bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B07: Metabolic liabilities of human colon carcinoma spheroids are different compared to standard 2D cultures
Authors: Dranka Brian P. , Swain Pamela , Rogers George W. , Divakaruni Ajit S. , Neilson Andy , Ferrick David A. 
Published: May 2015

Abstract
The search for metabolic liabilities in tumor cells is typically performed in standard 2D cultures. This approach lacks the 3D context and heterogeneity of tumor tissue in vivo, which has significant impact on their metabolic behavior. One solution to modeling complex tumor cell interactions is to use cultured tumor spheroids. To assess bioenergetic function in individual spheroids, a modified, 96-well plate for the Seahorse Bioscience XFe96 Extracellular Flux Analyzer was created. Here, we demonstrate the capability of measuring mitochondrial oxygen consumption – a measure or mitochondrial respiration – and extracellular acidification – a measure of glycolytic flux – in individual HCT116 colon carcinoma spheroids. Spheroids were cultured using the hanging drop method for 4 days. Mitochondrial function was determined using the Cell Mito Stress Test which profiles 6 specific indices of mitochondrial activity. Cells grown in spheroids had a markedly increased spare respiratory capacity compared to cells in 2D culture. These data are consistent with a shift from the highly proliferative nature of 2D culture to a more physiological model where proliferation and differentiation is more balanced. We hypothesize that viewing metabolism holistically allows for a more complete view of cellular bioenergetic function and potential liabilities. To understand the metabolic potential of cells in the context of their basal metabolism, two new metrics for describing mitochondrial function were established. By stimulating maximal oxygen consumption by combined exposure to oligomycin and FCCP, and maximal extracellular acidification rate (ECAR) using rotenone, antimycin A, and oligomycin, the potential to switch metabolic pathways was determined. Metabolic Capacity Index was identified using the maximal responses in each direction, and Metabolic Flexibility Index was calculated as the angle of the line to identify cellular preference for OXPHOS or glycolysis. Interestingly, plastic-adherent HCT116 cells only exhibited potential to increase glycolysis, while HCT116 spheroids had a more balanced response. These data are consistent with the finding that spheroids have increased spare capacity. Implications of this work for future studies in cancer biology will be discussed.
Citation Format: Brian P. Dranka, Pamela Swain, George W. Rogers, Ajit S. Divakaruni, Andy Neilson, David A. Ferrick. Metabolic liabilities of human colon carcinoma spheroids are different compared to standard 2D cultures. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B07. doi:10.1158/1538-7445.CHTME14-B07
Abstract B31: Lung fibroblast enhances MMP-1 secretion when co-cultured with human lung cancer cells in the 4D lung cancer model
Authors: Mishra Dhruva Kumar , Thrall Michael J. , Kurie Jonathan M. , Kim Min P. 
Published: May 2015

