me and for enhancement of TRAIL-induced apoptosis by CDDO-Me. CDDO-Me rapidly activated c-Jun NH2-terminal kinase (JNK) before DR up-regulation and caspase-8 activation. Moreover, application of the JNK-specific inhibitor SP600125 blocked CDDO-Me–induced increases in JNK activation, DR up-regulation, caspase-8 activation, and DNA fragmentation. These results show that activation of JNK pathway results in CDDO-Me–induced DR up-regulation, caspase-8 activation, and apoptosis. Collectively, we conclude that CDDO-Me induces apoptosis via the JNK-mediated DR up-regulation in human lung cancer cells.
Aberrant Expression of the Tyrosine Kinase Receptor EphA4 and the Transcription Factor Twist in Sézary Syndrome Identified by Gene Expression Analysis
Authors: van Doorn Remco , Dijkman Remco , Vermeer Maarten H. , Out-Luiting Jacoba J. , van der Raaij-Helmer Elisabeth M. H. , Willemze Rein , Tensen Cornelis P. 
Published: September 2005

AbstractSézary syndrome (Sz) is a malignancy of CD4+ memory skin-homing T cells and presents with erythroderma, lymphadenopathy, and peripheral blood involvement. To gain more insight into the molecular features of Sz, oligonucleotide array analysis was performed comparing gene expression patterns of CD4+ T cells from peripheral blood of patients with Sz with those of patients with erythroderma secondary to dermatitis and healthy controls. Using unsupervised hierarchical clustering gene, expression patterns of T cells from patients with Sz were classified separately from those of benign T cells. One hundred twenty-three genes were identified as significantly differentially expressed and had an average fold change exceeding 2. T cells from patients with Sz demonstrated decreased expression of the following hematopoietic malignancy-linked tumor suppressor genes: TGF-β receptor II, Mxi1, Riz1, CREB-binding protein, BCL11a, STAT4, and Forkhead Box O1A. Moreover, the tyrosine kinase receptor EphA4 and the potentially oncogenic transcription factor Twist were highly and selectively expressed in T cells of patients with Sz. High expression of EphA4 and Twist was also observed in lesional skin biopsy specimens of a subset of patients with cutaneous T cell lymphomas related to Sz, whereas their expression was nearly undetectable in benign T cells or in skin lesions of patients with inflammatory dermatoses. Detection of EphA4 and Twist may be used in the molecular diagnosis of Sz and related cutaneous T-cell lymphomas. Furthermore, the membrane-bound EphA4 receptor may serve as a target for directed therapeutic intervention.
Dendritic Cell Subsets Differentially Regulate Angiogenesis in Human Ovarian Cancer
Authors: Curiel Tyler J. , Cheng Pui , Mottram Peter , Alvarez Xavier , Moons Lieve , Evdemon-Hogan Melina , Wei Shuang , Zou Linhua , Kryczek Ilona , Hoyle Gary , Lackner Andrew , Carmeliet Peter , Zou Weiping 
Published: September 2005

AbstractAngiogenesis is essential for both primary and metastatic tumor growth. Tumor blood vessel formation is complex and regulated by many factors. Ovarian carcinomas have a poor prognosis, often associated with multifocal intraperitoneal dissemination accompanied by intense neovascularization. To examine tumor angiogenesis in the tumor microenvironment, we studied malignant ascites of patients with untreated ovarian carcinoma. We observed high numbers of plasmacytoid dendritic cells (PDCs) and significant stromal-derived factor (CXCL-12/SDF)-1 in their malignant ascites, attracting PDCs into the tumor environment. We now show that tumor-associated PDCs induced angiogenesis in vivo through production of tumor necrosis factor α and interleukin 8. By contrast, myeloid dendritic cells (MDCs) were absent from malignant ascites. MDCs derived in vitro suppressed angiogenesis in vivo through production of interleukin 12. Thus, the tumor may attract PDCs to augment angiogenesis while excluding MDCs to prevent angiogenesis inhibition, demonstrating a novel mechanism for modulating tumor neovascularization. Because dendritic cells (DCs) have long been known to affect tumor immunity, our data also implicate DCs in regulation of tumor neoangiogenesis, suggesting a novel role of DCs in tumor pathology.
The Role of DNA Polymerase η in Translesion Synthesis Past Platinum–DNA Adducts in Human Fibroblasts
Authors: Bassett Ekaterina , King Nicole M. , Bryant Miriam F. , Hector Suzanne , Pendyala Lakshmi , Chaney Stephen G. , Cordeiro-Stone Marila 
Published: September 2005

