bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2997: Vessel co-option in colorectal cancer liver metastases mediates resistance to VEGF-targeted therapy
Authors: Frentzas Sophia , Thompson Victoria L. , Vermeulen Peter B. , Foo Shane , Brown Gina , Cunningham David , Reynolds Andrew R. 
Published: May 2015

Abstract
The purpose of this study is to: (1) examine whether vessel co-option is associated with a lack of response to anti-angiogenic therapy in advanced colorectal cancer patients, (2) identify whether inhibition of pathways associated with vessel co-option sensitizes to anti-angiogenic therapy in vivo.
Sprouting angiogenesis is the process whereby new blood vessels are induced to sprout from existing vessels. The growth of metastatic tumors is considered to require sprouting angiogenesis. This hypothesis has driven the development and clinical application of vascular endothelial growth factor (VEGF) targeted agents, such as bevacizumab. However, responses to such agents in cancer patients, including metastatic colorectal cancer (CRC), are variable. It is not currently clear why this is the case and we have no way of selecting patients suitable for such therapies.
Importantly, it is now evident that tumors can also utilize a number of putative ‘VEGF-independent’ angiogenesis mechanisms, the existence of which may limit the efficacy of VEGF-targeted therapy. One such mechanism is ‘vessel co-option,’ whereby tumors engulf existing local blood vessels as they invade into surrounding host tissue. Published studies have reported that this mechanism occurs in ∼28-30% of CRC liver metastases.
Here we present data from a retrospective study of patients with CRC liver metatases that were treated with bevacizumab. We demonstrate that, in this patient cohort, the presence of vessel co-option in liver metastases was strongly associated with lack of response to bevacizumab. We also show that a similar result is observed in a mouse model of colorectal cancer liver metastasis. Interestingly, when we disable actin nucleation activity in colorectal cancer cells, vessel co-option is compromised and sensitivity to VEGF-targeted therapy is restored in vivo. These data demonstrate a potential role for vessel co-option as a negative predictive biomarker for anti-angiogenic therapy and also have consequences for the development of novel therapies for targeting tumor angiogenesis.
Citation Format: Sophia Frentzas, Victoria L. Thompson, Peter B. Vermeulen, Shane Foo, Gina Brown, David Cunningham, Andrew R. Reynolds. Vessel co-option in colorectal cancer liver metastases mediates resistance to VEGF-targeted therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2997. doi:10.1158/1538-7445.AM2014-2997
Abstract 300: Expression profiling of miRNA in asbestos-related lung adenocarcinoma
Authors: Mahmut Yasen , Ninomiya Hironori , Motoi Noriko , Itoh Satoru , Fujiwara Mutsunori , Ishikawa Yuichi 
Published: May 2015

Abstract
Lung cancer has the highest mortality rate of all of the cancers in the world and asbestos-related lung cancer is one of the leading occupational cancers. The identification of asbestos-related molecular changes has long been a topic of increasing research interest. Microarray technology is a powerful high-throughput tool capable of monitoring the expression of thousands of small noncoding RNAs at once within tens of samples processed in parallel in a single experiment. The aim of this study was to construct a genome-wide expression profile of miRNA of asbestos-related lung cancers, and was to identify novel asbestos-related molecular biomarkers. The miRNA profiling was performed on 31 patients (13 patients with asbestos-exposed and 18 patients with non- asbestos-exposed) undergoing lung resection for primary adenocarcinoma, both fresh and FFPE materials of whom were available. Data analyses on miRNA expression revealed four novel asbestos-related miRNAs (three over-expressed miR-210, miR-200a, miR-429, and one under-expressed miR-140-3p). Also, 16 target genes, expression of which were inversely correlated, were identified. Among them we obtained a set of miRNAs that were involved in hypoxia-regulated and oxidative stress responders, seemingly related to asbestos burden. For example, miR-210 is involved in a wide-range of processes, including cell proliferation, migration, apoptosis, differentiation, DNA repair and cell metabolism, and more recently in the regulation of antitumor immune responses, suggesting roles of this miRNA as a central master regulator of the hypoxic response. According to gene ontology analyses of the target genes were mostly transcription factors, cyclins and cyclin-dependent kinases. For validation, we compared the expression levels of miRNA between fresh and FFPE materials, resulting in good correlations (R=0.76-0.90). The miRNAs/genes presented here may be interesting targets for further investigation and could eventually have potential diagnostic implications.
Citation Format: Yasen Mahmut, Hironori Ninomiya, Noriko Motoi, Satoru Itoh, Mutsunori Fujiwara, Yuichi Ishikawa. Expression profiling of miRNA in asbestos-related lung adenocarcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 300. doi:10.1158/1538-7445.AM2014-300
Abstract 3006: Serum insulin growth factor/insulin growth factor receptor1 (IGF-I, IGF-I-1R) and VEGF-A as prognostic factors and surrogate biomarkers in triple negative breast cancer patients (TNBC)
Authors: Zekri Abdel-Rahman N. , Bahnassy Abeer 
Published: May 2015

