bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1313: Anti-tumorigenic effects of phenformin in human endometrial cancer cells
Authors: Jackson Amanda L. , Kilgore Joshua E. , Qiu Haifeng , Zhou Chunxiao , Gehrig Paola A. , Bae-Jump Victoria L. 
Published: May 2015

Abstract
Introduction: The anti-diabetic drugs, metformin and phenformin, are thought to have anti-tumorigenic benefits. Preclinical studies suggest that phenformin may be more potent for inhibiting tumor growth than metformin. Our objective was to assess the anti-tumorigenic effects of phenformin in endometrial cancer (EC) cell lines and primary cultures.
Methods: The EC cell lines, ECC-1 and Ishikawa, were treated with phenformin under low glucose (2 mM), normal glucose (5.5 mM) and high glucose (25 mM) conditions. EC tumors were collected from consenting patients, at the time of surgical staging for primary culture. Cell proliferation was assessed by MTT assay. Apoptosis was analyzed by Annexin V-FITC assay. Cellometer evaluated cell cycle progression. Invasion was demonstrated by transwell invasion assay. Adhesion was assessed by ELISA. Western blotting was performed to determine expression of the downstream targets of phenformin.
Results: Phenformin inhibited proliferation in a dose-dependent manner in both EC cell lines, within 48-72 hrs of exposure (IC50=1 mM, p=0.0004-0.009). Inhibition of proliferation was seen for all glucose concentrations, but greater potency was observed under low glucose conditions. Treatment with phenformin resulted in G1 arrest, induction of apoptosis (p=0.022-0.017) and inhibition of adhesion (p=0.0053-0.0144) and invasion (p=0.0063-0.05). Phenformin increased p21 and p27 and decreased cyclin D, cyclin E2, CDK4 and CDK 6, corresponding with G1 arrest. Phenformin significantly inhibited proliferation in 62% (8/13) of the EC primary cultures, within 48-72 hrs of exposure (IC50 0.1-5mM, p=0.00001-0.016). 3 additional EC samples (23%) were significantly inhibited by phenformin but did not reach an IC50 (p=0.0003-0.018), and 2/13 (15%) had no response to phenformin. Western blot analysis demonstrated that phenformin increased phosphorylation of AMPK and decreased phosphorylation of S6 coincident with inhibition of proliferation in the EC cell lines and primary cultures.
Conclusion: Phenformin potently inhibited cell growth via G1 arrest and induced apoptosis in EC cell lines and the majority of primary cultures. Inhibition of adhesion/invasion was also seen with phenformin. Continued work is needed to explore whether phenformin has superior benefits over metformin.
Citation Format: Amanda L. Jackson, Joshua E. Kilgore, Haifeng Qiu, Chunxiao Zhou, Paola A. Gehrig, Victoria L. Bae-Jump. Anti-tumorigenic effects of phenformin in human endometrial 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 1313. doi:10.1158/1538-7445.AM2014-1313
Abstract 1359: Identification of a novel hypermethylated tumor suppressor gene in human bladder cancer
Authors: Yeh Chia-Ming , Chen Pi-Che , Huang Wen-Yu , Shen Cheng-Huang , Hsu Cheng-Da , Chan Michael W. 
Published: May 2015

Abstract
Bladder cancer is the sixth most common cancer in the world and the incidence is particularly high in southwestern Taiwan. Although bladder cancer patients have a low mortality rate, long term follow-up with repeated cystoscopy is required due to the high recurrence nature of the tumor. Therefore, a non-invasive detection assay is urgently required for bladder cancer patients. Aberrant promoter hypermethylation which is considered as a hallmark of cancer for over a decade, plays an important role in controlling cancer progression. Nevertheless, detection of promoter hypermethylation in bodily fluid has been implicated as a non-invasive and sensitive tool for cancer diagnosis. We aim to identify novel markers that are hypermethylated in bladder cancer. In this regard, by using illumina 27K CpG island methylation array, we identified several novel targets that are hypermethylated in 7 bladder cancer patient samples but not in primary normal human urothelim. Combined bisulfite restriction analysis (COBRA) and bisulphite pyrosequencing confirmed the array result in bladder cancer cell lines. Further, bisulphite pyrosequencing demonstrated that a significantly higher methylation level of those targets in cancer samples with higher histological grade (P &lt; 0.05) and pathological stage (P &lt; 0.05). The potential of non-invasive diagnosis of bladder cancer detection by using the methylation of these targets in voided urine samples is under-way. The tumor suppressive function of these methylated targets in bladder cancer deserves further investigation.
