bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3938: BNip3 limits HIF-1α stabilization and metastasis in a mouse model of breast cancer through effects on mitochondrial integrity and ROS generation
Authors: Tracy Kristin , Chen Hong , Chourasia Aparajita , Macleod Kay F. 
Published: August 2012

Abstract
BNIP3 is a hypoxia-inducible mitochondrial protein that has been implicated in mitochondrial fragmentation and mitophagy. BNIP3 protein is also up-regulated at pre-malignant stages of various different human cancers, including breast cancer and down-regulated later through a variety of mechanisms. To examine the role of BNip3 in tumor progression to metastasis, we crossed mice carrying a targeted deletion in the mouse BNip3 gene to the MMTV-PyMT mouse model of breast cancer. All analyses were performed with mice on a pure FVB/N genetic background. Loss of BNip3 promoted S phase entry that was associated with increased primary tumor growth. There was highly significant increase in the numbers of lung metastases and a reduced latency to metastasis in the MMTV-PyMT;BNip3-/- mice compared to control MMTV-PyMT;BNip3+/+ mice. BNip3 null tumors showed increased invasive properties and nuclear grade at earlier stages, a phenotype that was transplantable to wild-type host mice arguing that the increased invasiveness was intrinsic to BNip3 null tumor cells. BNip3 null tumor cells exhibited abnormal mitochondria, reduced mitochondrial membrane potential, increased ROS levels and increased hypoxia. Their invasive pathology was also associated with increased HIF-1α levels, increased HIF target gene expression and increased CD31-positive blood vessel formation. Quenching ROS limited Hif-1α stabilization, reduced angiogenesis and metastasis in MMTV-PyMT;BNip3-/- mouse tumors to wild-type levels. These results suggest that BNip3 is a metastasis suppressor by virtue of its role in maintaining mitochondrial integrity that mitigates against the metastasis promoting activity of reactive oxygen and hypoxia. Work on this project is supported by NIH/NCI RO1-CA131188 and by Department of Defense BRCP W81XWH-09-1-0587.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3938. doi:1538-7445.AM2012-3938
Abstract 3941: HAF promotes the switch from HIF-1α to HIF-2α signaling during chronic hypoxia and promotes stem cell characteristics
Authors: Koh Mei Yee , Lemos Robert , Powis Garth 
Published: August 2012

Abstract
Most solid tumors and their metastases experience periods of hypoxia, which promotes tumor progression and resistance to therapy. Hypoxia is also an important micro-environmental factor supporting the maintenance of pluripotent cancer stem/progenitor cells (CSCs) within the stem cell niche. The clinical relevance of CSCs is underscored by their resistance to cytotoxic therapies, invasive potential and role in tumor recurrence. Critical mediators of the hypoxia response are the hypoxia-inducible factors HIF-1α and HIF-2α. Although they have some overlapping functions, the HIFs are generally non-redundant whereby HIF-1α regulates the acute metabolic changes required for hypoxic survival, whereas HIF-2α promotes the adaptation to chronic hypoxia, including the maintenance of CSCs. However, the mechanism determining selectivity for HIF-1α versus HIF-2α activation is unclear. Here we describe a new mechanism for the switch between HIF-1α and HIF-2α dependent transcription during chronic hypoxia by the hypoxia associated factor (HAF). HAF is overexpressed in a number of tumor types and is an E3 ubiquitin ligase that ubiquitinates HIF-1α independently of oxygen and pVHL, thus targeting HIF-1α for proteasomal degradation. HAF also binds to HIF-2α but at a different site than it binds to HIF-1α, increasing HIF-2α transactivation without causing its degradation. Hence HAF switches cellular dependence from HIF-1α towards HIF-2α, resulting in the activation of HIF-2α specific target genes (MMP9, OCT3/4)and the simultaneous inhibition of HIF-1α specific target genes (CA-IX, DDIT4). HAF itself is hypoxia regulated - decreasing during acute hypoxia, but increasing with hypoxic duration. Hence HAF is a key determinant of HIF-2 versus HIF-1 activation in response to hypoxia. Using cell-free recombinant proteins and in vitro binding assays, we show that HAF binding to HIF-2α requires a novel eukaryotic post-translational modification of HIF-2α within a unique region of HIF-2 that is absent from HIF-1. HAF binding to HIF-2α is increased in cells exposed to prolonged hypoxia and promotes the transcription of HIF-2α target genes important in CSC maintenance such as OCT3/4 and SOX2. HAF levels are elevated in CD133+ U87 glioblastoma stem/progenitor cells and HAF knockdown decreases neurosphere formation suggesting a key role for HAF in the maintenance of the stem cell phenotype. The HAF-induced switch to HIF-2α dependent transcription promotes invasion and enriches the proportion of stem/progenitor CD133+ U87 cells. This increases the rate of tumor take and increases tumor morbidity in vivo. Funded by NIH CA095060, CA17094, CA098920
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3941. doi:1538-7445.AM2012-3941
Abstract 3949: In vivo imaging of tumor hypoxia by a new near-infrared fluorescent carbonic anhydrase IX-targeted agent
Authors: Bao Bagna , Groves Kevin , Zhang Jun , Handy Emma , Kennedy Paul , Cuneo Garry , Supuran Claudiu T. , Yared Wael , Rajopadhye Milind , Peterson Jeffrey D. 
Published: August 2012

