bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hypoxia-Mediated Induction of the Polyamine System Provides Opportunities for Tumor Growth Inhibition by Combined Targeting of Vascular Endothelial Growth Factor and Ornithine Decarboxylase
Authors: Svensson Katrin J. , Welch Johanna E. , Kucharzewska Paulina , Bengtson Per , Bjurberg Maria , Påhlman Sven , Ten Dam Gerdy B. , Persson Lo , Belting Mattias 
Published: November 2008

Abstract
Hypoxia is a hallmark of solid tumors, which may offer opportunities for targeted therapies of cancer; however, the mechanisms that link hypoxia to malignant transformation and tumor progression are not fully understood. Here, we show that up-regulation of the polyamine system promotes cancer cell survival during hypoxic stress. Hypoxia was found to induce polyamine transport and the key enzyme of polyamine biosynthesis, ornithine decarboxylase (ODC), in a variety of cancer cell lines. Increased ODC protein expression was shown in hypoxic, GLUT-1–expressing regions of tumor spheroids and experimental tumors, as well as in clinical tumor specimens. Hypoxic induction of the polyamine system was dependent on antizyme inhibitor (i.e., a key positive regulator of ODC and polyamine transport), as shown by RNA interference experiments. Interestingly, depletion of the polyamines during hypoxia resulted in increased apoptosis, which indicates an essential role of the polyamines in cancer cell adaptation to hypoxic stress. These results were supported by experiments in an in vivo glioma tumor model, showing significantly enhanced antitumor effects of the antiangiogenic, humanized anti–vascular endothelial growth factor (VEGF) antibody bevacizumab when used in combination with the well-established, irreversible inhibitor of ODC, α-difluoromethylornithine. Our results provide important insights into the hypoxic stress response in malignant cells and implicate combined targeting of VEGF and ODC as an alternative strategy to treat cancer disease. [Cancer Res 2008;68(22):9291–301]
Transforming Growth Factor β: Tumor Suppressor or Promoter? Are Host Immune Cells the Answer?
Authors: Yang Li , Moses Harold L. 
Published: November 2008

Abstract
Therapies targeting transforming growth factor β (TGFβ) signaling using neutralizing antibodies and small molecular inhibitors are in multiple clinical trails. However, TGFβ is known to work as both a tumor suppressor and a tumor promoter, and current knowledge does not provide sufficient information on what factors mediate this switch in function and when this switch occurs. Recent advances in multiple disciplines suggest that immune cells from the tumor host may provide the answer. [Cancer Res 2008;68(22):9107–11]
Role of a Novel Splice Variant of Mitotic Arrest Deficient 1 (MAD1), MAD1β, in Mitotic Checkpoint Control in Liver Cancer
Authors: Sze Karen Man-Fong , Ching Yick-Pang , Jin Dong-Yan , Ng Irene Oi-Lin 
Published: November 2008

Abstract
Loss of mitotic checkpoint contributes to chromosomal instability, leading to carcinogenesis. In this study, we identified a novel splicing variant of mitotic arrest deficient 1 (MAD1), designated MAD1β, and investigated its role in mitotic checkpoint control in hepatocellular carcinoma (HCC). The expression levels of human MAD1β were examined in hepatoma cell lines and human HCC samples. The functional roles of MAD1β in relation to the mitotic checkpoint control, chromosomal instability, and binding with MAD2 were assessed in hepatoma cell lines. On sequencing, MAD1β was found to have deletion of exon 4. It was expressed at both mRNA and protein levels in the nine hepatoma cell lines tested and was overexpressed in 12 of 50 (24%) human HCCs. MAD1β localized in the cytoplasm, whereas MAD1α was found in the nucleus. This cytoplasmic localization of MAD1β was due to the absence of a nuclear localization signal in MAD1α. In addition, MAD1β was found to physically interact with MAD2 and sequester it in the cytoplasm. Furthermore, expression of MAD1β induced mitotic checkpoint impairment, chromosome bridge formation, and aberrant chromosome numbers via binding with MAD2. Our data suggest that the novel splicing variant MAD1β may have functions different from those of MAD1α and may play opposing roles to MAD1α in mitotic checkpoint control in hepatocarcinogenesis. [Cancer Res 2008;68(22):9194–201]
Human Adrenomedullin Up-regulates Interleukin-13 Receptor α2 Chain in Prostate CancerIn vitroandIn vivo: A Novel Approach to Sensitize Prostate Cancer to Anticancer Therapy
Authors: Joshi Bharat H. , Leland Pamela , Calvo Alfonso , Green Jeffrey E. , Puri Raj K. 
Published: November 2008