Abstract
Background: We evaluated the prognostic and predictive values of serum IGF-I, IGF-I-1R, VEGF and TGF-β1 in triple-negative and non-triple-negative breast cancer (TNBC&NTNBC) patients through correlation with standard prognostic factors and survival.
Methods: serum expression of VEGF-A, TGF-β1, IGF-I and IGF-I-1R proteins was measured in of 43 TNBC, 53 NTNBC and 20 normal control (NC) by quantitative enzyme linked immune-sorbant assay (ELISA). Results were correlated to patients’ characteristics, disease free and overall survival (DFS&OS).
Results: The cutoff points that discriminate between TNBC and NTNBC were: 10.09 ng/ml, 412.54 pg/ml and 106.96 ng/ml for IGF-I-1R, VEGF-A, and IGF-I. VEGF, IGF-I and IGF-I-1R differed significantly between groups (p &lt;0.001) whereas TGF-β1 differed significantly between NC and the other groups (p&lt;0.001). TNBC was associated with positive lymph nodes (p&lt;0.001), relapse and metastasis (p&lt;0.001). Response rate (RR) was significantly lower in TNBC patients (p&lt;0.001) with high serum VEGF-A, IGF-I-I/IGF-I-IR (p= 0.004, 0.001/0.003). Reduced DFS associated with high tumor grade, high VEGF-A (p&lt;0.001), high IGF-I/ IGF-I-IR (P&lt;0.001/ p&lt;0.001). Reduced OS associated with relapse (p&lt;0.001), high VEGF-A (p=0.001) and high IGF-I/ IGF-I-IR (p= 0.012/p= 0.02). in multivariate analysis positive nodes (P&lt; 0.001), high VEGF-A (P = 0.02) and IGF-I/ IGF-I-1R (P= 0.03, P= 0.01) were independent factor for disease recurrence.
Conclusions: TNBC represents an aggressive subset of breast tumors. IGF-I, IGF-I-IR, VEGF-A could be used as surrogate biomarkers for TNBC, as prognostic marker since their expression level correlates with reduced OS and high incidence of relapse. They also represent promising candidates for targeted therapy in TNBC patients.
Citation Format: Abdel-Rahman N. Zekri, Abeer Bahnassy. Serum insulin growth factor/insulin growth factor receptor1 (IGF-I, IGF-I-1R) and VEGF-A as prognostic factors and surrogate biomarkers in triple negative breast cancer patients (TNBC). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3006. doi:10.1158/1538-7445.AM2014-3006
Abstract 3024: Cancer stem-like cells in ovarian clear cell carcinoma are enriched in ALDH-high population associated with the accelerated scavenging system of reactive oxygen species
Authors: Mizuno Tomoko , Suzuki Noriko , Mori Minako , Makino Hiroshi , Furui Tatsuro , Ito Naoki , Yamamoto Akio , Morishige Kennichiro 
Published: May 2015