Abstract
Tumor microenvironment plays an important role in cancer development, progression and metastasis. However, it is difficult to determine the effect of fibroblast on lung cancer cells in patients with lung cancer. Recently, we have developed a novel ex vivo 4D lung cancer model that mimic the biology of human lung cancer growth. In order to determine the viability of the normal lung fibroblast, Wi-38, when grown in the 4D model, we grew Wi-38, alone or with A549, in the epithelial space of the acellular matrix of the 4D model with media that was continuously perfused through the vascular space. We performed a lobectomy on days 4, 6, 8, 11 and 14 from the 4D model. We performed H&E of the lobectomy specimen of Wi-38 grown alone and immunohistochemistry for CK7 cells for the lobectomy specimen of A549 grown with Wi-38. Next, we grew either A549 or H1299 alone or with Wi-38 in the 4D model and collected circulating media. We measured the matrix metalloproteinase (MMP) profiles of the circulating media on days 3, 6, 9,12 and 15 using Millipore Luminex kit. We used student t-test to determine the significant difference of MMP levels between the two conditions. When lung fibroblast, Wi-38, was grown on the 4D model alone there was viable fibroblast on day 14; however, when Wi-38 was grown with A549, there was a significantly less number of fibroblast (CK7 negative cells) on day 14 (2±1%) compared to day 4 (50±9%, p &lt; 0.0001). For both H1299 grown with Wi-38 and A549 grown with Wi-38, there were significantly higher levels of MMP-1 on day 3 and day 6 compared with cancer cells grown alone (p&lt; 0.05). However, there was no significant difference in the level of MMP-10 for all days of the experiment. Our study shows that when Wi-38 fibroblast is cultured with A549, the amount of fibroblast decreases over time and A549 grows in the acellular matrix. The study shows that fibroblast enhances MMP-1 production but not MMP-10 production for both H1299 and A549 cells. Overall, this study shows that both human fibroblast and cancer cells can grow together on acellular matrix and fibroblast may modify tumor progression by production of MMPs.
Citation Format: Dhruva Kumar Mishra, Michael J. Thrall, Jonathan M. Kurie, Min P. Kim. Lung fibroblast enhances MMP-1 secretion when co-cultured with human lung cancer cells in the 4D lung cancer model. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B31. doi:10.1158/1538-7445.CHTME14-B31
Abstract B36: The role of the microRNA-200 family in the regulation of tumor cell signaling and metastasis in lung cancer
Authors: Roybal Jonathon D. , Peng David H. , Ungewiss Christin , Mandal Pijus K. , McMurray John S. , Byers Lauren A. , Gibbons Don L. 
Published: May 2015

Abstract
Lung cancer is the deadliest cancer in the United States due primarily to the development of metastatic disease, resulting in a 16% five year overall survival. Regrettably response rates are poor with the current modalities used to treat patients, which implies that a greater understanding of the biology of invasion and metastasis is indispensable. It is thought that the epithelial-mesenchymal transition (EMT) plays a crucial role in regulating invasion, migration, and metastasis. The microRNA-200 family (miR-200) is a key maintenance factor of the epithelial phenotype by regulating EMT and metastatic potential, although the mechanistic details of this regulation are incompletely understood. Recent research has demonstrated that miRNAs are capable of regulating the target mRNAs that coordinate intracellular signaling pathways. Using our mutant Kras and p53 murine model of metastatic lung adenocarcinoma, we have shown through Reverse Phase Protein Array (RPPA) profiling that high levels of miR-200 in poorly metastatic lung tumor cells can suppress cancer-promoting signaling molecules, such as Signal Transducer and Activator of Transcription 3 (STAT3). In contrast, highly metastatic lung tumor cells with low miR-200 expression have STAT3 activation and increased migratory and invasive properties. Utilizing pharmacologic approaches to inhibit STAT3 in highly metastatic lung tumor cells decreased their ability to migrate and invade. Our data suggests that the STAT3 pathway is under the control of miR-200 and inhibition in metastatic lung cancer could provide benefit to lung cancer patients as a potential treatment option.
Citation Format: Jonathon D. Roybal, David H. Peng, Christin Ungewiss, Pijus K. Mandal, John S. McMurray, Lauren A. Byers, Don L. Gibbons. The role of the microRNA-200 family in the regulation of tumor cell signaling and metastasis in lung cancer. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B36. doi:10.1158/1538-7445.CHTME14-B36
Abstract B70: Targeting the Tie2/angiopoietin signaling pathway in glioblastoma
Authors: Plate Karl H. , Scholz Alexander , Harter Patrick , Mittelbronn Michel , Slyke Paul van , Dumont Dan , Reiss Yvonne 
Published: May 2015

