bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 892: Survey of human cancer tissues for the presence of bovine leukemia virus
Authors: Buehring Gertrude Case , Jensen Hanne M. , Tesluk Henry 
Published: June 2012

Abstract
Bovine leukemia virus (BLV) is an oncogenic retrovirus that causes B cell leukemia/lymphoma in 5% of infected cattle. Infection is widespread in the USA: 24% of beef herds, 84% of dairy herds, and 100% of large dairy operations. BLV has been detected in T cells, B cells, endothelium, and mammary epithelium, and infected cells may be present in the blood and milk of cattle. Previously we found IgG antibodies to BLV in 39% of humans sampled, and BLV-related DNA in 60% (67/112) of malignant human breast tissues. Presence of BLV-related DNA in human mammary epithelium was significantly associated with breast cancer risk (odds ratio = 3.4, confidence interval = 1.77-6.44; P≪ .0002).
The purpose of this study was to test other types of human cancers for BLV-related DNA as a first step in exploring whether BLV might be involved in malignancies of tissues other than breast. Specimens were surgical pathology archival material collected from 1992-2003. We performed PCR-in-situ hybridization (PCR-ISH) on formalin-fixed tissue sections, targeting the highly conserved tax region, which codes for the oncogenic protein of BLV. This method is not subject to molecular contamination, and can localize the signal to a particular cell type in the intact tissue. Our survey included the following malignancies: stomach, colon, pancreas, prostate, seminoma, ovary, endometrium, sarcoma (1 liposarcoma, 3 fibrosarcoma, 4 fibrohistiocytoma, 1 Ewing sarcoma), lymphoma (10 B cell, 2 T cell, 3 Hodgkin), squamous cell skin carcinoma, lung, thyroid, and brain (3 astrocytoma, 4 meningioma, 3 glioblastoma).
BLV-related amplicons were detected in the following cancer types: stomach (5/10), colon (1/11), brain (2/10 [1 astrocytoma and 1 glioblastoma]), lymphoma (1/15 [T cell lymphoma]), sarcoma (1/9 [poorly differentiated high grade sarcoma]), and squamous cell skin carcinoma (2/10). No tissue type we tested showed a frequency of BLV-related DNA as great as we previously detected in breast cancer (60%). Sample sizes in this pilot survey were too small to provide an accurate estimate of overall frequency in the population or to make any conclusions about the association of BLV-related DNA with the malignancies studied. However, the data do provide some interesting leads for further research with an increased number of specimens and normal control tissue, especially for the cancer types exhibiting at least one positive specimen.
This research was supported by a seed grant to HM Jensen from the Department of Pathology and Laboratory Medicine, School of Medicine, University of California, Davis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 892. doi:10.1158/1538-7445.AM2011-892
Abstract 897: Thymidine kinase 1, a novel biomarker specific to the plasma membrane of cancerous cell lines
Authors: Sharp Daniel W. , Estevez Dagoberto , Whitehurst Robert A. , Alegre Melissa M. , Germann Brit L. , Foster Joshua W. , Robison Richard A. , O'Neill Kim L. 
Published: June 2012