Citation Format: Chia-Ming Yeh, Pi-Che Chen, Wen-Yu Huang, Cheng-Huang Shen, Cheng-Da Hsu, Michael Wy Chan. Identification of a novel hypermethylated tumor suppressor gene in human bladder cancer. [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 1359. doi:10.1158/1538-7445.AM2014-1359
Abstract 1366: Discovery of biomarkers for antitumor drug resistance using 450K methylation data of NCI60
Authors: Nogales Vanesa , Moutinho Catia , Martinez-Cardús Anna , Varma Sudhir , Killian J. Keith , Reinhold William C. , Meltzer Paul S. , Pommier Yves , Esteller Manel 
Published: May 2015

Abstract
The National Cancer Institute Antitumor Cell line panel NCI60 is a very frequently used collection of cancer cell lines that has been largely characterized in different biological aspects. Data from proteomic and RNA expression analyses of this panel is already available to the scientific community. Also, the IC50 data for more than 100,000 different compound treatments is accessible in the developmental therapeutic program of NCI (dtp). However, very little has been explored about the epigenetic component of this panel. We have performed a thorough correlational study combining the available molecular information of NCI60, the data of our 450K NCI60 dataset and the IC50 data from the dtp to discover candidate genes for new biomarkers of resistance to antitumor agents. Finding new biomarkers to determine the most probable response to the therapy seems to be a key stage in the development of personalized medicine. Due to its stability and how easy it is to detect its level of methylation, DNA methylation changes appear to be a perfect candidate mark for the construction of this new generation of biomarkers. In this study we obtained multiples candidate genes whose methylation correlated to resistance to different drugs. In order to perform validation analyses we chose a gene that showed a strong positive correlation with the resistance to several DNA damage agents (DDA).Using overexpression and silencing assays we were able to demonstrate that the expression of this gene has a profound influence on the cell sensitivity to the DDA. Furthermore, through gene expression validation assays, such as 5-azacytidine treatments, we demonstrated that the promotor methylation of this gene is associated to its non-expression. In addition, we observed that this gene methylation correlates with a lower overall survival in an ovarian cancer cohort treated with platinum agents. Little is known about our candidate gene but it seems to be related to the DNA repair machine and also to have a function in the cell cycle control. These features could give an explanation to the importance of its presence in the response to DDA treatment. Our studies show that the analysis of DNA methylation changes in cancer cells in combination with other molecular alterations can be used in correlational studies to find trustworthy biomarkers for antitumor drug resistance.
Citation Format: Vanesa Nogales, Catia Moutinho, Anna Martinez-Cardús, Sudhir Varma, J. Keith Killian, William C. Reinhold, Paul S. Meltzer, Yves Pommier, Manel Esteller. Discovery of biomarkers for antitumor drug resistance using 450K methylation data of NCI60. [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 1366. doi:10.1158/1538-7445.AM2014-1366
Abstract 1400: Extended concurrent gene signatures of ER, HER2 and disease-free survival in breast cancers
Authors: Huang Chi-Cheng , Tu Shih-Hsin , Huang Ching-Shui , Lien Heng-Hui , Lai Liang-Chuan , Chuang Eric Y. 
Published: May 2015

Abstract
Our recent work had identified concurrent gene signatures which highlighted the interplay between copy number variation (CNV) and differential gene expression (GE) for Han Chinese breast cancers. The merit of the approach is the discovery of biomarkers not readily identified by conventional GE only data, for which phenotype-correlation or gene variability is the criteria of gene selection.
A total of 31 array CGH and 83 GE arrays (29 samples with data from both platforms) were performed. Potential targets of cancer therapy were revealed by Genomic Identification of Significant Targets in Cancer (GISTIC) from 31 array CGH. We used these concurrent genes as well as genes with significant GISTIC scores to derive signatures associated with clinical ER, HER2 status, and disease-free survival.
