bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4847: Alcoholic chronic pancreatitis increases tissue transformed macrophages (M2) which promote pancreatic cancer lesions in a Kras mouse model
Authors: Edderkaoui Mouad , Grippo Paul , Benhaddou Hajar , Ouhaddi Yassine , Tsukamoto Hidekazu , Swartwood Steven , Knudsen Beatrice , Goodridge Helen S. , Habtezion Aida , Go Vay-Liang , Pandol Stephen J. 
Published: May 2015

Abstract
Background: Alcoholic chronic pancreatitis (ACP) is a major risk factor for pancreatic cancer; however, the mechanism through which it promotes cancer is not known. In this study we developed a mouse model of pancreatic cancer induced by ACP and analyzed the effect of the interaction between macrophages and pancreatic cancer cells on progression of the disease.
Methods: Pdx1-Cre;LSL-Kras transgenic and wild-type (WT) mice were fed Lieber DeCarli control or alcohol diet for 6 weeks. Mice were subjected to 7-hourly cerulein injections (50µg/kg) twice a week for the last 3 weeks of the diet to induce chronic pancreatitis. Pancreatic intraepithelial neoplastic (PanIN) lesions, proliferation, fibrosis, inflammation, EMT and stem cell markers were analyzed by immunohistochemistry and Western. Monocytes/ macrophages from mice and their conditioned medium were applied to the pancreatic cancer cell line MIA PaCa-2. Cell survival and apoptosis were measured by MTT and ELISA. Expression of cytokines/ chemokines and growth factors by cancer cells and macrophages was measured by multiplex assay analysis.
Results: ACP increased fibrosis, stellate cell activation and inflammation in both WT and transgenic mouse pancreata. The increases were significantly greater in the transgenic mice. Further, ACP increased the number and stage of PanIN lesions in the pancreata of transgenic mice. EMT markers were stimulated by ACP in both WT and transgenic mice. Markers of type 2 macrophages (M2) were greater in ACP model compared to control mice. M2 macrophages conditioned media stimulated proliferation, EMT and cancer stemness in cancer cells. Cancer cells or PanIN cells conditioned media stimulated transformation of macrophages to the type 2 phenotype.
Conclusion: The results indicate that ACP promotes pancreatic cancer progression in transgenic mice. Our data suggest ACP as well as PanIN and cancer cells stimulate the phenotype change of macrophages toward type 2, which then stimulates cancer cell proliferation, EMT and cancer stemness. These results suggest that tissue macrophages play a key role in the increased risk for pancreatic cancer in patients with alcoholic pancreatitis.
Citation Format: Mouad Edderkaoui, Paul Grippo, Hajar Benhaddou, Yassine Ouhaddi, Hidekazu Tsukamoto, Steven Swartwood, Beatrice Knudsen, Helen S. Goodridge, Aida Habtezion, Vay-Liang Go, Stephen J. Pandol. Alcoholic chronic pancreatitis increases tissue transformed macrophages (M2) which promote pancreatic cancer lesions in a Kras mouse model. [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 4847. doi:10.1158/1538-7445.AM2014-4847
Abstract 4851: Kinase domain activation of FGFR2 yields high-grade lung adenocarcinoma sensitive to a pan-FGFR inhibitor in a mouse model of NSCLC
Authors: Akbay Esra A. , Tchaicha Jeremy H. , Altabef Abigail , Mikse Oliver R. , Kikuchi Eiki , Rhee Kevin , Liao Rachel , Bronson Roderick T. , Sholl Lynette M. , Meyerson Matthew , Hammerman Peter S. , Wong Kwok-Kin 
Published: May 2015

