bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of the Sodium-Potassium-Chloride Cotransporter Isoform-1 Reduces Glioma Invasion
Authors: Haas Brian R. , Sontheimer Harald 
Published: June 2010

AbstractMalignant gliomas metastasize throughout the brain by infiltrative cell migration into peritumoral areas. Invading cells undergo profound changes in cell shape and volume as they navigate extracellular spaces along blood vessels and white matter tracts. Volume changes are aided by the concerted release of osmotically active ions, most notably K+ and Cl−. Their efflux through ion channels along with obligated water causes rapid cell shrinkage. Suitable ionic gradients must be established and maintained through the activity of ion transport systems. Here, we show that the Sodium-Potassium-Chloride Cotransporter Isoform-1 (NKCC1) provides the major pathway for Cl− accumulation in glioma cells. NKCC1 localizes to the leading edge of invading processes, and pharmacologic inhibition using the loop diuretic bumetanide inhibits in vitro Transwell migration by 25% to 50%. Short hairpin RNA knockdowns of NKCC1 yielded a similar inhibition and a loss of bumetanide-sensitive cell volume regulation. A loss of NKCC1 function did not affect cell motility in two-dimensional assays lacking spatial constraints but manifested only when cells had to undergo volume changes during migration. Intracranial implantation of human gliomas into severe combined immunodeficient mice showed a marked reduction in cell invasion when NKCC1 function was disrupted genetically or by twice daily injection of the Food and Drug Administration–approved NKCC1 inhibitor Bumex. These data support the consideration of Bumex as adjuvant therapy for patients with high-grade gliomas. Cancer Res; 70(13); 5597–606. ©2010 AACR.
Premetastatic Lung “Niche”: Is Vascular Endothelial Growth Factor Receptor 1 Activation Required?
Authors: Duda Dan G. , Jain Rakesh K. 
Published: June 2010

Abstract
Inflammatory pathways may mediate preparation of the “metastatic soil” in the lungs. Some of these pathways—activation and/or the recruitment of certain inflammatory cells—might depend on vascular endothelial growth factor receptor 1 (VEGFR1) activity. Thus, blocking the activity of VEGFR1 (or the interaction with its ligands) has emerged as a potential antimetastasis strategy to target not only angiogenesis and cancer cell survival and migration, but also the recruitment of tumor growth–promoting bone marrow–derived cells (BMDC). However, inhibition of VEGFR1 activity by blocking antibodies or by genetic deletion of the tyrosine kinase domain neither prevented nor changed the rate of spontaneous metastasis formation after surgical removal of primary tumors. Thus, development of VEGFR1-targeted agents should be pursued in selected tumors (e.g., by identifying cancers that depend on VEGFR1 signaling for survival) or in specific combination therapies. Preventing metastasis will likely require identification and blockade of additional or alternative proinflammatory pathways that mediate the priming of the metastatic soil and the growth of micrometastases. Cancer Res; 70(14); 5670–3. ©2010 AACR.
Synthetic Lethality through Combined Notch–Epidermal Growth Factor Receptor Pathway Inhibition in Basal-Like Breast Cancer
Authors: Dong Yiyu , Li Aimin , Wang Jianbo , Weber Jason D. , Michel Loren S. 
Published: June 2010

Abstract
Basal-like breast cancers (BLBC) are highly aggressive, yet selective therapies targeting the specific oncoproteins driving these tumors have not been developed. These cancers frequently express epidermal growth factor receptor (EGFR), with resistance to its inhibition being well documented, albeit poorly understood. Notch pathway activation is also common in this breast cancer subtype and can be suppressed by γ-secretase inhibitors, which effectively block receptor cleavage and activation. Herein, we show that although inhibition of either EGFR or Notch signaling alone is insufficient to suppress basal-like breast tumor cell survival and proliferation, simultaneous inhibition uncovers a synthetic lethal relationship between these two oncogenic pathways. This lethality is due in part to significant decreases in AKT activation caused by combined EGFR and Notch inhibition. Expression of the activated form of Notch1 restores AKT activity and enables cells to overcome cell death after dual-pathway blockade. Combined pathway inhibition is also dramatically more effective at suppressing tumor growth in mice than blocking EGFR or Notch signaling alone. Thus, we show that Notch pathway activation contributes to resistance to EGFR inhibition, and provide a novel treatment strategy for BLBCs. Cancer Res; 70(13); 5465–74. ©2010 AACR.
Low Ascorbate Levels Are Associated with Increased Hypoxia-Inducible Factor-1 Activity and an Aggressive Tumor Phenotype in Endometrial Cancer
Authors: Kuiper Caroline , Molenaar Ilona G.M. , Dachs Gabi U. , Currie Margaret J. , Sykes Peter H. , Vissers Margreet C.M. 
Published: June 2010

