bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4794: NANOG represses mitochondrial energy production and promotes fatty acid synthesis to promote self-renewal in tumor-initiating cells
Authors: Chen Chia-Lin , Punj Vasu , Sher Linda , Petrovic Lydia , Machida Keigo 
Published: May 2015

Abstract
Stem cell markers such as Nanog have been implicated in various cancer, but whether they are functionally contributing to cancer pathogenesis has remained unclear. We previously reported that Toll-like receptor 4 (TLR4) signaling regulated NANOG expression in liver cancers (Chen et al., J. Clin. Inv., 2013). Here, we determined novel targets of NANOG in CD133+CD49f+ tumor-initiating cells (TICs) from patient and mouse models of hepatocellular carcinoma (HCC) using genome-wide NANOG-binding site analysis (ChIP-seq). Silencing NANOG inhibits tumor development in HCC mouse models and genesis of TICs as alcohol/obesity-associated increase of serum bacterial products activates TLR4 signaling. To determine novel targets of NANOG in TICs isolated from several HCC models, ChIP-seq in TICs was performed. NANOG binds genes of oxidative phosphorylation and β-oxidation in mitochondria. Silencing NANOG promotes oxidative phosphorylation and β-oxidation, indicating that NANOG is a suppressor of mitochondria-mediated energy production. We identified the TLR4-NANOG oncogenic pathway in the genesis of TICs and liver tumor in HCC mouse models, including alcohol/high-fat-diet-fed hepatitis C virus (HCV) transgenic mice, DEN/phenobarbtal-treated and Spnb2+/- mice. We identified the stimulation of TLR4 transactivates Nanog through E2F1 phosphorylation at serine residues 332/336 and generates TICs, leading to development of liver tumors. Metabolomic analysis demonstrates metabolic reprogramming in TICs through NANOG. Reduction of NANOG expression resulted in an improved cellular energy balance, including reduction of the glycolysis pathway, increased fatty acid consumption and greater uptake of amino acids. The improved energy status is linked to a shift away from glycolysis and a greater reliance on fatty acid β-oxidation and amino acid anaplerosis. Taken together, these results suggest that NANOG-mediated metabolic reprogramming through suppression of mitochondria function in both experimental and clinical HCC downstream of TLR4/NANOG generates TICs and drives liver tumorigenesis.
Citation Format: Chia-Lin Chen, Vasu Punj, Linda Sher, Lydia Petrovic, Keigo Machida. NANOG represses mitochondrial energy production and promotes fatty acid synthesis to promote self-renewal in tumor-initiating 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 4794. doi:10.1158/1538-7445.AM2014-4794
Abstract 4795: CCK2R marks gastric antral stem cell and mediates antral carcinogenesis
Authors: Yoku Hayakawa , Jin Guanchun , Wang Hongshan , Chen Xiaowei , Westphalen Christoph B. , Asfaha Samuel , Worthley Daniel L. , Renz Bernhard , Ariyama Hiroshi , Dubeykovskaya Zinaida A. , Takemoto Yoshihiro , Mulay Ashlesha , Tailor Yagnesh , Chen Duan , Muthupalani Sureshkumar , Fox James G. , Takaishi Shigeo , Wang Timothy C. 
Published: May 2015

