bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3818: TEL-AML1-induced STAT3 activation is essential for t(12;21)-associated childhood leukemia.
Authors: Mangolini Maurizio , de Boer Jasper , Walf-Vorderwülbecke Vanessa , Pieters Rob , den Boer Monique , Williams Owen 
Published: August 2014

Abstract
The t(12;21)(p13;q22) translocation is the most common chromosomal abnormality in pediatric leukemia, present in up to 25% of children with pre-B cell Acute Lymphoblastic Leukemia (ALL). This translocation involves two transcription factors, TEL(ETV6) and AML(RUNX1), both of which have crucial roles in regulating hematopoiesis.
Our lab has previously established a list of TEL-AML1 transcriptional target genes using Affymetrix GeneChip global gene expression analysis of mouse fetal liver hematopoietic progenitor cells (HPC) over-expressing the fusion cDNA. This analysis demonstrated deregulated expression of genes associated with STAT3 signaling, known to be one of the most important pathways required for proliferation and maintenance of multipotency in cancer stem cells.
In this study, we analyze the importance of STAT3 activity in a mouse model of TEL-AML1 overexpression, in human TEL-AML1 positive leukemia cells and primary human leukemic samples. Our results show that activation STAT3, via RAC1 induction, is necessary for the survival, proliferation and self-renewal of TEL-AML1 positive leukemia through transcriptional regulation of MYC expression.
In conclusion we show a novel signaling pathway important for the maintenance of TEL-AML1 leukemia that constitutes a promising novel therapeutic strategy for the treatment of TEL-AML1 leukemia.
Citation Format: Maurizio Mangolini, Jasper de Boer, Vanessa Walf-Vorderwülbecke, Rob Pieters, Monique den Boer, Owen Williams. TEL-AML1-induced STAT3 activation is essential for t(12;21)-associated childhood leukemia. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3818. doi:10.1158/1538-7445.AM2013-3818
Abstract 3819: DKK2 mediates osteolysis, invasiveness and metastatic spread in Ewing sarcoma.
Authors: Richter Günther H. , Burdach Stefan , Hauer Kristina 
Published: August 2014

Abstract
Ewing sarcomas (ES) are malignant osteolytic bone and soft tissue tumors mostly affecting children and young adults, and are characterized by early lung and distant bone metastases. Here we identified the dickkopf 2 homolog (DKK2) as a highly over-expressed gene in ES, compared to normal tissues. DKK family members are increasingly recognized to be deregulated in bone metastasis. Using RNA interference, we show that DKK2 promotes anchorage-independent colony formation and proliferation of ES cells in vitro and tumorigenicity in vivo. Analysis of the invasion potential in vitro and in an orthotopic xenotransplantation model revealed a strong correlation of DKK2 expression and ES invasiveness that is possibly mediated by its downstream effector matrix metalloproteinase 1 (MMP1). Gene expression analyses proved DKK2 to differentially regulate genes such as CXCR4, PTHrP, RUNX2 and TGFβ1, that are associated with homing, invasion and growth of cancer cells in bone tissue as well as genes important for osteolysis, like HIF1α, JAG1, IL6 and VEGF. Moreover, we observed that DKK2 promotes bone infiltration and osteolysis in vivo, identifying DKK2 as a key factor for osteotropic malignancy. Interestingly, suppression of DKK2 expression increases neuronal differentiation, but at the same time decreases chondrogenic and osteogenic differentiation potential of ES cells. These data provide evidence that DKK2 is a key player in ES invasiveness and osteolysis, validating a critical role of DKK2 for malignancy and the differential phenotype of ES. Findings further suggest a broadly important role for a member of a family of antagonists of the Wnt pathway in driving bone invasion and osteolysis with potential implications for bone invasion in cancer generally.
Citation Format: Günther H. Richter, Stefan Burdach, Kristina Hauer. DKK2 mediates osteolysis, invasiveness and metastatic spread in Ewing sarcoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3819. doi:10.1158/1538-7445.AM2013-3819
Abstract 3833: A novel 3D remodelable hydrogel for bioengineering tumor .
Authors: Han Bo , Fang Josephine , Yang Zhi , Nimni Marcel , Tayag Charisse 
Published: August 2014