Abstract
Carbonic anhydrase IX (CA IX), a cell surface enzyme involved in tumor cell acidification, is induced during tumor hypoxia (lack of oxygen) in many different types of tumors. CA IX expression is correlated to tumor cell proliferation and metastasis, poor prognosis, and resistance to therapeutic intervention, making CA IX an important biomarker in the study of hypoxia, tumor cell proliferation, and therapy. Therefore, determination of CAIX expression and identification of hypoxic tumors in vivo are critical for cancer research and treatments. We have designed and synthesized a near-infrared (NIR) fluorescent agent (VM3219) for in vivo detection and quantification of a cell surface biomarker of hypoxia, CA IX based on a well-known CA IX inhibitor, acetazolamide. VM3219 was characterized extensively in HeLa cells and in mouse HeLa tumor xenografts. Preliminary chemical and biochemical characterization of VM3219 showed excellent CA IX selectivity and affinity. In vitro, VM3219 detected 4-7-fold up-regulation of CA IX in live hypoxic HeLa cells as visualized by fluorescence microscopy and quantified by flow cytometry. VM3219 fluorescence signals were blocked by 80% when cells were pre-incubated with unlabeled acetazolamide. Fluorescent signal of VM3219 was low in normoxic HeLa cells and was comparable to the signal that were detected by using a non-binding control agent (VM3182) incubated with normoxic or hypoxic cells. In vivo imaging by fluorescence molecular tomography (FMTTM) showed that approximately 5% of the injected dose (2 nmol VM3219) was retained in the tumor tissues after 24 h (100 -120 pmol), 10-20-fold more than measured with a non-binding control agent. Tumor fluorescence was blocked &gt;65% by prophylactic acetazolamide treatment. Maintenance of tumor-bearing mice on low oxygen (8%), as compared to normally housed tumor bearing mice (20% oxygen), induced a &gt;2X (∼250 pmol) increase in VM3219 tumor fluorescence signal suggesting that CAIX expression was up-regulated within tumors by low oxygen. In tissue sections, VM3219 signal was shown to be specifically co-localized in the tumor hypoxic regions with CA IX antibody and Hypoxyprobe (pimonidazole), and the signal was away from non-hypoxic regions as determined by Hoechst stain. In conclusion, VM3219 is a new non-invasive tumor hypoxia imaging agent that offers a tool for specific imaging of a biologically important hypoxia biomarker, CA IX.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3949. doi:1538-7445.AM2012-3949
Abstract 3966: GenomeSpace: An environment for frictionless bioinformatics
Authors: Reich Michael , Liefeld John , Thorvaldsdottir Helga , Ocana Marco , Polk Eliot , Jang DK , Mesirov Jill 
Published: August 2012

Abstract
Over the past several years, cancer genome characterization initiatives such as The Cancer Genome Atlas and the Tumor Sequencing Project have produced an explosion of genomic data. The pace of data production has recently increased with the adoption of next-generation sequencing technologies and large-scale data production efforts to discover the breadth of genomic variation in humans. Comprehensive analysis of these datasets requires the coordinated use of Web-based applications and data repositories, desktop analysis tools and visualizers, and single-purpose algorithms. However, the effort required to transfer data between tools, convert between data formats, and manage results often prevents researchers from utilizing the wealth of methods available to them. Many integrative genomics and translational “bench to bedside” discoveries are possible with combinations of existing tools, but the necessary transitions between them puts them out of the reach of most researchers. GenomeSpace, http://www.genomespace.org, is an environment that brings together diverse computational tools, enabling scientists without programming skills to easily combine their capabilities. It aims to offer a common space to create, manipulate and share an ever-growing range of genomic analysis tools. GenomeSpace features support for cloud-based data storage and analysis, multi-tool analytic workflows, automatic conversion of data formats, and ease of connecting new tools to the environment. A set of six “GenomeSpace-enabled” seed tools developed by collaborating organizations provides a comprehensive platform for the analysis of cancer data: Cytoscape (UCSD), Galaxy (Penn State University), GenePattern (Broad Institute), Genomica (Weitzmann Institute), Integrative Genomics Viewer (Broad Institute), and the UCSC Genome Browser (UCSC). We show how researchers can use GenomeSpace to effortlessly combine the capabilities of all of these tools in several cancer research scenarios.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3966. doi:1538-7445.AM2012-3966
Abstract 4250: Deficiency of CD109, a negative regulator of TGF-β signaling, leads epidermal hyperplasia and appendage abnormalities in mice
Authors: Mii Shinji , Murakumo Yoshiki , Asai Naoya , Asai Masato , Takahashi Masahide 
Published: August 2012