The most common gain regions were 1q21.2 and 17q12-q21.1 while the most common lost region was 22q11.23. In subgroup analysis, recurrent gains for ER positive cancers were 8p23.1, and 8p11.23-11.21. For HER2 overexpressing tumors, recurrent gain was 17q12-21.1 and recurrent losses were 8p11.22, 8p12, and 8p23.1. We identified 1,584 concurrent genes from 29 samples assayed for both array CGH and GE microarrays, and enriched concurrent gene sets for ER, HER2 and disease-free survival were identified independently from our 83 GE arrays (GSE48391) and two series with Han Chinese origin (GSE5460 and GSE20685) as well as three studies of Western countries (GSE7390, GSE2034 and GSE3494). Signature genes were consensus genes from leading edge analysis across all studies, and we used supervised partial least square (PLS) regression to derived predictive model of clinical ER, HER2 and disease-free survival with each signature gene further weighted by the coefficient of concurrence as an additive tuning parameter. The predictive accuracy was 92.3% for ER and 84.6% for HER2 in 208 Han Chinese breast cancers and was 87.3% for ER in 735 breast cancers in Western countries. For five studies with disease-free survival data (no survival data for GSE5460), prognostic discrepancy was observed in four studies except GSE3493 between high-risk and low-risk patients predicted with the concurrent signature.
We conclude that parallel analysis of CGH and microarray data, in conjunction with known gene expression patterns, can be used to identify biomarkers with prognostic values in breast cancer.
Citation Format: Chi-Cheng Huang, Shih-Hsin Tu, Ching-Shui Huang, Heng-Hui Lien, Liang-Chuan Lai, Eric Y. Chuang. Extended concurrent gene signatures of ER, HER2 and disease-free survival in breast cancers. [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 1400. doi:10.1158/1538-7445.AM2014-1400
Abstract 1420: RRx-001 inhibits glucose erythrocyte and tumor glucose 6-phosphate dehydrogenase
Authors: Cabrales Pedro , Oronsky Bryan , Scicinski Jan 
Published: May 2015

Abstract
Cancer cells are characterized by an excess of reactive oxygen species (ROS) levels, which are balanced by high levels of glutathione (GSH) to protect against ROS-induced cytotoxicity. Glucose 6-phosphate dehydrogenase (G6PD), the first key enzyme of the pentose phosphate pathway (PPP), ensures NADPH supply for reduced glutathione regeneration. RRx-001, a novel redox active anticancer agent, derived from the aerospace industry, which has successfully completed a Phase 1 clinical trial and is scheduled to begin multiple Phase 2 studies, induces cell cycle-specific apoptosis through increase in intracellular ROS leading to free thiol depletion.
The purpose of the present study was to evaluate whether the mechanism by which RRx-001 targets the antioxidant capacity of tumor cells is related to G6PD inhibition. Since red blood cells (RBC) are particularly dependent on G6PD synthesis, we initially explored the effects of RRx-001 on the erythrocytic PPP.
Glucose consumption was higher for human RBC (hRBC) treated with RRx-001 (10 μM) compared to untreated cells. PPP was inhibited in RRx-001 treated hRBC. Methylene blue, which normally stimulates PPP flux, did not increase glucose utilization of treated cells. Analysis of PPP flux revealed that RRx-001 inhibits G6PD preventing conversion of glucose-6-phosphate to 6-phosphogluconolactone and reduction of NADP(+). Compared to G6PD inhibitors dehydroepiandrosterone and aminonicotinamide, RRx-001 was 10 fold more potent.
Given the critical importance of G6PD and NADPH to fuel both the proliferation of tumor cells and to detoxify ROS, we secondarily investigated whether RRx-001 has anti-proliferative and viability effects on hepatocellular carcinoma (Hep G2) and colorectal adenocarcinoma (Caco-2 and HT-29) cell lines. Through tetrazolium and bromodeoxyuridine incorporation assays, performed as indicators of cellular proliferation, RRx-001 inhibited cell growth in a dose dependent (1 - 20 μM) manner. The suppression of growth of the RRx-001 incubated cells was correlated with inhibition of G6PD (r=0.81, n=9, P&lt;0.05). RRx-001 also reduced viability of all carcinoma cell lines. Given the key roles of the PPP in GSH metabolism, and the observation that cell lines overexpressing G6PD are associated with the formation of tumors in mice, inhibition of G6PD by RRx-001 is an attractive target, particularly in combination with standard of care radiotherapy or cytotoxic drugs that also generate ROS or free radical intermediates either directly or indirectly.