Abstract
Thymidine Kinase 1 (TK1), an important nucleotide salvage pathway enzyme, has been shown to be upregulated in most malignant cancers. Recent studies have shown that TK1 not only has diagnostic and prognostic potential, but could also be used as a molecular target for therapeutic treatments. Previous research from our lab has shown the expression of TK1 on the plasma membrane of lymphoma. This study provides further insight on the role of TK1 as a diagnostic target for several different tumor cell lines. This study analyzed the localization of TK1 in ten different cancer cell lines using flow cytometry (FCM). The lines studied were A375, a malignant melanoma, CAL27, a squamous cell carcinoma derived from tongue, MDA-MB-231, a breast adenocarcinoma, MDA-MB-435S, previously described as a ductal carcinoma, HT29, a colorectal adenocarcinoma, SW620, a colorectal adenocarcinoma, A549, a lung carcinoma, NCI-H460, a large cell lung carcinoma, DU 145, a prostrate carcinoma, and PC3, a prostate adenocarcinoma. FCM was carried out using a polyclonal antibody against human TK1 as the primary antibody and a FITC conjugated secondary antibody. A sample stained with only secondary antibody was used as a negative control for the experiment. Five replicates were analyzed for each cell line. TK1 was found to bind between 48% and 96%, depending on the cell line. Non-cancerous tonsil tissue and normal lymphocytes were used as controls, where TK1 surface binding was less than 20%. These data indicate the feasibility of TK1 as a possible molecular target for immunotherapy in many types of cancer. Further research is ongoing to determine specific immunotherapy treatment options, and to verify the expression of TK1 in other cancer cell lines.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 897. doi:10.1158/1538-7445.AM2011-897
Abstract 922: Disruption of bone morphogenetic protein receptor 2 accelerates mammary carcinoma metastasis to the lung
Authors: Owens Philip , Pickup Michael W. , Novitskiy Sergey V. , Chytil Anna , Gorska Agnieszka E. , Aakre Mary , Moses Harold L. 
Published: June 2012

Abstract
Bone Morphogenetic Proteins (BMPs) are members of the Transforming Growth Factor β (TGFβ) superfamily of signaling molecules. BMPs can elicit a wide range of effects in many cell types and have previously been shown to induce growth inhibition in cancers as well as normal epithelia. Recently, it has been demonstrated that BMP4 and BMP7 are overexpressed in human breast cancers and may have both tumor suppressive and promoting effects. We sought to determine whether disruption of the Bone Morphogenetic Protein Receptor 2 (BMPR2) would alter mammary tumor progression in mice that express the Polyoma middle T antigen (PyVmT). Mice expressing PyVmT under the mammary specific MMTV promoter were combined with mice that have Doxycycline inducible expression of a dominant negative (DN) BMPR2. We did not observe any differences in tumor latency. However, when we measured pulmonary metastases, we found that mice expressing the BMPR2-DN had a five fold increase in lung metastases. We characterized several cell autonomous changes and found that BMPR2-DN expressing tumor cells had higher rates of proliferation and epithelial to mesenchymal transition (EMT). We also identified unique changes in the tumor microenvironment, which included inflammatory cells and secreted chemokines/ cytokines that accompanied BMPR2-DN expressing tumors. We identified several molecules including ccl-9 (MIP1γ), which was elevated in BMPR2-DN expressing tumors. Ccl-9 has recently been shown to be an important chemokine in the recruitment of myeloid cells that promote metastatic progression. We discovered that tumor cells treated exogenously with BMP4 ligand repressed ccl-9 mRNA and that this repression was limited in cells expressing BMPR2-DN. We conclude that BMPR2 has tumor suppressive function in mammary epithelia and that disruption can accelerate mammary carcinoma metastases via paracrine stimulation of myeloid cells in the tumor microenvironment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 922. doi:10.1158/1538-7445.AM2011-922
Abstract 96: The functional role of DNA hypomethylation in liver cancer
Authors: Stefanska Barbara , Bhattacharyya Bishnu , Suderman Matthew , Huang Jian , Hallett Michael , Han Ze-Guang , Szyf Moshe 
Published: June 2012

