bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3735: Preclinical studies of salinomycin as a therapeutic agent for pediatric high-grade glioma cancer stem cells.
Authors: Moses Emily S. , Chang Judy C. , Hung Jaclyn Y. 
Published: August 2014

Abstract
Brain tumors are the most prevalent childhood solid tumors. In the low-grade astrocytomas complete surgical resection has achieved over 90% five-year survival rate. In contrast, the aggressive anaplastic astrocytoma high-grade 3 and the fast growing glioblastoma multiforme high-grade 4 are often refractory to standard therapies; the majority of these patients at presentation are beyond cure by surgery and or radiotherapy. Emerging data substantiate the idea that a small pool of post-therapy residual cells within a tumor displaying stem-like properties is responsible for relapse. Therefore, selectively targeting these cancer stem-like cells (CSCs) may lead to advances in the treatment of these tumors. Salinomycin, an antibiotic potassium ionophore, has been shown to be highly effective against breast cancer stem cells and other malignancies; however, its potential use has not been studied in childhood astrocytomas. Recent studies indicate that salinomycin exerts its effect on components of the Wnt signaling cascade. In this study, we undertook in vitro and in vivo analyses on the effect of salinomycin on four pediatric high-grade astrocytoma cell lines, UW479 (provided by Dr. John Silber, University of Washington), SF188 (from Dr. Daphne Haas-Kogan, UCSF), SJ-GBM2, and CHLA-200 (COG Cell Culture and Xenograft Repository). Our results indicated that salinomycin was able to inhibit cellular viability in a dose-dependent manner. The soft-agar anchorage independent growth assay showed salinomycin inhibition of colony formation in 3 of the 4 cell lines tested. A decrease in the number of cycling cells (S-phase) was observed in cells treated with salinomycin. Notably, a 95% reduction in the glioma stem cells, read-out as CD133+, and impairment in the ability to form spheres (read-out as self-renewal) was observed. A xenograft mouse model was used to determine the effect of salinomycin on tumor growth in vivo and is ongoing. Salinomycin's modulation of Wnt targets measured by qRT-PCR, western blot analysis, and Bio-Plex protein assays, is in progress. Our data suggest that salinomycin could be exploited for the treatment of the aggressive form of pediatric gliomas.
Citation Format: Emily S. Moses, Judy C. Chang, Jaclyn Y. Hung. Preclinical studies of salinomycin as a therapeutic agent for pediatric high-grade glioma cancer stem 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 3735. doi:10.1158/1538-7445.AM2013-3735
Abstract 3752: Induction of lung cancer stem-like cells by chronic exposure to carbon nanotubes.
Authors: Luanpitpong Sudjit , Wang Liying , Manke Amruta , Barr Jamie , Rojanasakul Yon 
Published: August 2014

Abstract
Our previous studies have shown that chronic exposure to single-walled carbon nanotubes (SWCNTs) induces malignant transformation of human lung epithelial cells. Most solid tumors including lung cancer cells are believed to contain poorly differentiated cancer stem-like cells (CSCs) that initiate tumorigenesis and confer resistance to chemotherapy. In this study we investigated whether SWCNT-transformed lung epithelial cells present CSC traits. Similar to human non-small cell lung cancer H460 cells, SWCNT-transformed lung epithelial BEAS-2B cells but not its passage-matched control cells formed tumor spheres in stem cell-selective conditions, indicating the existence of lung CSCs. Lung CSCs have previously been reported to reside in the side population (SP) of parental lung cancer cells. Analysis of SP fractions based on the ability of SP to efflux Hoechst 33342 dye to generate a Hoechst blue-red profile revealed that the SWCNT-transformed cells and H460 cells have high SP fractions, while passage-matched control cells showed no SP, thus confirming the existence of CSC population in SWCNT-transformed and H460 cells. Compared with the corresponding parental cells, the SP cells of SWCNT-transformed and H460 cells acquired apoptosis resistance to various chemotherapy including antimycin A, cisplatin, doxorubicin and etoposide. Together, our results indicate the ability of SWCNT to transform human lung epithelial cells and induce CSCs which could represent a novel mechanism of carcinogenesis induced by CNTs.
Citation Format: Sudjit Luanpitpong, Liying Wang, Amruta Manke, Jamie Barr, Yon Rojanasakul. Induction of lung cancer stem-like cells by chronic exposure to carbon nanotubes. [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 3752. doi:10.1158/1538-7445.AM2013-3752
Abstract 3797: Regulation and function of the mucin-like glycoprotein podoplanin in glioma.
Authors: Peterziel Heike , Müller Julia , Andreas Danner , Barbus Sebastian , Liu Haikun , Pfenning Philipp , Harter Patrick N. , Mittelbronn Michel , Wick Wolfgang , Schuetz Günther , Radlwimmer Bernhard , Lichter Peter , Hess Jochen , Angel Peter 
Published: August 2014