AbstractInterleukin-13 (IL-13) receptor α2 (IL-13Rα2), a high-affinity IL-13 binding subunit and a tumor antigen, is amplified in a variety of human tumor cell lines and tumors in vivo. By cDNA microarray, we have shown that gene transfer of human and rat adrenomedullin (AM) up-regulates IL-13Rα2 in a human prostate tumor cell line. Here, we show that IL-13Rα2 mRNA and protein are also up-regulated in PC-3 prostate tumor cells by recombinant AM (rAM) and human synthetic AM peptide in a dose-dependent manner in vitro and in vivo in mouse prostate tumor model. The 8- to 10-fold up-regulation of IL-13Rα2 by rAM or AM peptide in prostate tumor cells in vitro and in vivo increased their sensitivity to IL-13PE cytotoxin consisting of IL-13 and a truncated form of Pseudomonas exotoxin. Immunodeficient mice with established prostate tumors transfected with AM or treated with AM peptide showed reduction in tumor size by intratumoral administration of IL-13PE in a dose-dependent manner. At the highest dose (three 100 μg/kg/d every alternate day), &gt;70% reduction of tumor size was observed compared with controls (P ≤ 0.01). These results indicate that two completely unrelated hormones (AM and IL-13) are closely related to each other and that we have identified a novel role of AM in sensitizing certain types of prostate tumors to IL-13R–directed therapeutic agent. [Cancer Res 2008;68(22):9311–7]
Antitumor Effect of SN-38–Releasing Polymeric Micelles, NK012, on Spontaneous Peritoneal Metastases from Orthotopic Gastric Cancer in Mice Compared with Irinotecan
Authors: Eguchi Nakajima Takako , Yanagihara Kazuyoshi , Takigahira Misato , Yasunaga Masahiro , Kato Ken , Hamaguchi Tetsuya , Yamada Yasuhide , Shimada Yasuhiro , Mihara Keichiro , Ochiya Takahiro , Matsumura Yasuhiro 
Published: November 2008

Abstract7-Ethyl-10-hydroxy-camptothecin (SN-38), an active metabolite of irinotecan hydrochloride (CPT-11), has potent antitumor activity. Moreover, we have reported the strong antitumor activity of NK012 (i.e., SN-38–releasing polymeric micelles) against human cancer xenografts compared with CPT-11. Here, we investigated the advantages of NK012 over CPT-11 treatment in mouse models of gastric cancer with peritoneal dissemination. NK012 or CPT-11 was i.v. administered thrice every 4 days at their respective maximum tolerable doses (NK012, 30 mg/kg/day; CPT-11, 67 mg/kg/day) to mice receiving orthotopic transplants of gastric cancer cell lines (44As3Luc and 58As1mLuc) transfected with the luciferase gene (n = 5). Antitumor effect was evaluated using the photon counting technique. SN-38 concentration in gastric tumors and peritoneal nodules was examined by high-performance liquid chromatography (HPLC) 1, 24, and 72 hours after each drug injection. NK012 or CPT-11 distribution in these tumors was evaluated using a fluorescence microscope on the same schedule. In both models, the antitumor activity of NK012 was superior to that of CPT-11. High concentrations of SN-38 released from NK012 were detected in gastric tumors and peritoneal nodules up to 72 hours by HPLC. Only a slight conversion from CPT-11 to SN-38 was observed from 1 to 24 hours. Fluorescence originating from NK012 was detected up to 72 hours, whereas that from CPT-11 disappeared until 24 hours. NK012 also showed antitumor activity against peritoneal nodules. Thus, NK012 showing enhanced distribution with prolonged SN-38 release may be ideal for cancer treatment because the antitumor activity of SN-38 is time dependent. [Cancer Res 2008;68(22):9318–22]
Repression of 15-Hydroxyprostaglandin Dehydrogenase Involves Histone Deacetylase 2 and Snail in Colorectal Cancer
Authors: Backlund Michael G. , Mann Jason R. , Holla Vijaykumar R. , Shi Qiong , Daikoku Takikoku , Dey Sudhansu K. , DuBois Raymond N. 
Published: November 2008