Abstract
Angiogenesis inhibitors have evolved in the past decade as one of the most promising biology based therapeutic strategies. Promising pre-clinical studies (published in 1993 and 1994) provided proof of principle that blocking of VEGF dramatically inhibits tumor growth. These observations led to the successful development of inhibitors for VEGF and VEGF receptors by various pharmaceutical companies. Bevacizumab, a monoclonal antibody neutralizing VEGF, was the first-in class drug to achieve FDA approval for the treatment of colorectal carcinoma in 2004 and later on in other cancer types, including glioblastoma. Anti-VEGF therapy led to an increase in progression free survival in recurrent and primary GBM, but its role in first-line treatment is less clear. Importantly, several preclinical studies suggested that resistance to anti-angiogenic therapy might evolve in the course of the treatment due to an infiltration of specially polarized myeloid cells.
In order to define new therapeutic options for anti-angiogenic therapy we investigated the Tie2/Angiopoietin (Angpt) signaling pathway in human and murine glioblastomas. In more than 200 human brain tumor specimens investigated, Angpt2 protein expression was found to be up-regulated in tumor endothelial cells whereas it was absent in the normal brain. Further, Angpt2 expression levels correlated with WHO grade as well as the number of infiltrating monocytes/macrophages. Notably, transgenic mice with endothelial cell-specific expression of Angpt2 showed a significant higher number of infiltrating myeloid cells, thus corroborating our findings in human GBM. These findings suggest, that Angpt signaling links inflammation and angiogenesis in GBM and may thus provides a therapeutic target.
In a GL261 orthotopic syngeneic glioma model, interference with Angpt signaling with pharmacologic agents and peptide-based blockers of Angpt2, lead to a significant increase in survival, increased pericyte coverage and altered myeloid cell/T-cell composition. Combining anti-Angpt with anti-VEGF based therapies showed synergistic effects. These findings argue for targeting the Tie2/Angpt signalling pathways in human GBM, either alone or in combination with anti-VEGF therapies.
Citation Format: Karl H. Plate, Alexander Scholz, Patrick Harter, Michel Mittelbronn, Paul van Slyke, Dan Dumont, Yvonne Reiss. Targeting the Tie2/angiopoietin signaling pathway in glioblastoma. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B70. doi:10.1158/1538-7445.CHTME14-B70
Abstract B71: Inhibiting the CSF-1 receptor on tumor-infiltrating monocytes may enhance the efficacy of radiotherapy for glioblastoma multiforme
Authors: Stafford Jason H. , Chernikova Sophia , West Brian L. , Brown J. Martin 
Published: May 2015

Abstract
Glioblastoma (GBM) is the most common brain tumor and is one of the most deadly forms of cancer with median survival only 15 months after diagnosis. Ionizing radiation (IR) is the most effective treatment for GBM, but the prognosis remains poor because the tumors invariably recur. We have previously shown that bone marrow-derived monocytes promote GBM recurrence after radiotherapy by homing to the irradiation site and stimulating the growth of new tumor blood vessels in a process referred to as vasculogenesis. We found that this infiltration of monocytes can be prevented and tumor recurrences delayed by inhibition of the SDF-1/CXCR4 chemokine axis. Here we present data that suggest Colony Stimulating Factor-1 (CSF-1) may also play an important role in this phenomenon. CSF-1 is a potent chemokine secreted by several different types of solid tumors and is also the main growth factor regulating the differentiation of monocytes into macrophages. RT-PCR analysis of U251 GBM tumors growing in mice revealed a more than 12.5-fold increase in expression of CSF-1 after treatment with a single dose of 12 Gy IR. Increased CSF-1 expression in these tumors correlated with increased recruitment of CD11b+ monocytes. Immunohistochemistry (IHC) and fluorescence activated cell sorting (FACS) showed that the number of CD11b+ monocytes in GBM tumors had approximately doubled within 2 weeks of IR treatment. F4/80 staining indicated that the majority of the CD11b+ cells were mature macrophages. Treatment with 40 mg/kg/day PLX3397, which inhibits the receptor for CSF-1 (CSF-1R), effectively blocked the recruitment of monocytes/macrophages to the irradiated tumors and inhibited tumor blood vessel formation. Moreover, bioluminescence imaging (BLI) of intracranial U251-luciferase tumors growing in mice showed that combined treatment with IR and PLX3397 was more effective at inhibiting tumor growth than IR alone. Eighty percent of mice treated with IR and PLX3397 were alive at 50 days post-irradiation whereas there were no survivors among groups receiving monotherapy. These results suggest inhibition of CSF-1R may prevent post-irradiation recurrence of GBM by blocking the recruitment of tumor-infiltrating monocytes/macrophages.
Citation Format: Jason H. Stafford, Sophia Chernikova, Brian L. West, J. Martin Brown. Inhibiting the CSF-1 receptor on tumor-infiltrating monocytes may enhance the efficacy of radiotherapy for glioblastoma multiforme. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B71. doi:10.1158/1538-7445.CHTME14-B71
Abstract IA04: Cancer-promoting immunity
Authors: Pittet Mikael 
Published: May 2015