Abstract
Podoplanin (PDPN) is a mucin like type-1 transmembrane protein consisting of 162 amino acids, which comprises a highly glycosylated extracellular domain and a nine amino acid intracellular domain. The specific expression of PDPN on lymphatic but not on blood vascular endothelial cells has established application as a histological marker for lymphangiogenesis and lymphatic vessels in different species. PDPN is highly expressed in tumors of different origin, including squamous cell cancers, germinal neoplasia and tumors of the central nervous system. Recently, we found strong overexpression of PDPN in human astrocytic brain tumors, specifically in primary glioblastoma multiforme (GB). Regulation of PDPN expression involves increased PI3 kinase activation, subsequent activation of protein kinaseB/Akt and the downstream transcription factor AP-1. Activation of this pathway is mediated by loss of PTEN function, consistently, mice lacking Pten exhibit elevated Pdpn protein levels in the subventricular zone of the brain tissue. Additionally, PDPN expression is subject to negative transcriptional regulation by promoter methylation in human GB and in glioma cell lines. In patients high expression of PDPN is associated with poor prognosis. Silencing of PDPN results in a decrease in proliferation, migration and invasion of glioma cell lines in vitro and slows down the migration in orthotopic brain slices. Consistently, tumor formation after injection of PDPN knock-down cells into SCID mice is significantly reduced compared to tumors after injection of parental cells. These data highlight a functional role of PDPN in glioma progression and suggest targeting of PDPN expression as a promising strategy for the treatment of patients with primary GB.
Citation Format: Heike Peterziel, Julia Müller, Danner Andreas, Sebastian Barbus, Haikun Liu, Philipp Pfenning, Patrick N. Harter, Michel Mittelbronn, Wolfgang Wick, Günther Schuetz, Bernhard Radlwimmer, Peter Lichter, Jochen Hess, Peter Angel. Regulation and function of the mucin-like glycoprotein podoplanin in glioma. [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 3797. doi:10.1158/1538-7445.AM2013-3797
Abstract 3805: Single cell evolution of AKT pathway activation drives T-cell acute lymphoblastic leukemia relapse.
Authors: Blackburn Jessica S. , Liu Sali , Dobrinski Kimberly , Ranalli Jayme , Martinez Sarah , Lee Charles , Langenau David 
Published: August 2014