Abstract
Prostaglandin E2 (PGE2) promotes cancer progression by modulating proliferation, apoptosis, angiogenesis, and the immune response. Enzymatic degradation of PGE2 involves the NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH). Recent reports have shown a marked diminution of 15-PGDH expression in colorectal carcinomas (CRC). We report here that treatment of CRC cells with histone deacetylase (HDAC) inhibitors, including sodium butyrate and valproic acid, induces 15-PGDH expression. Additionally, we show that pretreatment of CRC cells with HDAC inhibitors can block epidermal growth factor–mediated or Snail-mediated transcriptional repression of 15-PGDH. We show an interaction between Snail and HDAC2 and the binding of HDAC2 to the 15-PGDH promoter. In vivo, we observe increased Hdac2 expression in Apc-deficient mouse adenomas, which inversely correlated with loss of 15-Pgdh expression. Finally, in human colon cancers, elevated HDAC expression correlated with down-regulation of 15-PGDH. These data suggest that class I HDACs, specifically HDAC2, and the transcriptional repressor Snail play a central role in the suppression of 15-PGDH expression. These results also provide a cyclooxygenase-2–independent mechanism to explain increased PGE2 levels that contribute to progression of CRC. [Cancer Res 2008;68(22):9331–7]
Induction of Cytoplasmic Accumulation of p53: A Mechanism for Low Levels of Arsenic Exposure to Predispose Cells for Malignant Transformation
Authors: Huang Yelin , Zhang Jianglin , McHenry Kevin T. , Kim Mihee M. , Zeng Weiqi , Lopez-Pajares Vanessa , Dibble Christian C. , Mizgerd Joseph P. , Yuan Zhi-Min 
Published: November 2008

Abstract
Although epidemiologic studies have linked arsenic exposure to the development of human cancer, the mechanisms underlying the tumorigenic role of arsenic remain largely undefined. We report here that treatment of cells with sodium arsenite at the concentrations close to environmental exposure is associated with the up-regulation of Hdm2 and the accumulation of p53 in the cytoplasm. Through the mitogen-activated protein kinase pathway, arsenite stimulates the P2 promoter–mediated expression of Hdm2, which then promotes p53 nuclear export. As a consequence, the p53 response to genotoxic stress is compromised, as evidenced by the impaired p53 activation and apoptosis in response to UV irradiation or 5FU treatment. The ability of arsenite to impede p53 activation is further demonstrated by a significantly blunted p53-dependent tissue response to 5FU treatment when mice were fed with arsenite-containing water. Together, our data suggests that arsenic compounds predispose cells to malignant transformation by up-regulation of Hdm2 and subsequent p53 inactivation. [Cancer Res 2008;68(22):9131–6]
Genome-Wide Functional Synergy between Amplified and Mutated Genes in Human Breast Cancer
Authors: Nikolsky Yuri , Sviridov Evgeny , Yao Jun , Dosymbekov Damir , Ustyansky Vadim , Kaznacheev Valery , Dezso Zoltan , Mulvey Laura , Macconaill Laura E. , Winckler Wendy , Serebryiskaya Tatiana , Nikolskaya Tatiana , Polyak Kornelia 
Published: November 2008