Abstract
Cisplatin, a widely used chemotherapeutic agent, has been implicated in the induction of secondary tumors in cancer patients. This drug is presumed to be mutagenic because of error-prone translesion synthesis of cisplatin adducts in DNA. Oxaliplatin is effective in cisplatin-resistant tumors, but its mutagenicity in humans has not been reported. The polymerases involved in bypass of cisplatin and oxaliplatin adducts in vivo are not known. DNA polymerase η is the most efficient polymerase for bypassing platinum adducts in vitro. We evaluated the role of polymerase η in translesion synthesis past platinum adducts by determining cytotoxicity and induced mutation frequencies at the hypoxanthine guanine phosphoribosyltransferase (HPRT) locus in diploid human fibroblasts. Normal human fibroblasts (NHF1) were compared with xeroderma pigmentosum variant (XPV) cells (polymerase η-null) after treatment with cisplatin. In addition, XPV cells complemented for polymerase η expression were compared with the isogenic cells carrying the empty expression vector. Cytotoxicity and induced mutagenicity experiments were measured in parallel in UVC-irradiated fibroblasts. We found that equitoxic doses of cisplatin induced mutations in fibroblasts lacking polymerase η at frequencies 2- to 2.5-fold higher than in fibroblasts with either normal or high levels of polymerase η. These results indicate that polymerase η is involved in error-free translesion synthesis past some cisplatin adducts. We also found that per lethal event, cisplatin was less mutagenic than UVC. Treatment with a wide range of cytotoxic doses of oxaliplatin did not induce mutations above background levels in cells either expressing or lacking polymerase η, suggesting that oxaliplatin is nonmutagenic in human fibroblasts.
HOXB13 Induces Growth Suppression of Prostate Cancer Cells as a Repressor of Hormone-Activated Androgen Receptor Signaling
Authors: Jung Chaeyong , Kim Ran-Sook , Zhang Hong-Ji , Lee Sang-Jin , Jeng Meei-Huey 
Published: September 2005

Abstract
Androgen receptor (AR) signals play a decisive role in regulating the growth and differentiation of both normal and cancerous prostate cells by triggering the regulation of target genes, in a process in which AR cofactors have critical functions. Because of the highly prostate-specific expression pattern of HOXB13, we studied the role of this homeodomain protein in prostate cells. Expression of HOXB13 was limited to AR-expressing prostate cells. Reporter transcription assay demonstrated that HOXB13 significantly suppressed hormone-mediated AR activity in a dose-responsive manner, and suppression was specific to AR with which HOXB13 physically interacts. Overexpression of HOXB13 further down-regulated the androgen-stimulated expression of prostate-specific antigen, and suppression of endogenous HOXB13 stimulated transactivation of AR. Functionally, HOXB13 suppressed growth of LNCaP prostate cancer cells, which could be counteracted by additional hormone-activated AR. On the other hand, the growth-suppressive function of HOXB13 in AR-negative CV-1 cells was not affected by AR. These results suggest that HOXB13 functions as an AR repressor to modulate the complex AR signaling and subsequent growth regulation of prostate cancer cells. In addition to the loss of HOXB13 expression, maintaining AR may be an important step for prostate cancer cells to tolerate the suppressor function of HOXB13. Altogether, our data present a novel mechanism for the HOXB13-mediated repression of AR signaling, which can be interpreted to a growth-suppressive event.
Visualization of Intrathoracically Disseminated Solid Tumors in Mice with Optical Imaging by Telomerase-Specific Amplification of a Transferred Green Fluorescent Protein Gene
Authors: Umeoka Tatsuo , Kawashima Takeshi , Kagawa Shunsuke , Teraishi Fuminori , Taki Masaki , Nishizaki Masahiko , Kyo Satoru , Nagai Katsuyuki , Urata Yasuo , Tanaka Noriaki , Fujiwara Toshiyoshi 
Published: September 2005