Abstract
In ovarian cancer cases, disease recurrence after chemotherapy is frequently observed, suggesting ovarian cancer stem-like cells (CSCs) are involved. Ovarian clear cell carcinoma is especially chemo-resistant among epithelial ovarian cancer subtypes. We first, examined the CSC markers (CD133,CD44, ALDH1) using the ovarian clear cell carcinoma tissues (n=81). Immunohistochemical staining revealed that high ALDH1 expression levels are related to advanced stage in clear cell carcinoma cases. Other makers are not related to clinical staging and prognosis. Clear cellcarcinoma cells (KOC-7C) are separated to ALDH-high and ALDH-low population by ALDEFLUOR assay and fluorescence-activated cell sorting. ALDH-high cells showed more quiescent character (G0/G1 phase) than ALDH-low cells. Recent studies have suggested that CSCs might have a high antioxidant capacity to keep cellular reactive oxygen species (ROS) at a low level that allows them to survive adverse conditions. We examined the cellular ROS level using Cell-ROX assay. ALDH-high cells contained the lower levels of ROS than ALDH-low cells. Also, ALDH-high cells showed an increased expression of in nuclear factor-E2-related factor 2 (Nrf2), a key transcriptional factor of the antioxidant system, associated with the increased antioxidant enzymes (SOD2, HO-1). Thus, ALDH-positive CSCs might have increased Nrf2-induced antioxidant scavengers, which lower ROS level relevant to chemo-resistance in ovarian clear cell carcinoma.
Citation Format: Tomoko Mizuno, Noriko Suzuki, Minako Mori, Hiroshi Makino, Tatsuro Furui, Naoki Ito, Akio Yamamoto, Kennichiro Morishige. Cancer stem-like cells in ovarian clear cell carcinoma are enriched in ALDH-high population associated with the accelerated scavenging system of reactive oxygen species. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3024. doi:10.1158/1538-7445.AM2014-3024
Abstract 3039: The MELK/FOXM1 axis is a master regulator of proneural to mesenchymal transition (PMT) in glioma stem cells by controlling EZH2 transcriptional activity
Authors: Joshi Kaushal , Kim Sunghak , Lee Jeongwu , Waclaw Ronald , Salcini Lisa , Nakano Ichiro 
Published: May 2015

Abstract
In the Central Nervous System, stem cells are present in the normal brain and primary brain tumor, glioblasotoma multiforme (GBM). Both normal and oncogenic stem cells play central roles in organogenesis and tumorigenesis, respectively. Previously we identified that the mitotic kinase MELK binds and phosphorylates the oncogenic transcription factor FOXM1 to regulate the growth of both brain-derived and GBM-derived stem cells (GSCs). Here we demonstrate that the Enhancer of Zeste Homolog 2 (EZH2), the lysine methyltransferase of Polycomb repressive complex 2, is the major transcriptional target of the MELK-FOXM1 complex in GSCs. PCR-based analysis of FOXM1 immunoprecipitated chromatin determined the binding of FOXM1 to the EZH2 promoter region to drive its transcriptional activity. This signaling is mediated through the protein complex formation of FOXM1 and MELK in a MELK kinase-dependent manner. The MELK-FOXM1 driven EZH2 signals are required to retain the immature stem cell trait and mesenchymal identity in GBM, as well as GSCs' radiation resistant phenotype in a MELK kinase-dependent manner. Clinically, GBM tumors co-express MELK and EZH2 with significant elevation in post-irradiation recurrent tumors. This post-irradiation elevation of MELK and EZH2 was observed specifically in GSCs. Irradiation induces transformation of proneural (PN) GSCs into a Mesenchymal (Mes)-like GSC phenotype (PMT) that is highly resistant to radiation treatment, and inhibition of EZH2 by shRNA reverses the radiation-resistant phenotype of Mes GSCs. Elimination of MELK or FOXM1 by shRNA reduced EZH2 expression resulting in attenuated stemness and radiation resistance in vitro and in vivo. These phenotypes were completely restored by exogenous expression of EZH2. To our knowledge, this study provides the first evidence of the role of MELK-FOXM1-EZH2 signaling axis for maintenance of stem cell trait and PMT regulation in GSCs. Identification of the role of transcriptional regulator EZH2 in PMT by the mitotic kinase MELK and transcription factor FOXM1 complex sheds lights on a novel therapeutic target for aggressive cancers including GBM.
Citation Format: Kaushal Joshi, Sunghak Kim, Jeongwu Lee, Ronald Waclaw, Lisa Salcini, Ichiro Nakano. The MELK/FOXM1 axis is a master regulator of proneural to mesenchymal transition (PMT) in glioma stem cells by controlling EZH2 transcriptional activity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3039. doi:10.1158/1538-7445.AM2014-3039
Abstract 3052: Genomic, transcriptomic, and epigenomic analyses of gastric cancer stem cells
Authors: Kim Seon-Young , Baek Su-Jin , Han Myoung-Eun , Kim Hee-Jin , Kim Jeong-Hwan , Oh Sae-Ock 
Published: May 2015