Abstract
DNA hypomethylation, a process of losing methyl marks, may play an important role in cancer, especially through activating genes that promote cancer metastasis, the deadly aspect of cancer. We previously delineated using whole genome promoter methylation microarrays the landscape of hypomethylation in hepatocellular carcinoma which is one of the most common cancers worldwide. Our studies revealed that 50% of differentially methylated promoters in tumors are hypomethylated compared to adjacent normal tissue. In the present studies, using liver cancer cell lines as a model system, we evaluated the importance of the identified hypomethylated genes in liver cancer development and progression. We tested whether the hypomethylation observed in liver cancer is driven by MBD2, a protein reported previously to be implicated in DNA demethylation, which we found to be overexpressed in liver cancer patients.
Following siRNA MBD2 depletion in HepG2 hepatocellular carcinoma cell line, we used methylated DNA immunoprecipitation, chromatin immunoprecipitation (ChIP) and 60K custom microarrays covering 12K bp upstream and 10K bp downstream of transcription start site to determine methylation and MBD2 binding in 300 top genes hypomethylated and/or induced in liver cancer patients and/or HepG2 cells. The array data were validated by quantitative ChIP and/or pyrosequencing. For functional analyses, we used siRNA transfection, soft agar and invasion assays.
We discovered MBD2 binding peaks in 172 genes out of 300, mainly within their promoter regions. Using bioinformatic tools, we identified MBD2 binding motif and established putative transcription factors recognizing this sequence which may play a key role in recruiting MBD2 to target genes. 41% of those genes were hypermethylated in HepG2 cells after MBD2 depletion in a fragment corresponding to MBD2 binding site. In addition, expression analysis for some of the genes showed attenuation. In HepG2 cells, we depleted expression of several of the genes hypomethylated in cancer and regulated by MBD2 using siRNA and demonstrated a decrease in cell growth and invasive capacities.
Our results establish a role for MBD2 in coordinating inhibition of a panel of genes involved in cancer growth and metastasis.
This study was supported by a grant from the MDEIE program of the government of Quebec and the National Cancer Institute of Canada to MS.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 96. doi:10.1158/1538-7445.AM2011-96
Abstract 968: Invadopodia formation and microparticle release are required for cancer cell extravasation in vivo
Authors: Leong Hon S. , Robertson Amy E. , Ablack Amber A. , Turley Eva A. , Chambers Ann F. , Lewis John D. 
Published: June 2012

Abstract
During the metastatic process, cancer cells must undergo trans-endothelial migration from the vessel lumen into underlying tissue in a process known as extravasation. Little is known about the dynamic mechanical aspects of this process. To address this, we performed real-time, sub-cellular resolution intravital imaging of human cancer cells during arrest, intravascular migration and extravasation using a shell-less avian embryo xenograft model. We find that extravasation occurs at endothelial junctions and that the majority of extravasation events occurred during the 12 hours subsequent to the intravenous injection of cancer cells. In the majority of extravasation events, long cytoplasmic extensions identified as invadopodia were observed prior to extravasation which breached underlying endothelium. We observed the release of microparticles during these invadopodial extension events prior to extravasation, and this resulted in a ∼40% reduction in cell volume post-extravasation. Based on this, we hypothesized that invadopodia are required for extravasation, and that cancer cell extravasation could be abrogated by inhibiting factors required for invadopodia function. We found that treatment with Src kinase inhibitors significantly reduced invadopodia formation in vivo and resulted in a ∼60% decrease in extravasation events when compared to vehicle treated controls. Furthermore, a higher proportion of cells in the Src kinase inhibitor-treated animals remained intravascular compared to vehicle control. In conclusion, we determined that 1) extravasation occurs at junctions between adjacent endothelial cells, 2) cancer cells form invadopodia that breach the endothelial layer prior to successful extravasation and 3) cancer cells undergoing extravasation release cancer microparticles into both the vessel lumen and tissue interstitium with a corresponding decrease in cell volume. Pharmacological inhibition of invadopodia by Src kinase inhibitors (Bosutinib, Dasatinib) reduces cancer cell extravasation, revealing a novel and potentially important mechanism of action against metastatic cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 968. doi:10.1158/1538-7445.AM2011-968
Abstract 969: Molecular characterization of circulating tumor cells in breast cancer by liquid bead array hybridization assay
Authors: Markou Athina N. , Strati Areti , Malamos Nikos , Georgoulias Vassilis , Lianidou Evi 
Published: June 2012