Abstract
Currently available methods for detection of tumors in vivo such as X-ray, computed tomography, and ultrasonography are noninvasive and have been well studied; the images, however, are not specific for tumors. Direct optical imaging of tumor cells in vivo that can clearly distinguish them from surrounding normal tissues may be clinically useful. Here, we describe a new approach to visualizing tumors whose fluorescence can be detected using tumor-specific replication-competent adenovirus (OBP-301, Telomelysin) in combination with Ad-GFP, a replication-deficient adenovirus expressing green fluorescent protein (GFP). Human telomerase reverse transcriptase is the catalytic subunit of telomerase, which is highly active in cancer cells but quiescent in most normal somatic cells. We constructed an adenovirus 5 vector in which the human telomerase reverse transcriptase promoter element drives expression of E1A and E1B genes linked with an internal ribosome entry site and showed that OBP-301 replicated efficiently in human cancer cells, but not in normal cells such as human fibroblasts. When the human lung and colon cancer cell lines were infected with Ad-GFP at a low multiplicity of infection, GFP expression could not be detected under a fluorescence microscope; in the presence of OBP-301, however, Ad-GFP replicated in these tumor cells and showed strong green signals. In contrast, coinfection with OBP-301 and Ad-GFP did not show any signals in normal cells such as fibroblasts and vascular endothelial cells. We also found that established subcutaneous tumors could be visualized after intratumoral injection of OBP-301 and Ad-GFP. A549 human lung tumors and SW620 human colon tumors transplanted into BALB/c nu/nu mice were intratumorally injected with 8 × 105 plaque-forming units of Ad-GFP in combination with 8 × 106 plaque-forming units of OBP-301. Within 3 days of treatment, the fluorescence of the expressed GFP became visible by a three-chip color cooled charged-coupled device camera in these tumors, whereas intratumoral injection of Ad-GFP alone could not induce GFP fluorescence. Moreover, intrathoracic administration of Ad-GFP and OBP-301 could visualize disseminated A549 tumor nodules in mice after intrathoracic implantation. Our results indicate that intratumoral or intrathoracic injection of Ad-GFP in combination with OBP-301 might be a useful diagnostic method that provides a foundation for future clinical application.
Genetic Pathways to Glioblastoma
Authors: Ohgaki Hiroko , Dessen Pierre , Jourde Benjamin , Horstmann Sonja , Nishikawa Tomofumi , Di Patre Pier-Luigi , Burkhard Christoph , Schüler Danielle , Probst-Hensch Nicole M. , Maiorka Paulo César , Baeza Nathalie , Pisani Paola , Yonekawa Yasuhiro , Yasargil M. Gazi , Lütolf Urs M. , Kleihues Paul 
Published: September 2005

Abstract
We conducted a population-based study on glioblastomas in the Canton of Zurich, Switzerland (population, 1.16 million) to determine the frequency of major genetic alterations and their effect on patient survival. Between 1980 and 1994, 715 glioblastomas were diagnosed. The incidence rate per 100,000 population/year, adjusted to the World Standard Population, was 3.32 in males and 2.24 in females. Observed survival rates were 42.4% at 6 months, 17.7% at 1 year, and 3.3% at 2 years. For all of the age groups, younger patients survived significantly longer, ranging from a median of 8.8 months (&lt;50 years) to 1.6 months (&gt;80 years). Loss of heterozygosity (LOH) 10q was the most frequent genetic alteration (69%), followed by EGFR amplification (34%), TP53 mutations (31%), p16INK4a deletion (31%), and PTEN mutations (24%). LOH 10q occurred in association with any of the other genetic alterations and was predictive of shorter survival. Primary (de novo) glioblastomas prevailed (95%), whereas secondary glioblastomas that progressed from low-grade or anaplastic gliomas were rare (5%). Secondary glioblastomas were characterized by frequent LOH 10q (63%) and TP53 mutations (65%). Of the TP53 mutations in secondary glioblastomas, 57% were in hotspot codons 248 and 273, whereas in primary glioblastomas, mutations were more equally distributed. G:C→A:T mutations at CpG sites were more frequent in secondary than primary glioblastomas (56% versus 30%; P = 0.0208). This suggests that the acquisition of TP53 mutations in these glioblastoma subtypes occurs through different mechanisms.
Inhibition ofSmoothenedSignaling Prevents Ultraviolet B-Induced Basal Cell Carcinomas through Regulation of Fas Expression and Apoptosis
Authors: Athar Mohammad , Li Chengxin , Tang Xiuwei , Chi Sumin , Zhang Xiaoli , Kim Arianna L. , Tyring Stephen K. , Kopelovich Levy , Hebert Jennifer , Epstein Ervin H. , Bickers David R. , Xie Jingwu 
Published: September 2005