Abstract
CD109, a glycosylphosphatidylinositol (GPI)-anchored glycoprotein, is a member of the β2-macroglobulin/C3, C4, C5 family of thioester-containing proteins. It has been reported that CD109 is highly expressed in various tumor cell lines and in tumor tissues including squamous cell carcinomas (SCCs) of the lung, oral cavity, esophagus and uterine cervix, malignant melanoma of the skin, and urothelial carcinoma of the urinary bladder. CD109 is, therefore, thought to be a cancer-related gene. On the other hand, CD109 is a component of TGF-β receptor system and negatively regulates TGF-β signaling. However, its physiological function in vivo remains largely unknown. To investigate the physiological function of CD109 in vivo, we generated CD109-deficient (CD109-/-) mice in which exon 1 and 2 of CD109 genomic locus were replaced with the lacZ gene. CD109 protein is expressed in the skin, tongue, and testis of adult CD109+/+ mice, but not in CD109-/- mice. Macroscopically, CD109-/- mice showed hair growth impairment from postnatal day 7 (P7) and persisted until P28. Microscopically, hyperplasia of the epidermis and sebaceous glands became apparent at P7 in CD109-/- mice and sustained until P70, and the hair follicles of CD109-/- mice exhibited ectasia with kinked hair shafts at P14. The epidermis of CD109-/- mice showed apparent thickening of the basal / suprabasal layers, which are positive for CK14, compared with CD109+/+ mice, whereas no significant differences in Ki-67 or cleaved caspase-3-positive ratios were detected between the two groups. These results suggest that CD109 regulates the differentiation of keratinocytes in vivo, and impairment of hair growth and ectatic hair follicles may be secondary changes caused by narrowing of the infundibular portion of the hair follicles due to epithelial hyperplasia.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4250. doi:1538-7445.AM2012-4250
Abstract 4276: PGE2 induces LEF-1 expression in breast cancer cells, but is not required for the nuclear localization of beta-catenin
Authors: Stasinopoulos Ioannis , Greenwood Tiffany , Glunde Kristine , Bhujwalla Zaver M. 
Published: August 2012

Abstract
We have previously demonstrated that poorly differentiated MDA-MB-231 cells displayed delayed tumor onset, reduced frequency of occurrence and loss of their capacity for extrapulmonary colonization when transfected stably with a potent and specific cyclooxygenase (COX) −2 shRNA sequence. We attributed the reduction in tumor growth and extrapulmonary colonization to reduced invasive capabilities, reduced angiogenesis, altered metabolism and differences in the stabilization of hypoxia-inducible factor-1α. We also observed loss of expression of oncogenes, receptors and degradative enzymes associated with tumor growth and metastasis including matrix metalloproteinase-1, CXC Receptor-4, roundabout-1, hyaluronan synthase-2, and monocarboxylate transporter 2. In addition to these previously reported transcriptome changes, we observed that the most highly downregulated transcription factor was Lymphoid-Enhancer Factor-1 (LEF-1) a result validated by qPCR showing an 8-fold loss of LEF-1 in COX-2-silenced cells. Here, we present evidence demonstrating that LEF-1 accumulation in the nucleus of COX-2-silenced cells is reduced compared to COX-2 containing parental cells. Induction of COX-2 by phorbol esters resulted in nuclear accumulation of LEF-1 in COX-2 containing, but not in COX-2-silenced, cells. Addition of physiological concentrations of PGE2 to COX-2-silenced cells partially restored LEF-1 expression in the nucleus of these cells. LEF-1 is a member of the T-cell specific factor (TCF) family of transcription factors that direct transcription of downstream target genes upon nuclear translocation of β-catenin from the cytoplasm. β-catenin translocation to the nucleus occurs in response to canonical signaling of the ligand Wnt to its receptor Frizzled. An earlier study showed that the COX-2 product prostaglandin E2 promoted the translocation of β-catenin to the nucleus of colon cancer cells via G-protein coupled receptor signaling. As expected, immunofluorescence of COX-2 containing MDA-MB-231 breast cancer cells showed nuclear expression of β-catenin. However, the nuclear localization of β-catenin persisted even in the absence of PGE2, as observed in COX-2-silenced cells, suggesting that PGE2 expression is not necessary for the nuclear localization of β-catenin in MDA-MB-231 cells. Taken together, our results demonstrate that while PGE2 is not necessary for the nuclear localization of β-catenin in MDA-MB-231 cells, it can promote the nuclear accumulation of the TCF family member LEF-1, thereby further promoting the non-canonical activation of the Wnt pathway in breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4276. doi:1538-7445.AM2012-4276
Abstract 4294: GE152: In vivo detection of tumor apoptosis as a tool for assessment of therapeutic efficacy
Authors: Hiscock Duncan R. R. , McRobbie Graeme , Lear Rochelle E. , Danikas Antonios , Cawthorne Chris , Simpson Kathryn , Zivanovic Maureen , Brown Gavin , Price Andrew , Williams Kaye J. , Dive Caroline 
Published: August 2012