AbstractActivation of the transcription factor hypoxia-inducible factor (HIF)-1 allows solid tumors to thrive under conditions of metabolic stress. Because HIF-1 is switched off by hydroxylation reactions that require ascorbate, inadequate intracellular ascorbate levels could contribute to HIF-1 overactivation. In this study, we investigated whether the ascorbate content of human endometrial tumors [known to be driven by HIF-1 and vascular endothelial growth factor (VEGF)] influenced HIF-1 activity and tumor pathology. We measured protein levels of HIF-1α and three downstream gene products [glucose transporter 1 (GLUT-1), Bcl-2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3), and VEGF], as well as the ascorbate content of tumor and patient-matched normal endometrial tissue samples. HIF-1α and its downstream gene products were upregulated in tumor tissue, with the highest levels being present in high-grade tumors. High-grade tumors also had reduced capacity to accumulate ascorbate compared with normal tissue; however, all grades contained tumors with low ascorbate content. Tumors with the highest HIF-1α protein content were ascorbate deficient. Low ascorbate levels were also associated with elevated VEGF, GLUT-1, and BNIP3 protein levels and with increased tumor size, and there was a significant association between low tissue ascorbate levels and increased activation of the HIF-1 pathway (P = 0.007). In contrast, tumors with high ascorbate levels had lesser levels of HIF-1 activation. This study shows for the first time a likely in vivo relationship between ascorbate and HIF-1, with low tumor tissue ascorbate levels being associated with high HIF-1 activation and tumor growth. Cancer Res; 70(14); 5749–58. ©2010 AACR.
Increased Expression of α6 Integrin in Endothelial Cells Unveils a Proangiogenic Role for Basement Membrane
Authors: Primo Luca , Seano Giorgio , Roca Cristina , Maione Federica , Gagliardi Paolo Armando , Sessa Roberto , Martinelli Marianna , Giraudo Enrico , di Blasio Laura , Bussolino Federico 
Published: June 2010

Abstract
The integrin α6 subunit is part of the α6β1 and α6β4 integrin complexes, which are known to be receptors for laminins and to mediate several biological activities such as embryogenesis, organogenesis, and invasion of carcinoma cells. However, the precise role of α6 integrin in angiogenesis has not yet been addressed. We observed that both vascular endothelial growth factor-A and fibroblast growth factor-2 strongly upregulate α6 integrin in human endothelial cells. Moreover, α6 integrin was positively modulated in angiogenic vessels in pancreatic neuroendocrine carcinoma. In this transgenic mouse model of spontaneous tumorigenesis, α6 integrin expression increased in the angiogenic stage, while being expressed at low levels in normal and hyperplastic tissue. We studied the functional role of α6 integrin during angiogenesis by lentivirus-mediated gene silencing and blocking antibody. Cell migration and morphogenesis on basement membrane extracts, a laminin-rich matrix, was reduced in endothelial cells expressing low levels of α6 integrin. However, we did not observe any differences in collagen matrices. Similar results were obtained in the aortic ring angiogenesis assay. α6 integrin was required for vessel sprouting on basement membrane gels but not on collagen gels, as shown by stably silencing this integrin in the murine aorta. Finally, a neutralizing anti-α6 integrin antibody inhibited in vivo angiogenesis in chicken chorioallantoic membrane and transgenic tumor mouse model. In summary, we showed that the α6 integrin participated in vascular endothelial growth factor-A and fibroblast growth factor-2–driven angiogenesis in vitro and in vivo, suggesting that it might be an attractive target for therapeutic approaches in angiogenesis-dependent diseases such as tumor growth. Cancer Res; 70(14); 5759–69. ©2010 AACR.
Potential for Targeting the Fibroblast Growth Factor Receptors in Breast Cancer
Authors: Hynes Nancy E. , Dey Julien H. 
Published: June 2010