Abstract
Cancer stem cells are a small population of tumor cells with self-renewal and differentiation capacity, and have been isolated from many types of cancers including stomach. However, the molecular mechanisms underlying the self-renewal and tumorigenic potential of cancer stem cells are poorly understood. To understand the molecular characteristics of gastric cancer stem cells (GCSC), we performed five kinds of experiments including genomic (Exome-seq and Affymetrix SNP 6.0 array), transcriptomic (RNA-seq and small RNA-seq), and epigenomic (MBD-seq) analyses on GCSC, non-gastric cancer stem cells (non-GCSC), and normal tissues from three gastric cancer patients. Among the five data sets, miRNA changes were most significant between GCSC and non-GCSC showing that 39.4% of miRNAs were down-regulated and 1.25% of miRNAs were up-regulated in GCSC compared with non-GCSC. In RNA-seq, 217 (0.93%) genes were up-regulated while 470 (2.02%) genes were down-regulated. Gene-set analysis revealed that development-associated biological processes such as epidermis development and ectoderm development were most enriched terms. In MBD-seq, there were 2.80% of hypermethylated and 2.38% of hypomethylated genes in GCSC compared with non-GCSC. Detailed lists of genes, gene-sets and biological pathways that distinguish GCSC from non-GCSC will be presented and discussed.
Citation Format: Seon-Young Kim, Su-Jin Baek, Myoung-Eun Han, Hee-Jin Kim, Jeong-Hwan Kim, Sae-Ock Oh. Genomic, transcriptomic, and epigenomic analyses of gastric cancer stem cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3052. doi:10.1158/1538-7445.AM2014-3052
Abstract 3070: Capture, isolation, and mutational analysis of single pancreatic circulating tumor cells using NanoVelcro technology
Authors: Ankeny Jacob S. , Hou Shuang , Lin Millicent , Frias Matthew , OuYang Hank , Song Min , Rochefort Matthew M. , Girgis Mark D. , Tseng Hsian-Rong , Tomlinson James S. 
Published: May 2015

Abstract
Introduction: Circulating tumor cells (CTCs) have been developed as a biomarker in several cancers, but not in pancreatic cancer (PDAC). The available clinical technology for CTC study, CellSearch, suffers from limited ability to perform molecular analysis. We sought to evaluate a novel microfluidic NanoVelcro technology coupled to laser micro-dissection (LMD), for CTC capture and single cell analysis of KRAS mutations to confirm tumor origin of captured CTCs.
Methods: NanoVelcro utilizes a nano-spun polymer fiber, modified with streptavidin, to capture CTCs using biotinylated antibodies. The system was optimized with the CFPAC-1 (EpCAM+, KRAS G12 to V) cell line spiked into healthy donor blood. Patient samples were collected from 2 mL peripheral venous blood and run at the optimized flow rate of 1mL/hr. CTCs were defined by size (≥ 10 µm) and immuno-staining pattern (DAPI+/CK+/CD45-). Using LMD, single cells were isolated and subjected to whole genome amplification followed by PCR of KRAS exon 1 and subsequent Sanger Sequencing.
Results: The NanoVelcro system allowed for detection of mutant KRAS in isolated CFPAC-1 cells. 6 CTCs were then isolated from a known KRAS G12 to V mutant patient and 3/6 (50.0%) captured CTCs were found to have KRAS G12 to V mutations while normal WBCs from the same patient contained wild-type KRAS.
Conclusions: The microfluidic NanoVelcro technology demonstrated capture of pancreatic CTCs and may prove useful in the development of CTCs as a biomarker in PDAC. Application of LMD enabled single cell KRAS mutational analysis confirming cancer origin of isolated CTCs and supporting our current PDAC CTC identification criteria based on immuno-staining. This promising technology, combined with LMD, opens the door for molecular characterization of CTCs, thus providing insight into the biology of metastasis while potentially revealing molecular targets for therapeutics.
Citation Format: Jacob S. Ankeny, Shuang Hou, Millicent Lin, Matthew Frias, Hank OuYang, Min Song, Matthew M. Rochefort, Mark D. Girgis, Hsian-Rong Tseng, James S. Tomlinson. Capture, isolation, and mutational analysis of single pancreatic circulating tumor cells using NanoVelcro technology. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3070. doi:10.1158/1538-7445.AM2014-3070
Abstract 3940: Activation of HER2 changes the cetuximab sensitivity in radioresisitant head and neck cancer cells
Authors: Park Jung J. , Kim Sang Yoon , Seo Ji Hyun , Chang Hyo Won , Khalmuratova Roza , Carey Thomas E. , Kim Jin Pyeong , Woo Seung Hoon 
Published: May 2015