Abstract
A single cancer cell contains large numbers of genetic alterations that in combination create the malignant phenotype. However, whether amplified and mutated genes form functional and physical interaction networks that could explain the selection for cells with combined alterations is unknown. To investigate this issue, we characterized copy number alterations in 191 breast tumors using dense single nucleotide polymorphism arrays and identified 1,747 genes with copy number gain organized into 30 amplicons. Amplicons were distributed unequally throughout the genome. Each amplicon had distinct enrichment pattern in pathways, networks, and molecular functions, but genes within individual amplicons did not form coherent functional units. Genes in amplicons included all major tumorigenic pathways and were highly enriched in breast cancer–causative genes. In contrast, 1,188 genes with somatic mutations in breast cancer were distributed randomly over the genome, did not represent a functionally cohesive gene set, and were relatively less enriched in breast cancer marker genes. Mutated and gained genes did not show statistically significant overlap but were highly synergistic in populating key tumorigenic pathways including transforming growth factor β, WNT, fibroblast growth factor, and PIP3 signaling. In general, mutated genes were more frequently upstream of gained genes in transcription regulation signaling than vice versa, suggesting that mutated genes are mainly regulators, whereas gained genes are mostly regulated. ESR1 was the major transcription factor regulating amplified but not mutated genes. Our results support the hypothesis that multiple genetic events, including copy number gains and somatic mutations, are necessary for establishing the malignant cell phenotype. [Cancer Res 2008;68(22):9532–40]
Prediction of Recurrence-Free Survival in Postoperative Non–Small Cell Lung Cancer Patients by Using an Integrated Model of Clinical Information and Gene Expression
Authors: Lee Eung-Sirk , Son Dae-Soon , Kim Sung-Hyun , Lee Jinseon , Jo Jisuk , Han Joungho , Kim Heesue , Lee Hyun Joo , Choi Hye Young , Jung Youngja , Park Miyeon , Lim Yu Sung , Kim Kwhanmien , Shim Young Mog , Kim Byung Chul , Lee Kyusang , Huh Nam , Ko Christopher , Park Kyunghee , Lee Jae Won , Choi Yong Soo , Kim Jhingook 
Published: November 2008

Abstract
Purpose: One of the main challenges of lung cancer research is identifying patients at high risk for recurrence after surgical resection. Simple, accurate, and reproducible methods of evaluating individual risks of recurrence are needed.
Experimental Design: Based on a combined analysis of time-to-recurrence data, censoring information, and microarray data from a set of 138 patients, we selected statistically significant genes thought to be predictive of disease recurrence. The number of genes was further reduced by eliminating those whose expression levels were not reproducible by real-time quantitative PCR. Within these variables, a recurrence prediction model was constructed using Cox proportional hazard regression and validated via two independent cohorts (n = 56 and n = 59).
Results: After performing a log-rank test of the microarray data and successively selecting genes based on real-time quantitative PCR analysis, the most significant 18 genes had P values of &lt;0.05. After subsequent stepwise variable selection based on gene expression information and clinical variables, the recurrence prediction model consisted of six genes (CALB1, MMP7, SLC1A7, GSTA1, CCL19, and IFI44). Two pathologic variables, pStage and cellular differentiation, were developed. Validation by two independent cohorts confirmed that the proposed model is significantly accurate (P = 0.0314 and 0.0305, respectively). The predicted median recurrence-free survival times for each patient correlated well with the actual data.
Conclusions: We have developed an accurate, technically simple, and reproducible method for predicting individual recurrence risks. This model would potentially be useful in developing customized strategies for managing lung cancer.
Role of the Erythropoietin Receptor in ETV6/RUNX1-Positive Acute Lymphoblastic Leukemia
Authors: Inthal Andrea , Krapf Gerd , Beck Dominik , Joas Ruth , Kauer Max O. , Orel Lukas , Fuka Gerhard , Mann Georg , Panzer-Grümayer E. Renate 
Published: November 2008