Abstract
Breast cancer is the most common cancer of women, accounting yearly for approximately 30% of newly diagnosed cases and ranking second as a cause of death. Despite improvements in breast cancer detection and development of new therapeutic approaches, there are still tumors for which no targeted therapies are available. This review summarizes recent findings on the fibroblast growth factor receptors (FGFR) and the data supporting their role in breast cancer. We will describe the approaches being made to develop therapeutics targeting these receptors. Finally, to improve the chances for success with FGFR signal transduction inhibitors, strategies to choose appropriate breast cancer patients for treatment will be discussed. Cancer Res; 70(13); 5199–202. ©2010 AACR.
Epigenetic Inactivation of the Potential Tumor Suppressor Gene FOXF1 in Breast Cancer
Authors: Lo Pang-Kuo , Lee Ji Shin , Liang Xiaohui , Han Liangfeng , Mori Tsuyoshi , Fackler Mary Jo , Sadik Helen , Argani Pedram , Pandita Tej K. , Sukumar Saraswati 
Published: June 2010

Abstract
The expression of several members of the FOX gene family is known to be altered in a variety of cancers. We show that in breast cancer, FOXF1 gene is a target of epigenetic inactivation and that its gene product exhibits tumor-suppressive properties. Loss or downregulation of FOXF1 expression is associated with FOXF1 promoter hypermethylation in breast cancer cell lines and in invasive ductal carcinomas. Methylation of FOXF1 in invasive ductal carcinoma (37.6% of 117 cases) correlated with high tumor grade. Pharmacologic unmasking of epigenetic silencing in breast cancer cells restored FOXF1 expression. Re-expression of FOXF1 in breast cancer cells with epigenetically silenced FOXF1 genes led to G1 arrest concurrent with or without apoptosis to suppress both in vitro cell growth and in vivo tumor formation. FOXF1-induced G1 arrest resulted from a blockage at G1-S transition of the cell cycle through inhibition of the CDK2-RB-E2F cascade. Small interfering RNA–mediated depletion of FOXF1 in breast cancer cells led to increased DNA re-replication, suggesting that FOXF1 is required for maintaining the stringency of DNA replication and genomic stability. Furthermore, expression profiling of cell cycle regulatory genes showed that abrogation of FOXF1 function resulted in increased expression of E2F-induced genes involved in promoting the progression of S and G2 phases. Therefore, our studies have identified FOXF1 as a potential tumor suppressor gene that is epigenetically silenced in breast cancer, which plays an essential role in regulating cell cycle progression to maintain genomic stability. Cancer Res; 70(14); 6047–58. ©2010 AACR.
Induction of Anti-Glioma Natural Killer Cell Response following Multiple Low-Dose Intracerebral CpG Therapy
Authors: Alizadeh Darya , Zhang Leying , Brown Christine E. , Farrukh Omar , Jensen Michael C. , Badie Behnam 
Published: June 2010

AbstractPurpose: Stimulation of toll-like receptor-9 by CpG oligodeoxynucleotides (CpG-ODN) has been shown to counteract the immunosuppressive microenvironment and to inhibit tumor growth in glioma models. These studies, however, have used high doses of CpG-ODN, which can induce toxicity in a clinical setting. The goal of this study was to evaluate the antitumor efficacy of multiple low-dose intratumoral CpG-ODN in a glioma model.Experimental Design: Mice bearing 4-day-old intracranial GL261 gliomas received a single or multiple (two or four) intratumoral injections of CpG-ODN (3 μg) every 4 days. Tumor growth was measured by bioluminescent imaging, brain histology, and animal survival. Flow cytometry and cytotoxicity assays were used to assess anti-glioma immune response.Results: Two and four intracranial injections of low-dose CpG-ODN, but not a single injection, eradicated gliomas in 70% of mice. Moreover, surviving animals exhibited durable tumor-free remission (&gt; 3 months) and were protected from intracranial rechallenge with GL261 gliomas, showing the capacity for long-term antitumor immunity. Although most inflammatory cells seemed to increase, activated natural killer (NK) cells (i.e., NK+CD107a+) were more frequent than CD8+CD107a+ in the brains of rechallenged CpG-ODN–treated animals and showed a stronger in vitro cytotoxicity against GL261 target cells. Leukocyte depletion studies confirmed that NK cells played an important role in the initial CpG-ODN antitumor response, but both CD8 and NK cells were equally important in long-term immunity against gliomas.Conclusions: These findings suggest that multiple low-dose intratumoral injections of CpG-ODN can eradicate intracranial gliomas possibly through mechanisms involving NK-mediated effector function. Clin Cancer Res; 16(13); 3399–408. ©2010 AACR.
Diverse Associations betweenESR1Polymorphism and Breast Cancer Development and Progression
Authors: Ding Shian-ling , Yu Jyh-Cherng , Chen Shou-Tung , Hsu Giu-Cheng , Hsu Huan-Ming , Ho Jar Yi , Lin Yu Hsin , Chang Chien-Ching , Fann Cathy S.J. , Cheng Chun-Wen , Wu Pei-Ei , Shen Chen-Yang 
Published: June 2010