Abstract
Gastrin is a hormone that binds to the CCK2 receptor and promotes proximal gastric cancer, but inhibits distal gastric cancer development. However, the precise roles of the CCK2 receptor, and its alternative ligand, progastrin, in gastric carcinogenesis have not been clarified. In this study, we found that progastrin accelerated antral proliferation and carcinogenesis through CCK2R+ antral stem cell expansion, using mouse gastric cancer models and transgenic mice lines including human progastrin-overexpressing (hGAS) mice, CCK2R knockout mice, Lgr5-CreERT-IRES-GFP knockin mice, and newly generated CCK2R-BAC-CreERT mice. Progastrin promoted gastric antral cancer development induced by MNU and/or H. felis. During carcinogenesis, progastrin increased the expression of Lgr5 and gland fission in response to the chemical carcinogen MNU. Genetic ablation of CCK2R diminished these progastrin-mediated effects. In vitro 3D culture experiments revealed that progastrin, but not amidated gastrin, significantly increased gastric organoid formation and growth in Noggin-free condition, effects that were ablated by a CCK2R inhibitor YF-476 or CCK2R gene deletion. In the antrum, CCK2R was expressed in an Lgr5low cell population that displayed stemness, which could be enhanced by progastrin. In the presence of progastrin, Lgr5lowCCK2R+ cells interconverted to Lgr5hi cells. Finally, we generated a new BAC-transgenic CCK2R-CreERT murine line, and lineage tracing experiments showed that CCK2R+ cells, which reside slightly above the base of the antrum, contained long-lived stem cells in vivo and in vitro. Chemical inhibition of CCK2R attenuated progastrin-dependent cancer development in mice. In conclusion, CCK2R labels Lgr5low antral stem cells that can be activated and expanded by progastrin. These findings may help the understanding of the underlying mechanism in gastric stem cell regulation by a CCK2R signal.
Citation Format: Hayakawa Yoku, Guanchun Jin, Hongshan Wang, Xiaowei Chen, Christoph B. Westphalen, Samuel Asfaha, Daniel L. Worthley, Bernhard Renz, Hiroshi Ariyama, Zinaida A. Dubeykovskaya, Yoshihiro Takemoto, Ashlesha Mulay, Yagnesh Tailor, Duan Chen, Sureshkumar Muthupalani, James G. Fox, Shigeo Takaishi, Timothy C. Wang. CCK2R marks gastric antral stem cell and mediates antral carcinogenesis. [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 4795. doi:10.1158/1538-7445.AM2014-4795
Abstract 4803: Cancer-associated fibroblast promotes gastric cancer invasion and epithelial-mesenchymal transition via the IL-6/JAK/STAT3 signaling pathway
Authors: Su Liping , Wu Xiongyan , Zhou Quan , Wang Chenchen , Liu Bingya 
Published: May 2015

Abstract
Objectives: The molecular mechanisms involved in the regulation of gastric cancer progression by CAFs are still unclear. The aim of the present study was to determine if CAFs can enhance the tumor epithelial-to-mesenchymal transition (EMT) and invasion of gastric cancer cells, and link CAFs with activation of the IL-6/JAK/ STAT3 signaling pathway in the progression of gastric cancer.
Methods: Fibroblasts were isolated from gastric cancer. The identification of CAFs was defined by immunofluorescence staining and qRT-PCR. IL-6 expression in CAFs and gastric cancer cells was detected by qRT-PCR and ELISA. EMT and activation of Stat3 pathway in gastric cancer cells were detected by realtime PCR and western blot. Cell invasion assays were performed by using 8 μm transwell chambers.
Results: IL-6 expression in gastric cancer tissue was significantly higher than that in adjacent non-tumor tissue (3.450ng/g vs 2.665ng/g,P&lt;0.01). Using real time RT-PCR and ELISA, we found IL-6 expression was significantly higher in CAFs compared to that in gastric cancer cells. Co-culture with CAFs in a transwell system induced EMT of gastric cancer cells, which was demonstrated by decreased expression of E-cadherin and α-catenin, and increased expression of Twist1, MMP2 and ZEB2. However, deprivation of IL-6 using a neutralizing antibody or inhibition Stat3 activation with AG490 impaired the EMT of gastric cancer cells. Gastric cancer cells co-cultured with CAFs showed enhanced ability of migration and invasion than gastric cancer cells alone. However, adding neutralizing IL-6 antibody or AG490 into the co-culture system led to significantly decreased invasion (P &lt; 0.05) of SGC-7901 cells. Moreover, IL-6 secreted from CAFs activated the JAK/STAT3 pathway in gastric cancer cells, however, EMT and invasion of gastric cancer cells was inhibited when IL-6/JAK/STAT3 pathway was blocked.
Conclusions: CAFs induced EMT and invasion of gastric cancer cells through activation of the IL-6/JAK/STAT3 pathway.
Citation Format: Liping Su, Xiongyan Wu, Quan Zhou, Chenchen Wang, Bingya Liu. Cancer-associated fibroblast promotes gastric cancer invasion and epithelial-mesenchymal transition via the IL-6/JAK/STAT3 signaling pathway. [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 4803. doi:10.1158/1538-7445.AM2014-4803
Abstract 4817: Circulating tumor cells enriched by the negative selection system PowerMag is a useful predictor for treatment response of metastatic colorectal cancer patients
Authors: Hsieh Jason Chia-Hsun , Lin Hung-Chih , Hsu Hung-Chih , Chang John Wen-Cheng , Tseng Ching-Ping 
Published: May 2015