Abstract
The need for new tools and technologies to decrease the cost of drug discovery and reduce animal testing has long been recognized. Three-dimensional (3-D) cell cultures have great potential for reducing costly late-stage drug failures by providing an in vivo-like early stage evaluation of efficacy and toxicity. We have developed a novel 3D culture system, which will serve as a simple and rapid method to examine cell proliferation, migration, apoptosis, and tissue formation in a physiologically relevant 3-D environment, similar to the in vivo setting, than standard 2-D arrays. This transglutaminase crosslinked gelatin (T-gel) system provides a native ECM scaffold for cell-cell and cell-matrix interaction; its transparency property enables routine observation with ease; the proteolysis sensitivity scaffold supports cell migration and invasion; the controllable rigidity mimics physiological and pathological environments. Importantly, 3D gel models have great potential as drug evaluation tools as they exhibit in vivo-like cell-cell and cell-ECM interaction, possess metabolic, proliferative and diffusion gradients. It is simple to use on a large scale. Compare to Matrigel, Tgel is with well defined ingredients, wide range of handling properties, easy to prepare at room temperature, and little batch to batch variation. It supports both anchorage dependent and independent cell growth due to hydrogel and natural ECM network properties. We make 3D cultures more relevant by including two or more cell types in different configurations co-cultures. Cells can be tracked on their formation of aggregates, migration (individual or collective), invasion direction (random or directional), speed, and responses to hypoxic and nutritional gradients. At the end of test, viable cells can be easily removed from the 3D T-gel for further experimentation. T-gel can also be used as a carrier for xenograft tumor formation in nude mice models. Other applications include cell growth and differentiation studies, metabolism/toxicology Studies, in vitro/vivo angiogenesis assay, hESC and iPSC culture and Differentiation.
Citation Format: Bo Han, Josephine Fang, Zhi Yang, Marcel Nimni, Charisse Tayag. A novel 3D remodelable hydrogel for bioengineering tumor . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3833. doi:10.1158/1538-7445.AM2013-3833
Abstract 3840: Development of an innovative 3D cell culture system to study tumor-stroma interactions in cancer cells.
Authors: Amann Arno , Zwierzina Marit , Gamerith Gabriele , Bitsche Mario , Huber Julia M. , Vogel Georg , Blumer Michael , Koeck Stefan , Kelm Jens , Hilbe Wolfgang , Zwierzina Heinz 
Published: August 2014

Abstract
Introduction: We describe a novel 3D co-culture method using non-small cell lung cancer (NSCLC) cell lines in combination with a lung fibroblast cell line in the hanging drop technology. This method allows the investigation of tumour-stroma interactions and addresses the importance of having a more in vivo like cell culture model. Compared to other 3D models, it better reflects tumour growth in its microenvironment since no addition of growth factors or artificial extracellular matrix (ECM) substitutes are required.
Methods: 96-well hanging drop microtiter plates (InSphero AG, Zürich, Switzerland) were used for the production of 3D mono- and co-cultures. In these hanging drops the two NSCLC cell lines A549 and Colo699 were cultivated either alone or co-cultured with lung fibroblasts. The viability of tumour spheroids was confirmed after five and ten days by using Annexin V/Propidium Iodide staining for flow-cytometry. Tumour fibroblast spheroid aggregation was displayed either by scanning electron microscope, semi-thin sections, immunofluorescence or by immunohistochemistry (IHC). In addition to conventional histology (H&E), protein expression of e-cadherin, vimentin, Ki67 and α-smooth muscle actin (ASMA) was investigated by IHC.
Results: Lower viability was seen in A549 monocultures compared to co-cultures, whereas Colo699 monocultures showed better viability compared to co-cultures. Ki67 expression varied significantly between mono- and co-cultures in both tumour cell lines. The co-cultivation with fibroblasts led to an increased expression of this protein indicating increased proliferation. Furthermore, a vimentin upregulation and an e-cadherin downregulation could be detected during the course of the cultivation indicating a transition to a more mesenchymal phenotype.
Conclusion: We demonstrate that the hanging drops technology is a promising technique for the generation of tumour spheroid co-cultures. Furthermore, these spheroids allow the investigation of tumour-stroma interactions and a better reflection of in vivo conditions of cancer cells in their microenvironment. Our method holds potential to contribute to the development of anti-cancer agents and support the search for predictive biomarkers.
Citation Format: Arno Amann, Marit Zwierzina, Gabriele Gamerith, Mario Bitsche, Julia M. Huber, Georg Vogel, Michael Blumer, Stefan Koeck, Jens Kelm, Wolfgang Hilbe, Heinz Zwierzina. Development of an innovative 3D cell culture system to study tumor-stroma interactions in cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3840. doi:10.1158/1538-7445.AM2013-3840
Abstract 3841: 3D spheroid culture model for studying cancer progression: fine tuning the extracellular environment.
Authors: Benton Gabriel J. , Arnaoutova Irina , George Jay 
Published: August 2014