AbstractPurpose: To test the hypothesis that polymorphisms of ESR1, the gene encoding estrogen receptor α (ERα), are associated with susceptibility, clinical phenotype, and progression of breast cancer.Patients and Methods: A case-control study was done on 940 patients with incident breast cancer and 1,547 healthy female controls. Fifteen single-nucleotide polymorphisms (SNP) selected from chr6:152,170,379-152,466,100 (exons 1–8 of the ESR1 gene, excluding flanking sequences), reflecting major polymorphisms of this gene, were genotyped. Frequencies of SNPs were compared between cases and controls to identify SNPs associated with cancer susceptibility and between cases with different clinical phenotypes to determine the role of ESR1 polymorphism in cancer progression.Results: SNPs located in one cluster in intron 1 and one haplotype, based on these SNPs, showed a significant association with breast cancer susceptibility. The tumorigenic contribution of these intron 1 SNPs was more obvious in combination with reproductive risk factors (P for interaction &lt;0.05). One of these intron 1 SNPs was also significantly associated with low ERα expression in tumors. Interestingly, the same intron 1 SNPs showed a correlation with worse clinical phenotypes, including poor differentiation of tumor cells and a late stage. These intron 1 SNPs also showed a significant association with the 5-year breast cancer–specific survival rate of patients, but had opposite effects in ERα-negative and ERα-positive early-stage patients.Conclusions: Our findings provide support for diverse roles of ESR1 polymorphism in determining susceptibility in different stages of breast cancer. The differences between the important ESR1 SNPs identified in Chinese women in this study and those identified in studies on Western women with breast cancer suggest different roles of ERα in these two populations. Clin Cancer Res; 16(13); 3473–84. ©2010 AACR.
Development of a Multiplexed Tumor-Associated Autoantibody-Based Blood Test for the Detection of Non–Small Cell Lung Cancer
Authors: Farlow Erin C. , Patel Kalpa , Basu Sanjib , Lee Bao-Shiang , Kim Anthony W. , Coon John S. , Faber L. Penfield , Bonomi Philip , Liptay Michael J. , Borgia Jeffrey A. 
Published: June 2010

Abstract
Purpose: Non–small cell lung cancer (NSCLC) has an overall 5-year survival of &lt;15%; however, the 5-year survival for stage I disease is over 50%. Unfortunately, 75% of NSCLC is diagnosed at an advanced stage not amenable to surgery. A convenient serum assay capable of unambiguously identifying patients with NSCLC may provide an ideal diagnostic measure to complement computed tomography–based screening protocols.
Experimental Design: Standard immunoproteomic method was used to assess differences in circulating autoantibodies among lung adenocarcinoma patients relative to cancer-free controls. Candidate autoantibodies identified by these discovery phase studies were translated into Luminex-based “direct-capture” immunobead assays along with 10 autoantigens with previously reported diagnostic value. These assays were then used to evaluate a second patient cohort composed of four discrete populations, including: 117 NSCLC (81 T1-2N0M0 and 36 T1-2N1-2M0), 30 chronic obstructive pulmonary disorder (COPD)/asthma, 13 nonmalignant lung nodule, and 31 “normal” controls. Multivariate statistical methods were then used to identify the optimal combination of biomarkers for classifying patient disease status and develop a convenient algorithm for this purpose.
Results: Our immunoproteomic-based biomarker discovery efforts yielded 16 autoantibodies differentially expressed in NSCLC versus control serum. Thirteen of the 25 analytes tested showed statistical significance (Mann-Whitney P &lt; 0.05 and a receiver operator characteristic “area under the curve” over 0.65) when evaluated against a second patient cohort. Multivariate statistical analyses identified a six-biomarker panel with only a 7% misclassification rate.
Conclusions: We developed a six-autoantibody algorithm for detecting cases of NSCLC among several high-risk populations. Population-based validation studies are now required to assign the true value of this tool for identifying early-stage NSCLC. Clin Cancer Res; 16(13); 3452–62. ©2010 AACR.
A Distinct Spectrum of Copy Number Aberrations in Pediatric High-Grade Gliomas
Authors: Bax Dorine A. , Mackay Alan , Little Suzanne E. , Carvalho Diana , Viana-Pereira Marta , Tamber Narinder , Grigoriadis Anita E. , Ashworth Alan , Reis Rui M. , Ellison David W. , Al-Sarraj Safa , Hargrave Darren , Jones Chris 
Published: June 2010