Abstract
The aggressive and unpredictable behavior of relapsed T-cell acute lymphoblastic leukemia (T-ALL) presents a major clinical challenge, with &gt;70% of children and &gt;90% of adults unable to survive relapsed disease. Relapsed T-ALL often acquires mutations that are not found in the primary malignancy. It is these new mutations that allow clones to survive treatment and drive relapse growth. In order to identify the genes and pathways responsible for T-ALL relapse, we have developed a transgenic zebrafish model of relapsed T-ALL where single fluorescently-labeled leukemic cells are transplanted into genetically identical recipient fish and functionally assessed for differences in relapse growth. Using serial transplantation of single T-ALL cells and &gt;6,000 recipient animals, we have followed single-cell evolution of T-ALL and identified critical drivers of relapse. These experiments showed that 6 of 49 individual T-ALL cells significantly increased their ability to form relapse over time. Analysis of T-ALL clones pre- and post-evolution showed that AKT pathway activation was correlated with increased relapse potential. Subsequent studies utilizing transgenic zebrafish that over-expressed activated AKT in developing T-ALL demonstrated that AKT signaling increased relapse potential 10-fold. Transgenic epistatic experiments revealed that AKT signaling plays two distinct roles in T-ALL relapse: the AKT/mTORC1 pathway directly enhanced relapse potential, while AKT mediated stabilization of the Myc protein increased T-ALL aggressiveness. Moreover, small molecule inhibition of AKT signaling reduced T-ALL relapse potential in vivo by 25-fold and synergized with Dexamethasone, a common cytotoxic chemotherapy, to significantly enhance cell killing in both zebrafish and human T-ALL. Activation of AKT signaling is associated with poor prognosis and drug resistance in human T-ALL, which, together with our work, suggests that AKT will be a useful molecular target in the treatment of T-ALL. Our experiments have documented the functional heterogeneity of single leukemic cells and identified AKT as a critical driver of T-ALL aggression, relapse formation, and insensitivity to therapy. These are first studies performed in any model to follow single cell evolution as it relates to relapse, opening new and exciting avenues of study to uncover genetic pathways that drive cancer malignancy.
Citation Format: Jessica S. Blackburn, Sali Liu, Kimberly Dobrinski, Jayme Ranalli, Sarah Martinez, Charles Lee, David Langenau. Single cell evolution of AKT pathway activation drives T-cell acute lymphoblastic leukemia relapse. [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 3805. doi:10.1158/1538-7445.AM2013-3805
Abstract 3835: Ex vivo 3D assay: rapid and reliable replication of the in vivo anti-tumor efficacy of c-Met inhibitors.
Authors: Gorynia Sabine , Guo Jianing , Ackermann Andreas , Maier Armin , Krumbach Rebekka , Kelter Gerhard , Vuaroqueaux Vincent , Metz Thomas , Metcalfe Thomas , Fiebig Heiner H. 
Published: August 2014

Abstract
For compounds directed against molecular targets expressed in tumor cells, the ex vivo 3D tumor clonogenic assay (TCA) is a rapid and reliable ex vivo assay with a high predictive value for in vivo tumor sensitivity. Single cell suspensions prepared from patient-derived tumor xenografts (PDX) growing subcutaneously in nude mice or from cultured human tumor cell lines are seeded in semisolid medium and tumor colony formation is monitored in the presence or absence of test compounds over a period of one to three weeks.
Based on experiments with up to 70 PDX, we have demonstrated that the TCA accurately replicates the in vivo sensitivity of PDX towards cMet inhibitors across all major tumor histologies. More specifically, all three NSCLC PDX that regressed in response to cMet inhibition in in vivo efficacy tests were sensitive to several cMet inhibitors in the ex vivo TCA. By contrast, data obtained with a 2D cell proliferation and survival assay did not correlate with the 3D and in vivo situations, suggesting that cMet function does not affect cell survival and proliferation on plastic but confers the capacity for anchorage-independent growth. The correlation of 3D but not 2D data with in vivo sensitivity was confirmed using anti-cMet siRNAs in selected PDX-derived non-small cell lung cancer cell lines. Preliminary immunohistochemical analysis revealed that PDX sensitive to cMet inhibitors expressed high cMet levels while not all PDX expressing high cMet levels were sensitive to cMet inhibitors.
In conclusion, for cMet inhibitors the TCA replicates in vivo sensitivities of PDX to a high degree. Due to its short duration the TCA is an excellent tool for the screening of large numbers of cMet inhibitors and PDX. As all of the PDX qualified for use in the TCA (&gt;200) have been extensively molecularly characterised (gene expression, gene copy number variation and mutation analysis) this assay is also an excellent tool for generating high quality biomarker hypotheses during the preclinical profiling of molecules intended for oncology indications.
Citation Format: Sabine Gorynia, Jianing Guo, Andreas Ackermann, Armin Maier, Rebekka Krumbach, Gerhard Kelter, Vincent Vuaroqueaux, Thomas Metz, Thomas Metcalfe, Heiner H. Fiebig. Ex vivo 3D assay: rapid and reliable replication of the in vivo anti-tumor efficacy of c-Met inhibitors. [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 3835. doi:10.1158/1538-7445.AM2013-3835
Abstract 3839: Development of a 3-dimensional synthetic lethality screening approach targeting KRas-mut cells.
Authors: Tsuji Toshiya , Sapinoso Lisa M. , Lin I-Lin , Xu Shuichan , Boylan John F. 
Published: August 2014