Abstract
Introduction: The aim of our study was to develop and validate a multiplexed PCR-coupled liquid bead array to detect the expression of multiple genes in Circulating Tumor Cells (CTCs), and application of this assay in peripheral blood samples of breast cancer patients.
Patients and method: We designed a novel multiplexed PCR-coupled liquid bead array that consist of the following steps: a) in silico designed gene-specific primers and capture probes for CK-19, HER-2, Mammaglobin (hMAM), MAGE-A3, TWIST-1 and PBGD (as a control gene), b) RNA isolation from immunomagnetically enriched CTCs, c) multiplex PCR, d) sequence hybridization array, e) detection in the Luminex platform. We performed extensive optimization experiments using the SKBR3 and MDA-MB-231 cell lines as positive controls, to maximize analytical sensitivity and specificity and we further validated the performance of this array in respect to cross reactivity and intra and inter-precision. Finally, we applied the developed methodology in peripheral blood samples of 64 patients with operable breast cancer, 25 patients with verified metastasis and 17 healthy individuals.
Results: The analytical performance of the developed array was evaluated in tumor cell lines in respect to analytical sensitivity and specificity. Cross reaction studies were performed for each gene target in the presence of all other targets. The assay is highly specific for each gene in complex multiplexed formats, since the discriminatory power of fluorescent bead sets is unique to specifically detect by sequence hybridization the presence of individual gene specific PCR products. The developed liquid bead-based array is highly sensitive, since it can detect the expression of each individual gene at one SKBR3 cell level. The validation of the array included within day and between-days precision studies. None of the genes tested was detected in the CTC fraction of healthy donors while in patients with verified metastasis, CK-19 was detected in 65%, HER-2 in 20%, MAGE-A3 in 30%, hMAM in 20% and TWIST-1 in 20%. In operable breast cancer patients, CK-19 was detected in 26.6%, HER-2 in 12.5%, TWIST-1 in 31.2%, MAGE-A3 in 18.7% while hMAM was detected in 10.9% of the patients.
Conclusions: Our results show that individual gene expression can be readily measured in CTCs using a bead-based platform. This may form an efficient basis for a multiplex approach to measure multiple genes (up to 100) in the same sample, thus saving sample volume and reducing the total cost and time of analysis. This is the first time that the Luminex technology is used for gene expression studies in CTCs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 969. doi:10.1158/1538-7445.AM2011-969
Abstract 978: A regulatory role for TAZ in mesenchymal differentiation of glioblastoma
Authors: L Bhat Krishna P. , Salazar Katrina , Vaillant Brian , Aldape Kenneth 
Published: June 2012

Abstract
Gene expression profiling studies have revealed that the mesenchymal signature (MES) is a predictor for poor survival and treatment resistance in glioblastoma (GBM) patients, whereas patients with a proneural (PN) signature perform better in the clinic. We found that the HIPPO pathway transcription co-factor TAZ, but not YAP is epigenetically silenced by CpG island hypermethylation in lower grade/PN tumors whereas its promoter is hypomethylated in GBM/MES tumors. Treatment of a demethylation agent (2′-deoxy-5-azacytidine) increased TAZ mRNA levels in glioma stem cells lacking this protein. Using bioinformatic approaches we found TAZ to be significantly connected to the MES gene signature network that was distinct from recently reported regulators of MES transition in GBM, viz., STAT3 and CEBPβ. Approximately 60% of the in silico inferred targets were confirmed to be direct targets of TAZ by ChIP-PCR. Silencing TAZ in GSCs decreased invasion and blocked tumorigenesis when implanted intracranially into mice. Conversely, overexpression of TAZ in GSCs that lack this protein resulted in increased MES gene expression, suppressed PN gene expression, increased invasion, differentiation toward an osteogenic and chondrocytic lineage and reduced tumor latency in the xenograft model. In primary NSCs, forced TAZ resulted in increased expression of mesenchymal markers such as fibronectin, and smooth muscle actin, whereas astrocytic or neuronal differentiation was suppressed. All aforementioned phenotypes were abolished when overexpressing a single point mutant version of TAZ (S51A) that lacks binding to its bona fide transcription partner, TEAD. Finally overexpression of TAZ in a PGDF-RCAS transgenic mouse model caused increased tumor grade and incidence and shift toward a MES phenotype. Our study identifies TAZ as important master regulator of PN to MES transition in gliomas and presents as an attractive therapeutic target for this devastating disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 978. doi:10.1158/1538-7445.AM2011-978
Abstract 995: The role of intracellular ATP in regulating glycolysis, HIF1α and drug resistance of cancer cells
Authors: Chen Jinyu , Weihua Zhang 
Published: June 2012