Abstract
There is a need for more comprehensive and physiologically predictive cancer progression models. Tumor cell aggregates or spheroids are more demonstrative of tumors in vivo as they display several physiological traits including comparable morphology, reduced proliferation rates, elevated cell survival, cell-cell bond formation, tumor dormancy, and a hypoxic core. Embedding these spheroids in a physiological hydrogel composed of basement membrane proteins provides networks on which cells can travel out of the spheroid, mimicking early events during metastasis. Recent studies implicate the tumor microenvironment as a key component of the cancer progression process, and changes in tissue rigidity and collagen I content have been associated with this pathological process. The purpose of this study is to model the effects of differing extracellular matrix composition on morphology and invasiveness in different metastatic cell types during early metastatic events. Here, human cell lines representing different cancer types were grown in spheroid culture and subjected to embedding in hydrogels of differing extracellular matrix protein composition. The cell panel includes MDA-MB-231 for breast cancer, PC-3 for prostate cancer, U-87 MG for glioblastoma and HT-1080 for fibrosarcoma. Spheroids were photographed every 24 hours, and photographs were subjected to image analysis. The composition of the extracellular matrix hydrogel had a significant effect on the morphology of the invading cells as well as the rate of invasion. Increasing the collagen I content to model a more fibrotic environment resulted in fewer but longer process formation, representing a more motile cancer model; however, collagen I, alone, was insufficient to support robust invasion. In conclusion, the 3D spheroid invasion model suggests that the composition of the extracellular matrix proteins is important for cancer cell behavior during metastasis.
Citation Format: Gabriel J. Benton, Irina Arnaoutova, Jay George. 3D spheroid culture model for studying cancer progression: fine tuning the extracellular environment. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3841. doi:10.1158/1538-7445.AM2013-3841
Abstract 3843: Design of a novel three-dimensional biomimetic nano bone model for breast cancer bone metastasis and therapeutics discovery.
Authors: Wang Mian , Fu Sidney W. , Zhang Lijie 
Published: August 2014