Citation Format: Pedro Cabrales, Bryan Oronsky, Jan Scicinski. RRx-001 inhibits glucose erythrocyte and tumor glucose 6-phosphate dehydrogenase. [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 1420. doi:10.1158/1538-7445.AM2014-1420
Abstract 158: Sustained adrenergic signaling activates pro-inflammatory networks in ovarian carcinoma
Authors: Nagaraja Archana S. , Armaiz-Pena Guillermo , Allen Julie , Sadaoui Nouara C. , Zand Behrouz , Yang Peiying , Tan Lin , Cole Steve , Lutgendorf Susan , Sood Anil K. 
Published: May 2015

Abstract
Purpose: To determine the role of adrenergic activation in driving tumor inflammation through COX-2/Prostaglandin E2 (PGE2) axis as PGE2 is known to play an important role in the induction of a pro-inflammatory signature in the tumor microenvironment that promotes tumor growth and metastasis.
Methods We first analyzed global metabolic changes in tumors isolated from patients with known Center for Epidemiologic Studies Depression Scale (CES-D; depressive) scores and tumoral norepinephrine (NE) levels. Beta-adrenergic receptor (ADRB) positive cells (Skov3 and HeyA8) were used to study mechanism at gene and protein levels of PTGS2 (cyclooxygenase2), PTGES (prostaglandin E synthase) and metabolite levels (all prostaglandins, PGs) in vitro and in vivo.
Results Our results revealed that levels of PGs were significantly increased in patients with high CESD scores (&gt;16). PGE2 was upregulated by 2.38 fold when compared to the low CES-D scores. A similar trend was also observed with other pro-inflammatory eicosanoids, such as 6-keto prostaglandin F1 Alpha (2.03), prostaglandin A2 (1.39) and prostaglandin E1 (1.39). Exposure to NE resulted in increased PTGS2 and PTGES (prostaglandin E2 synthase) gene expression in adrenergic receptor positive cell lines. Mass-spectroscopy analyses confirmed that upon treatment with NE and arachidonic acid (substrate), PGE2 levels were increased in conditioned medium from Skov3 cells. Treatment with a broad ADRB agonist (isoproterenol) or ADRB2 specific agonist (terbutaline) led to increases in expression of PTGS2 and PTGES. Conversely, treatment with a broad antagonist (propranolol) or an ADRB2 specific antagonist (butoxamine) in the presence of NE abrogated gene expression changes of PTGS2 and PTGES. Silencing PTGS2 resulted in significantly decreased migration (40%) and invasion (25%) of Skov3 and HeyA8 cells in the presence of NE. Importantly, silencing PTGS2 in a restraint stress orthotropic model decreased tumor burden by 70% and metastasis (tumor confined to the ovary) in Skov3-ip1 orthotopic mouse model as compared to control siRNA with restraint stress.
Conclusion Increased adrenergic stimulation results in a pro-inflammatory milieu that drives tumor progression and metastasis.