Abstract
Background: For patients with recurrent head and neck cancer after radiation therapy (RT), there are limited therapeutic selections. There is great interest in mechanisms of resistance to RT. To investigate these mechanisms, we established RT-resistant clones from head and neck squamous cell carcinoma (HNSCC) cells.
Methods: To develop cell lines with acquired resistance to RT, we utilized the human HNSCC cell line AMC-HN3 and UDSCC-2. We irradiatied clinically relevant cumulative irradiation to cell lines and characterized for the molecular changes in the radioresistant lines relative to the parent cell lines.
Results: A comparative analysis revealed that acquired resistance to RT was associated consistently with the overexpression of HER2 and cross-resistance to cetuximab. To examine the role of HER2, we knocked down HER2 in both radio-resistant and -sensitive parental cells and found an increase in sensitivity to cetuximab. Conversely, inhibition of HER2 in RT-resistant cells was sufficient in resensitizing them to cetuximab in vitro. Further studies indicated that HER2 may diminish sensitivity to cetuximab via activation of the phosphatidyl-inositol-3-kinase (PI3K)/AKT pathway.
Conclusion: Taken together, these findings suggest a central role of HER2 in the development of acquired resistance to RT and prompt consideration to apply HER2 inhibition strategies in future clinical trials of recurrent HNSCC after RT.
Citation Format: Jung Je Park, Sang Yoon Kim, Ji Hyun Seo, Hyo Won Chang, Roza Khalmuratova, Thomas E. Carey, Jin Pyeong Kim, Seung Hoon Woo. Activation of HER2 changes the cetuximab sensitivity in radioresisitant head and neck cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3940. doi:10.1158/1538-7445.AM2014-3940
Abstract 3946: Wnt/ß-catenin signaling mediates resistance of colorectal cancer cells to chemoradiotherapy
Authors: Emons Georg , Spitzner Melanie , Reineke Sebastian , Möller Janneke , Kendziorra Emil , Beissbarth Tim , Rave-Fraenk Margret , Gaedcke Jochen , Ried Thomas , Ghadimi Michael , Grade Marian 
Published: May 2015

Abstract
Background: Preoperative chemoradiotherapy represents the standard treatment for patients with rectal cancer. However, the clinical response of individual tumors to multimodal treatment is not uniform, and ranges from complete response to complete resistance. Therefore, the identification of novel therapeutic targets whose modification could be harnessed to sensitize a priori resistant tumors is exceedingly important. In this context, we have previously demonstrated that the Wnt transcription factor TCF4 was over-expressed in rectal cancers that were resistant to chemoradiotherapy. The aim of this study was to explore the functional relevance of TCF4 and Wnt/β-catenin signaling for mediating treatment resistance.
Methods: Colorectal cancer cell lines SW837, SW480, and HT-29 were transfected with shRNAs targeting TCF4. After establishing stable single-cell clone (SCC) populations, selected clones were irradiated at 0, 1, 2, 4, 6 and 8 Gy of X-rays. To assess the putative Wnt/β-catenin dependency, β-catenin was inhibited in cancer cell lines using siRNAs, the tankyrase inhibitors XAV939 / JW55 and the porcupine inhibitor LGK 974. Furthermore Wnt/β-catenin signaling activity was stimulated in normal retinal pigment epithelial (RPE) cells through incubation with Wnt3a.
Results: RNAi-mediated silencing of TCF4 led to a significant radiosensitization in SW837 and SW480, two cell lines with a high basal TCF4-activity, whereas no effect was observed in HT-29 a cell line with low activity. Inhibition of β-catenin similarly caused a pronounced sensitization of CRC cells to clinically relevant doses of X-rays. Finally, exogenous stimulation of canonical Wnt signaling with Wnt3a resulted in a significantly decreased sensitivity of RPE cells to radiotherapy, i.e. induced radioresistance.
Conclusion: We have uncovered a novel role of Wnt/β-catenin signaling in mediating resistance to chemoradiotherapy. Moreover, these data suggest that targeting key components of this pathway may represent a potential therapeutic strategy to increase the proportion of patients that respond to chemoradiotherapy, with considerable clinical implications.
Citation Format: Georg Emons, Melanie Spitzner, Sebastian Reineke, Janneke Möller, Emil Kendziorra, Tim Beissbarth, Margret Rave-Fraenk, Jochen Gaedcke, Thomas Ried, Michael Ghadimi, Marian Grade. Wnt/ß-catenin signaling mediates resistance of colorectal cancer cells to chemoradiotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3946. doi:10.1158/1538-7445.AM2014-3946