Abstract
Enumeration of circulating tumor cells (CTCs) provides prognostic and predictive value to guide treatment options. This study aims to (1) evaluate the merits of the PowerMag system, an immunomagnetic separation technique that we recently developed for negative selection of CTCs, in the prediction of treatment response; (2) perform analysis to investigate whether there is a correlation between the imaging response and the changes of CTCs counts before and during chemotherapy for the patients with metastatic colorectal cancer (mCRC). A total of 47 mCRC patients were enrolled in this prospective single-center study. CTCs were isolated from the peripheral blood of these patients by PowerMag at baseline and 2 weeks after starting first dose of chemotherapy. CTCs enumeration was then performed by immunofluorescence staining using the anti-epithelial cell adhesion molecule (EpCAM) antibody. Tumor response at 12 weeks after chemotherapy of the whole cohort was monitored by computed tomography (CT) scans following RECIST criteria 1.0. Our data revealed that PowerMag is a cost-effective negative selection-based CTCs isolation platform with a CTCs detection rate of 89.4% (42/47). The CTCs counts could successfully differ mCRC patients from healthy donors (P = 0.0015). The higher baseline CTCs number was associated with initially metastatic status rather than recurrent settings (P = 0.042). In all assessable patients, a high correlation rate of 86.7% was found between changes of CTCs (decline or elevation) and CT responses (progressive disease, and partial response/stable disease) with a P value of 0.005 (Fisher exact test). These data indicate that the change of CTCs counts before and during treatment is in accord with the image response evaluation at 12 weeks after initiation of treatment. In conclusion, PowerMag is a cost-effective method for negative selection of CTCs from cancer patients. Moreover, comparison of CTCs counts before and during treatment is a useful predictor for disease progression of mCRC patients that warrants further investigation in large-scale validation trial.
Citation Format: Jason Chia-Hsun Hsieh, Hung-Chih Lin, Hung-Chih Hsu, John Wen-Cheng Chang, Ching-Ping Tseng. Circulating tumor cells enriched by the negative selection system PowerMag is a useful predictor for treatment response of metastatic colorectal cancer patients. [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 4817. doi:10.1158/1538-7445.AM2014-4817
Abstract 4821: Circulating tumor cells: A key deliverable in oncology clinical trials
Authors: Xue Chengsen , Cortes Kasia E. , Hura Dorina , Baptiste Melissa L. , Renato Paradiso , Cuomo Joanne , Closkey Thomas W. Mc 
Published: May 2015

Abstract
Circulating tumor cell (CTC) enumeration is a new pharmacodynamic biomarker developed from an emerging rare event technology showing prognostic potential for the management and monitoring of patients with colon, breast, and prostate cancer. As more evidence is gradually accumulating at multiple cancer institutes, CTC has the potential to become a surrogate marker for cancer prognosis. There are challenges in performing CTC testing, however this assay has the opportunity to become a key deliverable in oncology clinical trials.
Our experience in the implementation of CTC testing in clinical trials over the past four years has led to recommendations for future CTC applications, including critical aspects such as sample accessioning and logistics, operational maintenance and method training, data collection and sufficient IT infrastructure to accommodate large data files in full scale trial operations. To have a successful trial using the CTC test as a monitored biomarker, the estimation of sample size for the clinical trial has to take into consideration the anticipated disqualification rate of collected samples. In our clinical trial experiences, 10% of samples submitted were disqualified for reasons ranging from insufficient sample volume to severe hemolysis. Sample logistics and transportation considerations are keys to successful sample management. Strict quality control (QC) measurements, a robust training program, effective data management, and proper maintenance of the CTC system are keys for delivering standardized results in a timely manner.
Our results indicate that CTC testing can be effectively incorporated into large scale clinical trials and the data can be seamlessly integrated into the Laboratory Information Management System (LIMS). CTC results may offer clinically useful information about patients and their response to therapy. From a patient perspective, the CTC test only requires a tube of blood and is well suited to multiple sampling time points during a clinical trial.
Citation Format: Chengsen Xue, Kasia E. Cortes, Dorina Hura, Melissa L. Baptiste, Paradiso Renato, Joanne Cuomo, Thomas W. Mc Closkey. Circulating tumor cells: A key deliverable in oncology clinical trials. [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 4821. doi:10.1158/1538-7445.AM2014-4821
Abstract 4830: Prognostic value of circulating tumor cells with podoplanin expression in locally advanced and metastatic head and neck squamous cell carcinoma
Authors: Tseng Ching-Ping , Lin Hung-Chih , Hsieh Chia-Hsun , Wang Hung-Ming , Cheng Ju-Chien 
Published: May 2015