Abstract
Tumors often promote the expansion and recruitment of a variety of circulating immune cells. Among them, macrophages can accumulate in large numbers in the tumor stroma and participate actively in cancer growth; however, our understanding of the origins and dynamics of these cells remains not fully explored. By using various modalities, including in vivo imaging, we have started to define where, when and how macrophage precursors are produced and traffic to the tumor stroma. The findings suggest new cancer-induced mechanisms that foster tumor-promoting immunity and identify novel cellular and molecular targets for therapeutic intervention.
Citation Format: Mikael Pittet. Cancer-promoting immunity. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr IA04. doi:10.1158/1538-7445.CHTME14-IA04
Abstract IA15: Overcoming tumor resistance to VEGF blockade by co-targeting ANG2/TIE2 signaling and macrophages
Authors: Palma Michele De 
Published: May 2015

Abstract
Angiopoietin-2 (ANG2/ANGPT2) is a proangiogenic factor that promotes endothelial-cell survival and growth by activating the TIE2 receptor. We and others have shown that ANG2 blockade inhibits tumor angiogenesis and progression in mouse models of cancer. However, it is unclear whether ANG2 may limit tumor sensitivity to vascular-endothelial growth factor (VEGF)-targeted therapies. By employing mouse tumor models that are either sensitive or insensitive to VEGF inhibition, we found that the efficacy of VEGF signalling blockade may be limited by the adaptive upregulation of ANG2 in the resistant tumors. Indeed, combined ANG2/VEGF signaling blockade suppressed tumor angiogenesis and progression in anti-VEGF-resistant tumors, without eliciting increased tumor invasion or metastasis. These findings clearly strengthen the clinical rationale for co-targeting ANG2 and VEGF in tumors that develop resistance to VEGF inhibition. Notably, a minority of the tumors revascularized after VEGF/ANG2 blockade, showing adaptive resistance to the double antiangiogenic treatment. Because we noted an increase of tumor-associated macrophages (TAMs) in association with resistance to dual VEGF/ANG2 blockade, we have explored the opportunity to combine effective antiangiogenic therapy with pharmacological TAM depletion. The results of these studies will be presented at the meeting.
Citation Format: Michele De Palma. Overcoming tumor resistance to VEGF blockade by co-targeting ANG2/TIE2 signaling and macrophages. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr IA15. doi:10.1158/1538-7445.CHTME14-IA15
Abstract A19: Epigenetic drug combination induces genome-wide demethylation and altered gene expression in neuro-ectodermal tumor-derived cell lines
Authors: Noesel Max M. van , Duijkers Floor A M , Menezes Renee X. de , Stumpel Dominique J. P. M. , Admiraal Pieter , Pieters Rob , Meijerink Jules P P 
Published: May 2015