AbstractAbnormal activation of the hedgehog-signaling pathway is the pivotal abnormality driving the growth of basal cell carcinomas (BCCs), the most common type of human cancer. Antagonists of this pathway such as cyclopamine may therefore be useful for treatment of basal cell carcinomas and other hedgehog-driven tumors. We report here that chronic oral administration of cyclopamine dramatically reduces (∼66%) UVBinduced basal cell carcinoma formation in Ptch1+/− mice. Fas expression is low in human and murine basal cell carcinomas but is up-regulated in the presence of the smoothened (SMO) antagonist, cyclopamine, both in vitro in the mouse basal cell carcinoma cell line ASZ001 and in vivo after acute treatment of mice with basal cell carcinomas. This parallels an elevated rate of apoptosis. Conversely, expression of activated SMO in C3H10T1/2 cells inhibits Fas expression. Fas/Fas ligand interactions are necessary for cyclopamine-mediated apoptosis in these cells, a process involving caspase-8 activation. Our data provide strong evidence that cyclopamine and perhaps other SMO antagonists are potent in vivo inhibitors of UVB-induced basal cell carcinomas in Ptch1+/− mice and likely in humans because the majority of human basal cell carcinomas manifest mutations in PTCH1 and that a major mechanism of their inhibitory effect is through up-regulation of Fas, which augments apoptosis.
Deregulated Akt3 Activity Promotes Development of Malignant Melanoma
Authors: Stahl Jill M. , Sharma Arati , Cheung Mitchell , Zimmerman Melissa , Cheng Jin Q. , Bosenberg Marcus W. , Kester Mark , Sandirasegarane Lakshman , Robertson Gavin P. 
Published: September 2005

Abstract
Malignant melanoma is the skin cancer with the most significant impact on man, carrying the highest risk of death from metastasis. Both incidence and mortality rates continue to rise each year, with no effective long-term treatment on the horizon. In part, this reflects lack of identification of critical genes involved and specific therapies targeted to correct these defects. We report that selective activation of the Akt3 protein promotes cell survival and tumor development in 43 to 60% of nonfamilial melanomas. The predominant Akt isoform active in melanomas was identified by showing that small interfering RNA (siRNA) against only Akt3, and not Akt1 or Akt2, lowered the amount of phosphorylated (active) Akt in melanoma cells. The amount of active Akt3 increased progressively during melanoma tumor progression with highest levels present in advanced-stage metastatic melanomas. Mechanisms of Akt3 deregulation occurred through a combination of overexpression of Akt3 accompanying copy number increases of the gene and decreased PTEN protein function occurring through loss or haploinsufficiency of the PTEN gene. Targeted reduction of Akt3 activity with siRNA or by expressing active PTEN protein stimulated apoptotic signaling, which reduced cell survival by increasing apoptosis rates thereby inhibiting melanoma tumor development. Identifying Akt3 as a selective target in melanoma cells provides new therapeutic opportunities for patients in the advanced stages of this disease.
Functional Integrity of Nuclear Factor κB, Phosphatidylinositol 3′-Kinase, and Mitogen-Activated Protein Kinase Signaling Allows Tumor Necrosis Factor α-Evoked Bcl-2 Expression to Provoke Internal Ribosome Entry Site-Dependent Translation of Hypoxia-Inducible Factor 1α
Authors: Zhou Jie , Callapina Melvin , Goodall Gregory J. , Brüne Bernhard 
Published: September 2005