Abstract
Podoplanin (PDPN) is a biomarker for poor prognosis in head and neck squamous cell carcinoma (HNSCC). A prospective study was designed to investigate the prognostic value of circulating tumor cells (CTCs) with PDPN expression (PDPN+-CTCs) in HNSCC patients. Sixty-one healthy donors and fifty-three HNSCC patients with locally advanced and metastatic diseases were enrolled in this study. CTCs were enriched from the peripheral blood by the negative selection method PowerMag that has been validated in our previous study. Enumeration of CTCs was performed by co-immunofluorescence staining using the anti-epithelial cell adhesion molecule (EpCAM) and anti-PDPN antibodies. The CTCs (EpCAM+) and PDPN+-CTCs (EpCAM+PDPN+) counts between the patients and healthy volunteers were statistically different (p &lt; 0.0001). When assessed the progression-free survival (PFS) and overall survival (OS) of the patients, we found that the median PFS for the patient group was 8.6 (95% CI: 4.781-12.419) months and the median OS has not reached 50% after the follow-up duration of 9.1 (5.2-17.1) months. Analysis of the CTCs and PDPN+-CTCs counts revealed that neither of them can be considered as a predictive factor for PFS and OS. Notably, the ratio for the PDPN+-CTCs over total CTCs has progonic value in the assessment of PFS and OS. Based on the ROC curve, the prediction of 6-month death could be revealed at the cutoff value of 20% (AUC: 0.718, sensitivity: 94.7%, specificity: 51.7%, p = 0.011). The patients with PDPN+/EpCAM+-CTCs ratio &gt;20% were associated with poor PFS (hazard ratio (HR): 4.666, 95% CI: 1.373-15.856, p = 0.016) and OS (HR: 12.400, 95% CI: 1.643-93.570, p = 0.015). Kaplan-Meier survival curve further confirmed that the PDPN+/EpCAM+-CTCs ratio had significant impact on PFS (p = 0.006) and OS (p = 0.008). In conclusion, CTCs enumeration clearly differentiates HNSCC patients from healthy individuals, while the PDPN+/EpCAM+-CTC ratio is more important than the absolute CTCs count in determining the degree of malignancy and serves as an independent prognostic factor for PFS and OS.
Citation Format: Ching-Ping Tseng, Hung-Chih Lin, Chia-Hsun Hsieh, Hung-Ming Wang, Ju-Chien Cheng. Prognostic value of circulating tumor cells with podoplanin expression in locally advanced and metastatic head and neck squamous cell 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 4830. doi:10.1158/1538-7445.AM2014-4830
Abstract 4859: Hepatocyte growth factor activator inhibitor type 1 suppresses invasion of pancreatic adenocarcinoma cells through inhibition of matriptase/protease-activated receptor-2 axis
Authors: Haruyama Yukihiro , Ye Jing-Jia , Kawaguchi Makiko , Kanemaru Ai , Fukushima Tsuyoshi , Kataoka Hiroaki 
Published: May 2015