Citation Format: Archana S. Nagaraja, Guillermo Armaiz-Pena, Julie Allen, Nouara C. Sadaoui, Behrouz Zand, Peiying Yang, Lin Tan, Steve Cole, Susan Lutgendorf, Anil K. Sood. Sustained adrenergic signaling activates pro-inflammatory networks in ovarian carcinoma. [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 158. doi:10.1158/1538-7445.AM2014-158
Abstract 1968: Breast cancer cells escape from chemotherapy and hypoxia by distinct mechanisms
Authors: O'Brien Siobhan , Chen Liang , Zhong Wenyan , Armellino Douglas , Follettie Maximillian , Damelin Marc 
Published: May 2015

Abstract
Cancer relapse following treatment remains a significant barrier to achieving cures for many patients. An emerging framework for addressing this problem focuses on cancer stem cells (CSCs). Clinical and preclinical data suggest that CSCs survive chemotherapy and antiangiogenic therapy. In breast cancer, CSCs are marked by the cell surface expression of CD44, the major receptor for hyaluronic acid. The SKBR3 cell line was previously shown to be a clinically relevant model of breast CSCs in vivo, and we have further developed this model to enable mechanistic studies of tumor relapse in vitro. We found that chemotherapy and hypoxia both enriched for CD44hi populations in SKBR3, but surprisingly, the populations were phenotypically distinct. CD44hi cells from chemotherapy but not hypoxia exhibited increased tumor cell growth and increased sensitivity to the CSC-specific inhibitor salinomycin, compared to CD44lo cells. To examine these CD44hi and CD44lo populations further, we performed transcriptional profiling with sorted cells. We found that the growth factor TGF beta-2 was upregulated in chemotherapy-treated CD44hi cells and also enhanced the growth of these cells, which suggests that TGF beta-2 autocrine/paracrine signaling can promote the growth of surviving cells. We also observed an increase in xCT (SLC7A11) expression upon chemotherapy treatment and identified the CD44v8-10 variant expressed in the CD44hi SKBR3. CD44v could therefore stabilize xCT and promote survival by lowering intracellular reactive oxygen species (ROS). We have also established a functional role for CD44 in SKBR3 cell growth: CD44 knockdown prevented colony formation, and conversely the CD44 ligand hyaluronic acid enhanced colony formation. These findings indicate that CD44 not only marks CSC populations that arise in response to chemotherapy but also functions in their survival. Our work suggests that mechanisms of tumor relapse vary based on the particular therapy, and defining these mechanisms will allow for the development of novel therapeutic strategies to enable long-term responses in the clinic.
Citation Format: Siobhan O'Brien, Liang Chen, Wenyan Zhong, Douglas Armellino, Maximillian Follettie, Marc Damelin. Breast cancer cells escape from chemotherapy and hypoxia by distinct mechanisms. [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 1968. doi:10.1158/1538-7445.AM2014-1968
Abstract 2008: CUL7 promotes non-small cell lung cancer cells migration and invasion
Authors: Song Qiong , Wang Lihui , Lu Yi , Zhang Jian , Fu Jiejun 
Published: May 2015

Abstract
Cullin7 (CUL7) is a scaffold protein of the CUL7 E3 ubiquitin ligase containing Fbxw8, Skp1 and ROC1. Germ line mutations of the CUL7 are linked to 3-M syndrome and Yakuts short stature syndrome, both of which are characterized by growth retardation and few bone abnormalities. We have previously shown that CUL7 promotes trophoblast cells migration and invasion. However, the role of CUL7 on cancer invasion and metastasis remains unknown. It has been reported that CUL7 mRNA is overexpressed in non-small cell lung cancer (NSCLC). In this study, we investigated the effects of CUL7 on NSCLC cells migration and invasion. Firstly, we evaluated CUL7 expression on tissue microarray slides by immunohistochemical staining. We found that CUL7 significantly overexpressed in NSCLC and its expression was associated with advanced TNM stage, nodal or bone metastasis and poor overall survival. Next, we determined CUL7, CUL1 and Fbxw8 expression in different NSCLC cell lines by real-time PCR and western blot. Higher level of CUL7 was observed in H1299, H358, H1437, and H1792 cells which derived from metastatic sites compared to H460 and human bronchial epithelial cells (BEAS2B). Knockdown CUL7 expression in NSCLC cells decreased cell motility and invasive ability using wound healing and matrigel invasion assay. Real-time PCR revealed that knockdown of CUL7 significantly decreased expression of CCL2, IL-6 and CXCL16. However, the expression of uPA, MMP-2 and MMP-9 were not changed. Furthermore, Knockdown of CUL7 in NSCLC cells decreased secretion of CCL2, CXCL16 and IL-6. This study indicates that CUL7 may be a potential biomarker as well as a novel therapeutic target in NSCLC progression. Supported by National Natural Sciences Foundation (NSFC) projects (81201669, 81171993 and 81272415); NSFC key project (81130046).
Note: This abstract was not presented at the meeting.
Citation Format: Qiong Song, Lihui Wang, Yi Lu, Jian Zhang, Jiejun Fu. CUL7 promotes non-small cell lung cancer cells migration and invasion. [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 2008. doi:10.1158/1538-7445.AM2014-2008