Abstract
Purpose: As genome-scale technologies begin to unravel the complexity of the equivalent tumors in adults, we can attempt detailed characterization of high-grade gliomas in children, that have until recently been lacking. Toward this end, we sought to validate and extend investigations of the differences between pediatric and adult tumors.
Experimental Design: We carried out copy number profiling by array comparative genomic hybridization using a 32K bacterial artificial chromosome platform on 63 formalin-fixed paraffin-embedded cases of high-grade glioma arising in children and young people (&lt;23 years).
Results: The genomic profiles of these tumors could be subclassified into four categories: those with stable genomes, which were associated with a better prognosis; those with aneuploid and those with highly rearranged genomes; and those with an amplifier genotype, which had a significantly worse clinical outcome. Independent of this was a clear segregation of cases with 1q gain (more common in children) from those with concurrent 7 gain/10q loss (a defining feature of adults). Detailed mapping of all the amplification and deletion events revealed numerous low-frequency amplifications, including IGF1R, PDGFRB, PIK3CA, CDK6, CCND1, and CCNE1, and novel homozygous deletions encompassing unknown genes, including those at 5q35, 10q25, and 22q13. Despite this, aberrations targeting the “core signaling pathways” in adult glioblastomas are significantly underrepresented in the pediatric setting.
Conclusions: These data highlight that although there are overlaps in the genomic events driving gliomagenesis of all ages, the pediatric disease harbors a distinct spectrum of copy number aberrations compared with adults. Clin Cancer Res; 16(13); 3368–77. ©2010 AACR.
Phage Display–Derived Peptides for Osteosarcoma Imaging
Authors: Sun Xilin , Niu Gang , Yan Yongjun , Yang Min , Chen Kai , Ma Ying , Chan Nicholas , Shen Baozhong , Chen Xiaoyuan 
Published: June 2010

Abstract
Purpose: Osteosarcoma represents the most common malignant primary bone tumor in childhood; however, the survival rate has remained unchanged for the past 20 years. To improve existing diagnosis and treatment methods and broaden the spectrum of imaging agents that can be used for early detection and assessment of tumor response to therapy, we performed a phage display–based screening for peptide sequences that bind specifically to osteosarcoma cells.
Experimental Design: From the Ph.D.-12 phage display peptide library composed of 2.7 × 109 different displayed peptides, one peptide was enriched after four rounds of in vitro selection in 143B osteosarcoma tumor cells with 293T human embryonic kidney cells as a control. Both the peptide and the phage clone displaying the peptide were conjugated with fluorescent dyes for in vitro cell and ex vivo tumor tissue stainings. The peptide was further labeled with 18F for positron emission tomography imaging studies. Cell uptake and efflux and ex vivo biodistribution were also done with 18F-labeled osteosarcoma specific peptide.
Results: ASGALSPSRLDT was the dominant sequence isolated from biopanning and named as OSP-1. OSP-1 shares a significant homology with heparinase II/III family protein, which binds and reacts with heparan sulfate proteoglycans. The fluorescence staining showed that FITC-OSP-1-phage or Cy5.5-OSP-1 had high binding with a panel of osteosarcoma cell lines, much less binding with UM-SCC1 human head and neck squamous cell carcinoma cells, and almost no binding with 293T cells, whereas the scrambled peptide OSP-S had virtually no binding to all the cell lines. 18F-OSP-1 had significantly higher accumulation in 143B tumor cells both in vitro and in vivo than 18F-OSP-S. 18F-OSP-1 also had higher uptake in 143B tumors than in UM-SCC-1 tumors.
Conclusions: Our data suggest that OSP-1 peptide is osteosarcoma specific, and the binding site of OSP-1 might be related to heparan sulfate proteoglycans. Appropriately labeled OSP-1 peptide has the potential to serve as a novel probe for osteosarcoma imaging. Clin Cancer Res; 16(16); 4268–77. ©2010 AACR.