Abstract
Three-dimensional (3D) in vitro models have been used in cancer research to overcome limitations of 2D systems. 3D in vitro models recapitulate many aspects of actual tumors including hypoxia, metabolism, proliferation gradients, cell-cell and cell-matrix interactions and closer clinical gene expression profiles than those seen in 2D. Importantly, some cancer drugs showed high potency only in the 3D environment compared to 2D (Muranen, et al, Cancer Cell, 2012). In order to identify improved cancer drugs, we established a simple and versatile 3D spheroid culture approach for high-throughput screening for compounds that selectively kill cancer cells with certain genetic backgrounds. We used HCT116 (parental: HCT116/KRas-mut) and an isogenic counterpart that expresses a genetically modified KRas gene (HCT116/KRas-wt) for 3D cell culture. To validate this approach, HCT116/KRas-mut and HCT116/KRas-wt were cultured separately, treated with 15 selected tool compounds and viability was measured using a caspase 3/7 assay. We found 4 compounds that induced caspase 3/7 activity only in 3D culture of HCT116/KRas-mut and not in 2D. Furthermore, 5 compounds were predominantly sensitive to HCT116/KRas-wt cells in 3D culture, but not in HCT116/KRas-mut 3D culture. These results indicate that the more physiological relevant 3D synthetic lethal screen is an attractive approach to cancer drug discovery and may identify compounds missed in conventional 2D culture model screens.
Citation Format: Toshiya Tsuji, Lisa M. Sapinoso, I-Lin Lin, Shuichan Xu, John F. Boylan. Development of a 3-dimensional synthetic lethality screening approach targeting KRas-mut 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 3839. doi:10.1158/1538-7445.AM2013-3839
Abstract 3845: Developing a novel 3D model to study colon cancer cell invasion.
Authors: Adams Rosie 
Published: August 2014

Abstract
Introduction: Colon cancer is the fifth most diagnosed in the UK, with nearly 22,000 cases diagnosed in 20101 with a five-year survival rate of 54.75%2. The formation of distant metastases also influences patient survival, causing a decline from 93% for the earliest stage tumours down to below 7% for tumours with distant metastases3. Previous literature has highlighted the limitations of two-dimensional (2D) cancer cell migration assays4. These include alterations in gene expression of cells and the provision of a migration substrate that does not closely reflect that of the in vivo environment. This project aims to mimic the in vivo situation to investigate factors that affect cancer cell invasion; including the expression of EMT markers and signalling by developing a three-dimensional (3D) model of colon cancer. Methods: This project utilises commercial scaffold known as Alvetex®5 and two colon cancer cell lines (SW480 and SW620) were used to look at the differences between pre- and post-metastatic colon cancer respectively. Both cell lines were cultured prior to analysis using various biochemical assays and histological processing. Results: Our data show a difference in cell penetration between the two cell lines. The later stage SW620 cells, which have a more motile phenotype in 2D, migrate and penetrate the scaffold to a greater extent than the earlier stage, less invasive, SW480 cells. This reflects a known difference in the level of EMT markers between the two cell lines, a result of the Wnt signalling pathway. This model also allows for the use of the known chemoattractant Insulin-like Growth Factor (IGF) to encourage cell penetration. IGF has been shown to play an important role in cancer cell migration. The use of IGF results in a 54% increase in cell penetration by the SW480 cell line, but not the SW620 cell line. Discussion: Our data shows great potential for further development of a 3D cancer invasion model using these scaffolds. This model provides a more realistic 3D environment and will be a tool for chemoattractant and co-culture studies to determine the mechanism of invasion utilised by these cells and to develop this model further to obtain an assay which is closer to the in vivo situation.
Acknowledgements: This work was carried out with funding from the Grevillea Trust, Reinnervate Limited and BBSRC.
Citation Format: Rosie Adams. Developing a novel 3D model to study colon cancer cell invasion. [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 3845. doi:10.1158/1538-7445.AM2013-3845
Abstract 3847: High-throughput 3D screening reveals differences in drug sensitivities between culture models of JIMT1 breast cancer cells .
Authors: Hongisto Vesa J. , Nyberg Sandra , Fey Vidal , Mpindi John-Patrick , Kallioniemi Olli , Perälä Merja 
Published: August 2014