Abstract
Purpose: We explored the mechanisms leading to the distinct overexpression of EPOR as well as the effects of EPO signaling on ETV6/RUNX1-positive acute lymphoblastic leukemias.
Experimental Design: ETV6/RUNX1-expressing model cell lines and leukemic cells were used for real-time PCR of EPOR expression. Proliferation, viability, and apoptosis were analyzed on cells exposed to EPO, prednisone, or inhibitors of EPOR pathways by [3H]thymidine incorporation, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and Annexin V/propidium iodide staining. Western blot analysis was done to detect activation of signaling proteins. Serum EPO levels and sequences of the EPOR (n = 53) as well as hemoglobin levels were taken from children with acute lymphoblastic leukemia enrolled in Austrian protocols.
Results: We show here that ectopic expression of ETV6/RUNX1 induced EPOR up-regulation. Anemia, however, did not appear to influence EPOR expression on leukemic cells, although children with ETV6/RUNX1-positive leukemias had a lower median hemoglobin than controls. Exposure to EPO increased proliferation and survival of ETV6/RUNX1-positive leukemias in vitro, whereas blocking its binding site did not alter cell survival. The latter was not caused by activating mutations in the EPOR but might be triggered by constitutive activation of phosphatidylinositol 3-kinase/Akt, the major signaling pathway of EPOR in these cells. Moreover, prednisone-induced apoptosis was attenuated in the presence of EPO in this genetic subgroup.
Conclusions: Our data suggest that ETV6/RUNX1 leads to EPOR up-regulation and that activation by EPO might be of relevance to the biology of this leukemia subtype. Further studies are, however, needed to assess the clinical implications of its apoptosis-modulating properties.
Circulating Biomarkers of Cell Death After Treatment with the BH-3 Mimetic ABT-737 in a Preclinical Model of Small-Cell Lung Cancer
Authors: Micha Dimitra , Cummings Jeff , Shoemaker Alex , Elmore Steven , Foster Kelly , Greaves Martin , Ward Tim , Rosenberg Saul , Dive Caroline , Simpson Kathryn 
Published: November 2008

Abstract
Purpose: This study evaluated epithelial cell death ELISAs that measure circulating cytokeratin 18 in mice bearing small-cell lung cancer xenografts treated with a proapoptotic dose of the BH-3 mimetic ABT-737.
Experimental Design: H146 tumor–bearing and non–H146 tumor-bearing severe combined immunodeficient (SCID)/bg mice were treated with ABT-737 or vehicle control. Plasma collected before and 2 to 360 hours after treatment was analyzed by M30 (caspase-cleaved cytokeratin 18) and M65 (intact and cleaved cytokeratin 18) ELISA. In parallel, tumors were interrogated for cleaved caspase-3 and cleaved cytokeratin 18 as biomarkers of apoptosis.
Results: ABT-737–treated tumors regressed by 48 hours (P &lt; 0.01) compared with controls, correlating with increased cleaved cytokeratin 18 (P &lt; 0.01; 6 and 24 hours) and increased intact cytokeratin 18 (P &lt; 0.01; 24 hours). Cleaved cytokeratin 18 levels decreased below baseline between 72 and 360 hours for ABT-737–treated and control mice whereas intact cytokeratin 18 decreased below the level of detection at 8 and 15 days in ABT-737–treated mice only. Apoptosis in tumors reflected changes in circulating cytokeratin 18 (cleaved caspase-3, P &lt; 0.05 at 2 hours and P &lt; 0.001 at 6, 12, and 24 hours; caspase-cleaved cytokeratin 18, P &lt; 0.05 at 15 days, for drug treated versus controls).
Conclusions: ABT-737 caused tumor regression by apoptosis in H146 xenografts that mapped to a drug-specific, early increase in circulating cleaved cytokeratin 18 that subsequently declined. Circulating, intact cytokeratin 18 levels correlated with tumor burden. Cleaved caspase-3 and caspase-cleaved cytokeratin 18 in tumor correlated with treatment (P &lt; 0.05, 2 hours; P &lt; 0.001, 6, 12, and 24 hours; cleaved caspase-3, P &lt; 0.05, 15 days; caspase-cleaved cytokeratin 18), indicating that events in plasma were tumor derived. These circulating biomarker data will be translated to clinical trials wherein serial tumor biopsies are rarely obtained.
High Risk for Ovarian Cancer in a Prospective Series Is Restricted to BRCA1/2 Mutation Carriers
Authors: Mæhle Lovise , Apold Jaran , Paulsen Torbjørn , Hagen Bjørn , Løvslett Kjell , Fiane Bent , Van Ghelue Marijke , Clark Neal , Møller Pål 
Published: November 2008