Abstract
Breast cancer is the leading cause of cancer-related death in American women, accounting for more than 200,000 new cases and 40,000 deaths annually. Most breast cancer patients will eventually develop complications due to bone metastasis. However, the mechanisms by which breast cancer metastasizes to bone are not well investigated. Traditional tumor metastasis models contain many inherent limitations. Therefore, the objective of this research is to design an innovative biomimetic 3D tissue engineered in vitro bone model via hydroxyapatites (HA), human bone marrow mesenchymal stem cell (hMSC) and natural chitosan hydrogel for breast cancer metastasis study and therapeutics discovery. 3D porous HA-chitosan scaffolds with different crystalline, size and concentration of HA (specifically, 10% and 20% nanocrystalline HA, microcrystalline HA and amorphous HA) were fabricated via a lyophilization procedure. Metastasis breast cancer cells MDA-MB-231 were seeded on all scaffolds and cultured for 4h, 1, 3 and 5 days. The cell adhesion and proliferation results showed that concentration, size and crystallinity of HA have a significant impact on metastasis breast cancer cell behavior. 10% nanocrystalline HA can significantly enhance breast cancer cell attachment when compared to all of other HA. Considering natural bone also consisting of nanocrystalline HA, 10% synthesized nanocrystalline HA in porous chitosan scaffold can create a more biomimetic bone environment for breast cancer bone metastasis study. Furthermore, our bone model was further modified by inducing hMSC osteogenic differentiation in the scaffold resulting in deposition of bioactive protein and calcium by MSC. SEM images of the MSC modified scaffolds revealed that protein and calcium were deposited on both its surface and inner architecture. Two different metastatic breast cancer cells with different metastasis potential (less metastatic MCF-7 and highly metastatic MDA-MB-231) were evaluated in this modified bone model in vitro. The results showed that MDA-MB-231 expanded faster than MCF-7 in the scaffold after 24h culture. Confocal microscopy was used to verify two cells metastasis ability and showed that MDA-MB-231 could migrate deeper in this modified bone model compared to MCF-7. Our results revealed that this model can well reflect the two different metastasis behaviors, making this biomimetic 3D tissue engineered nano bone model promising for future breast cancer cell metastasis study and therapeutics discovery.
Citation Format: Mian Wang, Sidney W. Fu, Lijie Zhang. Design of a novel three-dimensional biomimetic nano bone model for breast cancer bone metastasis and therapeutics discovery. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3843. doi:10.1158/1538-7445.AM2013-3843
Abstract 3848: Cryopreserved, viable and architecturally intact lung tissue from patients as a model to study drug therapies.
Authors: Spyropoulos Demetri D. , Denlinger Chadrick E. , Riemer Ellen C. , Newton Danforth A. , Jones E. Ellen , Drake Richard R. , Baatz John E. 
Published: August 2014

Abstract
RATIONALE: Surgery, chemotherapy and radiation have not appreciably improved lung cancer patient survival rates over the past 20 years. Preclinical anti-tumor efficacy testing models could be improved by being rapid, reliable and capable of demonstrating tumor responses to dosing (concentration/timing) and drug interactions, while accounting for inter-patient variation. High-throughput, 3D in vitro systems hold promise as such therapeutic models, but linking these models to clinical responses in patients has been a dilemma.
METHODS: We developed a lung tissue cryopreservation/banking method that optimizes cell viability and maintains tissue architecture after thawing. This method involves the expansion-perfusion of fresh patient lung tissue samples with non-toxic cryoprotectant solutions, followed by controlled-rate freezing of samples.
RESULTS: We used this method to cryopreserve lung tissues from multiple patients. Although inter-patient variability in lung tissue compliance was anticipated, a wide range of expansion volumes can be tolerated without architectural damage. In contrast, tissue integrity was more sensitive to variations in expansion-perfusion rates (as gauged by lymphatic expansion/tearing). Cryosubstitution demonstrated that crystal formation varies with cryoprotectant cocktail and region within the lung, but can be virtually eliminated under certain conditions. From thawed lung tissues, we have 1) isolated and expanded viable lung cell types; 2) isolated decellularized extracellular components; and, 3) reconstituted intact lung tissue with fluorescent-tagged lung tumor cells. We performed patient surgeries/preservations individually, thawing, processing and analysis of lung tissue from multiple patients was performed simultaneously.
CONCLUSION: Cancer cell drug responses are being compared in lung tissues ex vivo versus on standard monolayer culture using advanced proteo-/lipidomic mapping techniques (including MALDI MS and DIGE). Comparing multiple patient-specific lung tissues simultaneously should afford patient population stratification based on molecular profiles and achieve more rapid methods for determining personalized clinical treatment regiments.
Citation Format: Demetri D. Spyropoulos, Chadrick E. Denlinger, Ellen C. Riemer, Danforth A. Newton, E. Ellen Jones, Richard R. Drake, John E. Baatz. Cryopreserved, viable and architecturally intact lung tissue from patients as a model to study drug therapies. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3848. doi:10.1158/1538-7445.AM2013-3848
Abstract 3850: The interaction of RUNX1 with CBFβ-SMMHC during leukemogenesis.
Authors: Zhao Ling , Hyde R Katherine , Alemu Lemlem , Liu P Paul 
Published: August 2014