Abstract
Background: Epigenetic alterations are inherent to cancer cells, and epigenetic drugs are currently primarily used to treat hematological malignancies. Pediatric neuro-ectodermal tumors originate from neural crest cells and also exhibit epigenetic alterations involving e.g. apoptotic pathways, which suggests that also these tumors may be sensitive to epigenetic drugs. This notion prompted us to assess molecular and functional effects of low dosage epigenetic drugs in neuro-ectodermal tumor-derived cell lines of pediatric origin.
Results: In 17 neuroblastoma (NBL) and 5 peripheral primitive neuro-ectodermal tumor (PNET) cell lines a combination treatment of 5-aza-2′-deoxycytidine (DAC) and Trichostatin A (TSA) at nanomolar dosages was found to reduce proliferation and to induce wide-spread DNA demethylation, accompanied by major changes in gene expression profiles. Approximately half of the genes that were significantly up-regulated upon treatment exhibited a significant demethylation in their promoter regions. In the NBL cell lines, almost every cellular pathway (193/200) investigated showed expression alterations after treatment, especially a marked up-regulation of genes in the p53 pathway. The combination treatment also resulted in up-regulation of known epigenetically regulated genes such as X-chromosomal genes, tissue-specific genes and a limited number of imprinted genes, as well as known tumor suppressor genes and oncogenes.
Conclusions: Nanomolar dosages of epigenetic drugs have a dramatic impact on the genomes of neuro-ectodermal tumor derived cell lines, including alterations in DNA methylation and concomitant alterations in gene expression.
Citation Format: Max M. van Noesel, Floor A M Duijkers, Renee X. de Menezes, Dominique J. P. M. Stumpel, Pieter Admiraal, Rob Pieters, Jules P P Meijerink. Epigenetic drug combination induces genome-wide demethylation and altered gene expression in neuro-ectodermal tumor-derived cell lines. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A19.
Abstract A33: Exploring pediatric cancer genomics with the UCSC Cancer Genomics Browser
Authors: Cline Melissa , Morozova Olena , Swatloski Teresa , Craft Brian , Goldman Mary , Haussler David , Zhu Jingchun 
Published: May 2015

Abstract
The UCSC Cancer Genomics Browser (https://genome-cancer.ucsc.edu) is a set of web-based tools to display, investigate and analyze cancer genomics data and associated clinical data. Experimental quantities such as gene expression levels, copy number variation and somatic mutations are displayed next to clinical features such as age of onset and cancer subtype. Users can interactively group or sort data by clinical features to dynamically explore how genomic aberrations relate to clinical outcomes. Integrated Kaplan–Meier plots help investigators assess how clinical or genomic values impact long-term survival. The browser currently hosts data from 144 cancer studies including TCGA, CCLE and LINCS. It can display data from multiple studies at once, facilitating cross-cancer comparisons.
We are currently interested in hosting new pediatric cancer datasets, and can offer either public or protected access as appropriate.
Figure 1 illustrates the power of this approach. It compares patterns of somatic mutations in pediatric high-risk neuroblastoma, a cancer of the peripheral nervous system (Pugh, Morozova et al, Nature Genetics 2013) to those in two adult cancers of the central nervous system: lower grade glioma (LGG, TCGA) and glioblastoma multiforme (GBM, TCGA), and contrasts the age of the patient with frequency of mutations in the Alpha Thalassemia/Mental Retardation Syndrome X-linked (ATRX) gene. The data for all three cancers is sorted by the age of the patient, with yellow being the oldest. The age ranges overlap: the oldest neuroblastoma patients are 16, while the youngest LGG and GBM patients are 14 and 21 respectively. While the three cancers show distinct patterns of somatic mutations, all three show frequent mutations in the ATRX gene in older teens or young adults.
This suggests that these cancers may share age-related subtypes with similar genomic signatures. These subtypes may indicate the age-dependent importance of ATRX in the development of both central and peripheral nervous systems, and may ultimately highlight common therapeutic avenues for the two groups of diseases.
This data set can be explored at the UCSC Cancer Genomics Browser at https://genome-cancer.ucsc.edu/proj/site/hgHeatmap/#?bookmark=pc
Citation Format: Melissa Cline, Olena Morozova, Teresa Swatloski, Brian Craft, Mary Goldman, David Haussler, Jingchun Zhu. Exploring pediatric cancer genomics with the UCSC Cancer Genomics Browser. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A33.