Abstract
Hypoxia-inducible factor (HIF)-1, a heterodimeric transcription factor composed of HIF-1α and HIF-1β subunits coordinates pathophysiologic responses toward decreased oxygen availability. It is now appreciated that enhanced protein translation of HIF-1α under normoxia accounts for an alternative regulatory circuit to activate HIF-1 by hormones, growth factors, or cytokines such as tumor necrosis factor α (TNF-α). Here, we aimed at understanding molecular details of HIF-1α translation in response to TNF-α. In tubular LLC-PK1 cells, activation of nuclear factor κB (NFκB) by TNF-α resulted in HIF-1α protein synthesis as determined by [35S]methionine pulse experiments. Protein synthesis was attenuated by blocking NFκB, phosphatidylinositol 3′-kinase (PI3k), and mitogen-activated protein kinase (MAPK). Use of a dicistronic reporter with the HIF-1α 5′-untranslated region (5′UTR) between two coding regions indicated that TNF-α promoted an internal ribosome entry site (IRES) rather than a cap-dependent translation. IRES-mediated translation required the functional integrity of the NFκB, PI3k, and MAPK signaling pathways. Although no signal cross-talk was noticed between NFκB, PI3k, and MAPK signaling, these pathways are needed to up-regulate the anti-apoptotic target protein Bcl-2 by TNF-α. Expression of Bcl-2 provoked not only IRES-dependent translation but also HIF-1α protein synthesis. We conclude that Bcl-2 functions as an important determinant in facilitating HIF-1α protein expression by TNF-α via an IRES-dependent translational mechanism. These observations suggest a link between Bcl-2 and HIF-1α expression, a situation with potential relevance to cancer biology.
Crucial Role for Interferon γ in the Synergism between Tumor Vasculature-Targeted Tumor Necrosis Factor α (NGR-TNF) and Doxorubicin
Authors: Sacchi Angelina , Gasparri Anna , Curnis Flavio , Bellone Matteo , Corti Angelo 
Published: September 2005

AbstractNGR-TNF is a derivative of TNF-α, consisting of TNF fused to CNGRCG, a tumor vasculature-targeting peptide. Previous studies showed that NGR-TNF can exert synergistic antitumor effects with doxorubicin and with other chemotherapeutic drugs in murine models. In this study, we have investigated the role of endogenous IFN-γ on the antitumor activity of NGR-TNF in combination with doxorubicin. The study was carried out using murine B16F1 melanoma and TS/A mammary adenocarcinoma implanted subcutaneously in (a) immunocompetent mice, (b) athymic nude mice, and (c) IFN-γ–knockout mice. Synergism between NGR-TNF and doxorubicin was observed in immunocompetent mice but not in nude or IFN-γ–knockout mice. Preadministration of a neutralizing anti-IFN-γ antibody to immunocompetent mice inhibited the NGR-TNF/doxorubicin synergism, whereas administration of IFN-γ to nude and to IFN-γ–knockout mice restored the synergistic activity. The synergism in nude mice was restored also by transfecting tumor cells with the IFN-γ cDNA. Administration of NGR-TNF in combination with IFN-γ to nude mice, but not of NGR-TNF alone, doubled the penetration of doxorubicin in TS/A tumors. These findings point to a crucial role for locally produced IFN-γ in tumor vascular targeting with NGR-TNF and doxorubicin. Finally, addition of IFN-γ to the treatment of immunocompetent mice with NGR-TNF/doxorubicin induced only modest improvement in response, suggesting that exogenous IFN-γ can improve the therapeutic activity of these drugs only in case of suboptimal production of endogenous IFN-γ.
Notch1
and
Notch2
Have Opposite Effects on Embryonal Brain Tumor Growth
Authors: Fan Xing , Mikolaenko Irina , Elhassan Ihab , Ni XingZhi , Wang Yunyue , Ball Douglas , Brat Daniel J. , Perry Arie , Eberhart Charles G. 
Published: September 2005

Abstract
The role of Notch signaling in tumorigenesis can vary; Notch1 acts as an oncogene in some neoplasms, and a tumor suppressor in others. Here, we show that different Notch receptors can have opposite effects in a single tumor type. Expression of truncated, constitutively active Notch1 or Notch2 in embryonal brain tumor cell lines caused antagonistic effects on tumor growth. Cell proliferation, soft agar colony formation, and xenograft growth were all promoted by Notch2 and inhibited by Notch1. We also found that Notch2 receptor transcripts are highly expressed in progenitor cell-derived brain tumors such as medulloblastomas, whereas Notch1 is scarce or undetectable. This parallels normal cerebellar development, during which Notch2 is predominantly expressed in proliferating progenitors and Notch1 in postmitotic differentiating cells. Given the oncogenic effects of Notch2, we analyzed its gene dosage in 40 embryonal brain tumors, detecting an increased copy number in 15% of cases. Notch2 gene amplification was confirmed by fluorescence in situ hybridization in one case with extremely high Notch2 mRNA levels. In addition, expression of the Notch pathway target gene Hes1 in medulloblastomas was associated with significantly shorter patient survival (P = 0.01). Finally, pharmacological inhibition of Notch signaling suppresses growth of medulloblastoma cells. Our data indicate that Notch1 and Notch2 can have opposite effects on the growth of a single tumor type, and show that Notch2 can be overexpressed after gene amplification in human tumors.