Abstract
Chromosome 16 inversion is associated with acute myeloid leukemia subtype M4Eo and produces a fusion gene CBFB-MYH11 that contains part of the core binding factor (CBF) β gene CBFB, and part of the smooth muscle myosin heavy chain (SMMHC) gene MYH11. This fusion gene encodes a fusion protein CBFβ-SMMHC, which is oncogenic and binds to the runt domain (RD) of RUNX1, another member of the CBF transcription factor family, resulting in repression of RUNX1 transactivation. We have generated mouse models by conventional and conditional knock-in of the Cbfb-MYH11 fusion gene and demonstrated that Cbfb-MYH11 represses Runx1 function in hematopoiesis and predisposes mice to myeloid leukemia (Castilla et. al., Cell 1996; Nat Genet, 1999).
RUNX1 binding and repression was previously considered a key step in leukemogenesis by CBFβ-SMMHC. In order to dissect the molecular mechanism of RUNX1 and CBFβ-SMMHC interaction during leukemogenesis, we generated a knock-in mouse model with deleted high affinity binding site of Cbfb-MYH11. We found accelerated leukemia development in these mice (Kamikubo et.al., Cancer cell, 2010) suggesting that Cbfb-MYH11 play an independent role apart from Runx1 binding and repression. To test if Runx1 is involved in the leukemia development and progression, we crossed Cbfb-MYH11 knock-in mice with mice harboring one of the two mutant alleles of Runx1 - Runx1+/- and Runx1+/Lzd. Runx1+/- contains a null allele while Runx1+/Lzd contains a knocked-in fusion between the RD of Runx1 and the LacZ gene, which is partially dominant-negative in reporter assays. We have determined the rate and percentage of leukemia development in these mice. We found that the Cbfb-MYH11 mice that were Runx1+/- had a similar rate of leukemogenesis when compared with Cbfb-MYH11 mice that were Runx1+/+. However, the Cbfb-MYH11 mice that were Runx1+/Lzd had significantly delayed leukemogenesis as compared to Cbfb-MYH11 mice that were Runx1+/+. Moreover, some of the Cbfb-MYH11; Runx1+/Lzd mice did not develop leukemia at the end of the one-year observation. We detected a decrease of BrdU incorporation in the bone marrow cells in mice with the Runx1+/Lzd allele, suggesting that the delayed leukemia development resulted, at least in part, from decreased proliferation. These data demonstrated that Runx1 is likely required for leukemogenesis by CBFβ-SMMHC.
Citation Format: Ling Zhao, R Katherine Hyde, Lemlem Alemu, P Paul Liu. The interaction of RUNX1 with CBFβ-SMMHC during leukemogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3850. doi:10.1158/1538-7445.AM2013-3850
Abstract 3858: Chronic myeloid leukemia in the aryl hydrocarbon receptor knockout mouse.
Authors: Butler Ryan , Warner Margaret , Gustafsson Jan-Åke 
Published: August 2014

Abstract
The aryl hydrocarbon receptor (AhR) is a sensor of environmental toxins such as TCDD and its activation by these ligands can lead to immune system impairment, endocrine disruption and cancer. However, the normal physiological functions of AhR are still under investigation. We have previously reported the presence of large uric acid stones in the urinary bladder of AhR-/- mice and have traced this uric acid to rapid degradation of cells. In order to identify the cells that are dying, we examined the immune system of these mice. AhR -/- mice develop splenomegaly, increased number of megakaryocytes, increased circulating white blood cell count, enlarged lymph nodes, abnormalities in the bone marrow with many immature blast cells and severe myeloid cell infiltration into the liver and other tissues. The immune phenotype in these mice worsens as they age. The AhR -/- mouse phenotype, diagnosed as chronic myeloid leukemia, is similar to that of ERβ -/- mice but there is no loss of ERβ in AhR-/- mice. These studies suggest a novel mechanism for the development of chronic myeloid leukemia.
Citation Format: Ryan Butler, Margaret Warner, Jan-Åke Gustafsson. Chronic myeloid leukemia in the aryl hydrocarbon receptor knockout mouse. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3858. doi:10.1158/1538-7445.AM2013-3858