Abstract
Cancer is also considered to be a metabolic disease due to a shift of glucose metabolism from oxidative phosphorylation to anaerobic glycolysis. This study is to understand the effect of intracellular ATP of cancer cells on various metastatsis related phenotypes, including glycolysis, hypoxia stability and drug resistance. In this study, we delivered ATP directly into cancer cells by embedding ATP into liposomes. Normal cells and its corresponding tumor cells were measured for their whole cell ATP content. Glycolysis was evaluated by measurement of glucose consumption and lactate accumulation of cell culture media. Cell cycle was analyzed using flow cytometry after drug treatment and delivery of ATP. HIF-1α expression level was measured by western blot after delivery of ATP. In summary, normal cells have overall higher ATP content than tumor cells. After delivery of ATP, cells consumed less glucose and produced less lactate acid, which indicated a decrease in glycolysis. ATP liposomes prevented MDA-MB-231 cells from G2 arrest by adriamycin. HIF1a was down regulated after delivery of ATP. Taken together, ATP content is lower in cancer cells than normal cells, and intracellular ATP plays a role in regulating glycolysis, HIF-1α stability and drug resistance of cancer cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 995. doi:10.1158/1538-7445.AM2011-995
Abstract DDT01-01: Preclinical profile of AZD4547: A selective inhibitor of FGF-receptors 1, 2, and 3
Authors: Brooks Nigel A. 
Published: June 2012

Abstract
The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling axis comprises 18 ligands which exert their actions via 4 transmembrane tyrosine kinase receptors. FGFs signaling though their cognate receptors play an important role in normal organ, vascular and skeletal development. Deregulation of FGFR signaling through genetic modification or overexpression of the receptors (or their ligands) has been observed in numerous tumor settings, whilst the FGF/FGFR axis also plays an important role in driving tumor angiogenesis. A growing body of data demonstrates that inhibition of FGFR signaling can result in antiproliferative and/or proapoptotic effects, both in vitro and in vivo, thus confirming the validity of FGFR as a cancer therapeutic target.
AZD4547 is a small molecule inhibitor which competes with ATP for binding to FGF receptors 1, 2 and 3, thus inhibiting autophosphorylation and downstream signaling. Using in vitro kinase assays, we demonstrate that AZD4547 is a potent inhibitor of FGFR's 1,2 and 3 with IC50 values of 0.2, 2.5 and 1.8 nM respectively. AZD4547 is also highly selective vs. a panel of over 70 other kinases (no activity at 10 μM) and importantly vs. kinase insert domain receptor (KDR) (&gt;120-fold window in cellular assays vs. FGFR2).
In vitro treatment of a large panel of cell lines (&gt;100, representing several tumor types) with AZD4547 resulted in varying antiproliferative responses, the most potent of which were almost exclusively confined to those cell-lines in which FGFR signaling was deregulated by either gene amplification, mutation or translocation. Treatment of these sensitive cell lines with AZD4547 for 1 hr, demonstrated potent inhibition of phosphorylation of FGF receptors and downstream substrates including pFRS2α and p44/42 MAPK. The antiproliferative effects of AZD4547 appear to be cell line dependent and vary between potent G1-phase cell cycle arrest and apoptotic induction. Chronic in vivo dosing of AZD4547 up to 12.5 mg/kg qd was well tolerated and resulted in dose-dependent growth inhibition in KMS11 (FGFR3 translocated, multiple myeloma) and Snu16 (FGFR2 amplified, gastric) tumour xenograft models. This in vivo antitumor activity is correlated with exposure to AZD4547 and associated pharmacodynamic modulation of phospho-FGFR and downstream substrates. In addition to the single-agent efficacy, combining of AZD4547 with cytotoxic agents, currently used for the treatment of gastric cancer patients, revealed enhanced growth inhibition of Snu-16 xenografts.
Collectively, these data confirm the suitability of AZD4547 as a potent and selective agent for the therapeutic treatment of tumors with deregulated FGF/FGFR signaling.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr DDT01-01. doi:10.1158/1538-7445.AM2011-DDT01-01