Abstract
Previously, we reported that S2-CP8 cells, a metastatic variant of SUIT-2 pancreatic adenocarcinoma cell line, showed markedly decreased expression of hepatocyte growth factor activator inhibitor type 1 (HAI-1) compared to SUIT-2 and acquired EMT phenotype. Matrigel invasion assay revealed that S2-CP8 cells show enhanced invasion compared to SUIT-2 cells in vitro and forced HAI-1 expression alleviate the invasion. Consequently, in vivo study using a nude mouse orthotopic xenograft model showed reduced spontaneous metastasis by the forced HAI-1 expression. This study aimed to clarify molecular mechanisms underlying the HAI-1-mediated suppression of invasion of S2-CP8 cells. In S2-CP8 cells, activity of matriptase, a cognate protease of HAI-1, was clearly suppressed by forced expression of HAI-1. As matriptase is known to activate protease-activated receptor-2 (PAR-2) and PAR-2 agonist enhanced migration and invasion of S2-CP8, we analyzed the role of PAR-2 in HAI-1 loss-induced enhanced invasion of S2-CP8 in vitro. The HAI-1 loss-induced enhanced migration and invasion were significantly alleviated by PAR-2 antagonist, as well as by PAR-2 silencing. Moreover, knock down of matriptase also showed similar suppressive effects on the invasion of S2-CP8 cells. These results indicated that HAI-1 may have a suppressive role in the invasion of pancreatic cancer cells through its regulatory function on matriptase/PAR-2 axis.
Citation Format: Yukihiro Haruyama, Jing-Jia Ye, Makiko Kawaguchi, Ai Kanemaru, Tsuyoshi Fukushima, Hiroaki Kataoka. Hepatocyte growth factor activator inhibitor type 1 suppresses invasion of pancreatic adenocarcinoma cells through inhibition of matriptase/protease-activated receptor-2 axis. [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 4859. doi:10.1158/1538-7445.AM2014-4859
Abstract 486: Uncovering novel PERK signaling pathways through chemical-genetic screening
Authors: Maas Nancy L. , Levin Rebecca , Singh Nickpreet , Shokat Kevan , Diehl J. Alan 
Published: May 2015

Abstract
The ER kinase PERK, a key mediator of the Unfolded Protein Response, is known to promote tumorigenesis, cell migration, and metastasis, as well as inhibit anoikis. Though PERK has these and other important cellular functions, only a handful of its direct substrates are currently known. Therefore, in order to provide an expanded view of PERK function and further definition of its signaling networks, we have used a chemical-genetic approach to screen for additional PERK substrates. We find that a mutation in the PERK ATP binding pocket renders it sensitive to bulky ATP analogs both in vitro and in cells. Furthermore, bulky ATPγS analogs were used exclusively by the analog-sensitive version of PERK to label substrates with thiophosphate. After labeling, thiophosphopeptides were affinity purified by covalent capture and subsequently identified by tandem mass spectrometry. Utilization of this analog-sensitive PERK allele for substrate characterization will be discussed.
Citation Format: Nancy L. Maas, Rebecca Levin, Nickpreet Singh, Kevan Shokat, J. Alan Diehl. Uncovering novel PERK signaling pathways through chemical-genetic screening. [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 486. doi:10.1158/1538-7445.AM2014-486
Abstract 4861: Pharmacological reversal of caffeine-mediated phagocytic suppression
Authors: Steck Ryan , Hill Spencer , Robison Richard A. , O'Neill Kim L. 
Published: May 2015

Abstract
Caffeine's mechanism of action on immune cells has been an issue of debate for some time. Previous studies suggest caffeine inhibits cyclic AMP (cAMP)-phosphodiesterase, resulting in increased cAMP levels, increased protein kinase A (PKA) activation, and subsequently a decreased pro-inflammatory response. Caffeine is also an antagonist of adenosine receptors, resulting in delayed resolution of inflammation. If the primary effect of caffeine in macrophages was to antagonize adenosine receptors, we would expect caffeine to stimulate phagocytosis. We treated human macrophages with varying concentrations of caffeine (0 - 13mM) and measured their phagocytic ability to engulf fluorescent microspheres. Engulfment rates were measured by flow cytometry. Our results indicate that caffeine suppresses phagocytosis by 22% at physiological concentrations (35 uM- 750uM). At supraphysiological (4-13 mM) levels of caffeine, however, there is no significant decrease in phagocytosis. We wanted to find out if this suppressive effect at physiological concentrations could be blocked with a PKA inhibitor. We tested this by treating the cells with a PKA inhibitor at each of the different caffeine concentrations previously used. Initial results indicate that phagocytosis increased up to 27% in macrophages treated with PKA and caffeine compared to caffeine treated and control cells.These results need further validation but, initial results suggest inhibition of PKA results in increased engulfment, and indicate that the suppressive effects of caffeine on macrophage phagocytosis can be reversed with the treatment of PKA inhibitor suppression can be reversed. Macrophages are highly involved in regulation of inflammation and dysregulation has been implicated in a number of diseases, including cancer. These results suggest further potential for the therapeutic applications of caffeine, its analogs, and PKA inhibitors for the control of inflammation.
Citation Format: Ryan Steck, Spencer Hill, Richard A. Robison, Kim L. O'Neill. Pharmacological reversal of caffeine-mediated phagocytic suppression. [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 4861. doi:10.1158/1538-7445.AM2014-4861