Abstract
The traditional method for studying cancer in vitro is to grow immortalized cancer cells in two-dimensional (2D) monolayers on plastic. However, many cellular features are impaired in these unnatural conditions and big alterations in gene expression in comparison to tumors have been reported. Three-dimensional (3D) cell culture models have become increasingly popular and are suggested to be better models than 2D monolayers due to improved cell-to-cell contacts and structures that resemble in vivo architecture.
The aim of this study was to develop a simple high-throughput 3D drug screening method and to compare drug responses in JIMT1 breast cancer cells when grown in 2D, in polyHEMA coated anchorage independent 3D models and in Matrigel on-top 3D cell culture models. We screened 102 compounds with multiple concentrations and biological replicates for their effects on cell proliferation. The cells were either treated immediately upon plating or they were allowed to grow in 3D for four days prior to the drug treatment. Big variations in drug responses were observed between the models indicating that comparisons of culture model influenced drug sensitivities cannot be made based on effects of a single drug. However, we show with the 63 most prominent drugs that, in general, JIMT1 cells grown on Matrigel were significantly more sensitive to drugs than cells grown in 2D cultures, while responses of cells grown in polyHEMA resembled those of 2D. Furthermore, comparison of gene expression profiles of the cell culture models to xenograft tumors indicated that cells cultured in Matrigel and as xenografts most closely resembled each other. In this study we also suggest that 3D cultures can provide a platform for systematic experimentation of larger compound collections in a high-throughput mode and be used as alternatives for traditional 2D screens towards better comparability to in vivo state.
Citation Format: Vesa J. Hongisto, Sandra Nyberg, Vidal Fey, John-Patrick Mpindi, Olli Kallioniemi, Merja Perälä. High-throughput 3D screening reveals differences in drug sensitivities between culture models of JIMT1 breast 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 3847. doi:10.1158/1538-7445.AM2013-3847
Abstract 3852: Bcl-xL and IL-6 act independently and synergistically to accelerate plasmacytopoiesis and plasma cell tumor formation in Balb/c mice.
Authors: Sakai Tomomi , Kovalchuk Alexander L. , Morse Herbert 
Published: August 2014

Abstract
Accelerated development of spontaneous plasma cell tumors (PCT) occurs in mucosal-associated lymphoid tissues of mice bearing both IL-6 and BCL-XL transgenes (double transgenic (dTg)). 91% of dTG mice developed PCTs at a mean age of 89 days. In contrast, 53% of the IL-6 Tg mice developed PCTs at a mean age of 301 days and 12% BCL-XL Tg mice developed PCTs with a mean age of 433 days. The PCTs formed primarily in Peyer's Patches, medullary cords of the mesenteric lymph node and/or the lamina propria of small intestinal villi where they were preceded by massive plasma cell hyperplasia. To investigate the molecular basis of the cooperation between IL-6 and BCL-xL transgenes to accelerate PCT development we performed detailed analysis of cell lines developed from dTG mice and and spontaneous or pristane-induced tumors of Bcl-xL TG mice. All the tumors carry Ig/Myc-deregulating chromosomal translocations, which are thought to be the initiating event of PCT development. Therefore we focused on finding possible differences in secondary alterations. Although the subsets were poorly distinguished by microarray-based gene expression profiling, there were significant differences in the expression of p21, p19ARF, p53, HUWE1 and pRb as determined by western blotting and qPCR. DTG tumors were characterized by alterations in pathways governing expression of pRb that included increased expression of INK4A and down regulation of pRb itself as well as down regulation of p19ARF. Most notably we discovered discordance between protein and mRNA levels for pRb and p19Arf. Efforts to understand the molecular basis for these distinctions and their contributions to the biology of these PCT subsets are in progress.
Citation Format: Tomomi Sakai, Alexander L. Kovalchuk, Herbert Morse. Bcl-xL and IL-6 act independently and synergistically to accelerate plasmacytopoiesis and plasma cell tumor formation in Balb/c mice. [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 3852. doi:10.1158/1538-7445.AM2013-3852