Abstract
A major challenge in personalized healthcare is predicting how effective a drug treatment is. This is particularly the case in oncology, where there is a call for better therapy monitoring to maximize drug treatment effectiveness leading to improved patient survival and help reduce healthcare costs. GE152, a nuclear imaging agent under development at GE Healthcare, is being evaluated preclinically as a tool to assess therapeutic efficacy by detecting tumor apoptosis. GE152 is based on a 99mTechnetium radiolabelled peptide that shows nanomolar affinity for a specific cell death target, as demonstrated by studies using Biacore technology. Biodistribution using the murine lymphoma (EL4) tumour therapy model has shown increased tumor uptake and retention of GE152 following chemotherapy, with positive tumor:muscle and tumor:blood ratios. Correlation of tumor apoptosis levels (determined by caspase activity) with GE152 tumor retention suggest a trend of increasing agent retention with rising levels of apoptosis (GE152 retention in low apoptotic tumors is 4.9%ID/g; GE152 retention in high apoptotic tumors is 8.2%ID/g).Further validation of GE152 was carried out using an apoptosis-specific inducible cell death model whereby HT29 colorectal cancer cell xenografts engineered to inducibly express either a constitutively active form of caspase-3 (which causes synchronous cell death in vivo when exposed to doxycycline) or an inactive point mutant. GE152 demonstrated greater uptake in tumors undergoing apoptosis (3.6% ID/g) than in controls (1.2% ID/g), correlating with caspase activity levels (and subsequent apoptosis) as determined both enzymatically and by IHC and blood-borne biomarkers of cell death. These results are in agreement with preliminary preclinical imaging studies using SPECT/CT, where region of interest analysis has demonstrated increased post-therapy tumor retention of GE152. We are currently optimizing the performance of GE152 by assessing different radiolabelling precursors to improve imaging agent pharmacokinetics. In addition to the current 99mTechnetium-based approach, we are exploring 18F radiolabelling options that would allow expansion of the agent's utility to PET imaging.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4294. doi:1538-7445.AM2012-4294
Abstract 4316: Villin expression is frequently lost in colon cancers with microsatellite instability.
Authors: Arango Diego , Al-Obaidi Sheren , Williams David S. , Dopeso Jose , Mazzolini Rocco , Corner Georgia A. , Byun Do-Sun , Murone Carmel , Togel Lars , Zeps Nikolajs , Aaltonen Lauri A. , Iacopetta Barry , Mariadason John Martin 
Published: August 2012

Abstract
Colorectal cancers are classified as having chromosomal instability (CIN) or microsatellite instability (MSI). MSI colon cancers frequently display poorly differentiated histology the molecular basis of which is not well understood. Gene expression profiling of CIN and MSI colon cancer cell lines and tumours revealed significant downregulation of the intestinal-specific cytoskeletal protein villin, in MSI tumours, with complete absence observed in 62% and 17% of MSI cell lines and primary tumours, respectively. Investigation of 577 colon cancers demonstrated loss of villin expression was linked to poorly differentiated histology in MSI and MSS (microsatellite stable) tumours. Furthermore, mislocalization of villin away from the membrane was prognostic for poorer outcome in MSS patients. Loss of villin expression was not due to coding sequence mutations, epigenetic inactivation, or promoter mutation. Conversely, villin promoter activity reflected endogenous villin expression, suggesting villin loss is transcriptionally mediated. A screen of gut-specific transcription factors revealed a significant correlation between expression of villin and the homeobox transcription factor, Cdx-1. Cdx-1 overexpression induced villin promoter activity, Cdx-1 knockdown downregulated endogenous villin expression, and deletion of a key Cdx binding site within the villin promoter attenuated promoter activity. Loss of Cdx-1 expression was associated with Cdx-1 promoter methylation. These findings demonstrate that loss of villin expression as a result of Cdx-1-dependent transcriptional deregulation is a feature of poorly differentiated colon cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4316. doi:1538-7445.AM2012-4316