Abstract
Purpose: Inherited ovarian cancer carries a serious prognosis. Prophylactic oophorectomy has been advocated. The degree to which inherited ovarian cancer is restricted to BRCA mutation carriers is not fully known. We wanted to determine the prevalence of BRCA mutation carriers in women at high risk from ovarian cancer.
Experimental Design: Healthy women who were found to be at increased risk judged by family history were followed prospectively. Full BRCA1/2 mutation analysis was conducted on all patients who contracted pelvic cancer.
Results: We identified 1,582 women at risk during 5,674 person-years. Forty infiltrating epithelial ovarian cancers, six peritoneal cancers, and one fallopian tube cancer were diagnosed. All but one of these patients (98%) had a BRCA mutation, a frequency that was significantly higher than for the 3 patients with borderline ovarian cancers, who were all mutation negative (P = 0.0002). Eighty-two percent of the detected mutations belonged to one of the 10 Norwegian founder mutations previously reported. At prophylactic bilateral salpingo-oophorectomy, cancer was found in 18 of 345 (5.2%) of mutation carriers compared with none in the 446 mutation negative (P = 0.0000).
Conclusions: In healthy women with a family history of ovarian cancer, high risk for ovarian cancer was restricted to BRCA1/2 mutation carriers. A woman at risk for ovarian cancer according to her family history should have access to full BRCA1/2 mutation testing before deciding on prophylactic bilateral salpingo-oophorectomy.
Phase I Study of Copper-Binding Agent ATN-224 in Patients with Advanced Solid Tumors
Authors: Lowndes Sarah A. , Adams Avril , Timms Anthony , Fisher Nita , Smythe Jon , Watt Suzanne M. , Joel Simon , Donate Fernando , Hayward Carolyn , Reich Steven , Middleton Mark , Mazar Andrew , Harris Adrian L. 
Published: November 2008

Abstract
Purpose: Copper chelation reduces the secretion of many angiogenic factors and reduces tumor growth and microvascular density in animal models. ATN-224 is a second-generation analogue of ammonium tetrathiomolybdate. The aim of our phase I study was to reduce serum copper levels, as measured by ceruloplasmin, to 5 to 15 mg/dL (normal 16-60) in 14 to 21 days, to determine the pharmacokinetic profile of ATN-224 and to evaluate dose-limiting toxicities.
Patients and Methods: Cohorts of patients were treated with escalating oral doses of ATN-224 until copper depletion followed by a titrated maintenance dose.
Results: Eighteen patients received 78 cycles of ATN-224. Mean baseline ceruloplasmin was 39.6 mg/dL. The maximum administered dose was 330 mg/d where grade 3 fatigue was dose-limiting. At the maximum tolerated dose of 300 mg/d, the median time to achieve target ceruloplasmin was 21 days, and toxicities included grade 3 anemia, grade 3 neutropenia, fatigue, and sulfur eructation. ATN-224 treatment caused a significant reduction (&gt;90%) in RBC superoxide dismutase 1 activity and circulating endothelial cells. Pharmacokinetic data indicate greater absorption of ATN-224 and more rapid ceruloplasmin reduction when administered with a proton pump inhibitor. Stable disease of &gt;6 months was observed in 2 patients.
Conclusions: Oral ATN-224 is a well-tolerated therapy and at a loading dose of 300 mg/d leads to a reduction of serum ceruloplasmin levels in 80% patients within 21 days. A loading dose of 300 mg/d for 2 weeks followed by a titrated maintenance dose will be the recommended starting dose for phase II study.