Abstract
Somatic mutations in Fibroblast Growth Factor Receptor 2 (FGFR2) have been found in 4-5% of patients diagnosed with non-small cell lung cancer (NSCLC). FGFR2 and other FGFR kinase family gene alterations have been found in lung squamous cell carcinoma, adenocarcinoma, and other malignancies though mouse models of FGFR driven lung cancers have not been reported. Here, we generated a genetically engineered mouse model (GEMM) of NSCLC driven by a kinase domain mutation in FGFR2. Combined with p53 ablation, primary grade III/IV adenocarcinoma was induced in the lung epithelial compartment exhibiting locally invasive and pleiotropic tendencies largely made up of multinucleated cells. Tumors were acutely sensitive to pharmacological inhibition of FGFR signaling. In preliminary studies tumors also responded to Programmed death pathway immune checkpoint blockade using anti-PD-1 antibody arguing for activated immune evasion mechanisms in this model.This is the first autochthonous FGFR2-driven lung cancer GEMM that can be applied across different cancer indications in a preclinical setting.
Citation Format: Esra A. Akbay, Jeremy H. Tchaicha, Abigail Altabef, Oliver R. Mikse, Eiki Kikuchi, Kevin Rhee, Rachel Liao, Roderick T. Bronson, Lynette M. Sholl, Matthew Meyerson, Peter S. Hammerman, Kwok-Kin Wong. Kinase domain activation of FGFR2 yields high-grade lung adenocarcinoma sensitive to a pan-FGFR inhibitor in a mouse model of NSCLC. [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 4851. doi:10.1158/1538-7445.AM2014-4851
Abstract 4864: Tumor promoting role of NF-kappa B in the glioma environment
Authors: Kwiatkowska Aneta , Nandhu Mohan Sobana , Viapiano Mariano Sebastian 
Published: May 2015

Abstract
Introduction: Gliomas are the most common primary malignant brain tumors. Their characteristic features are extensive growth and lack of the clear borders due to diffuse invasion of surrounding tissue. Invasive glioma cells have been shown to interact through soluble signals with other cells in the neural microenvironment, which is normally highly inhibitory to cell motility. This communication changes the behavior of the tumor microenvironment to become permissive and facilitate tumor invasion. Here, we investigated the role of NFκB signaling in the glioma microenvironment and demonstrate that activation of NFκB in neural cells is critical for tumor growth and invasion. Methodology: We analyzed the growth and invasion of malignant gliomas using an NFκB-deficient mouse model (RelA(p65)-/- TNFR1-/-). Since p65-/- mice do not survive to adulthood, mouse glioma cells were implanted in p65+/- mice (which have significantly reduced NFκB activity) or their control littermates. Organotypic cultures of p65-/- brain slices and cultures of p65-/- neonatal astrocytes were used to assess the role of active NFκB signaling in astroglia on tumor invasion. Results: Using the mouse glioma cell line GL261 (poorly invasive) we observed significantly reduced tumor volume in NFκB -deficient mice compared to wild-type littermates. Further studies using mouse glioma stem-like cells Mut4 (highly invasive; GFAP-Cre: Nf1loxP/+ Trp53-/+ PTENloxP/+; Alcantara-Llaguno et al., Cancer Cell, 2009) demonstrated reduction both in tumor size and extent of invasion in the NFκB-deficient microenvironment. Importantly, immunohistochemical analysis demonstrated significantly reduced number of protoplasmic GFAP- positive astrocytes surrounding the tumors in p65+/- brains. Further analysis in brain slice cultures showed that invasion of glioblastoma cells was highly reduced through p65+/- tissue. Moreover, p65+/- astrocytes exhibited significantly reduced responses towards glioma cells, including reduced invasion through Matrigel in response to signals released by
GL261 cells. Conclusions: Our results strongly suggest that NFκB signaling may be involved in the recruitment or activation of reactive astrocytes surrounding the invasive borders of gliomas. This activation is likely necessary for enhanced tumor invasion through brain tissue. Our results highlight the relevance of the astroglial compartment as a collateral target that should be considered in future strategies targeting brain tumor invasion.
Citation Format: Aneta Kwiatkowska, Mohan Sobana Nandhu, Mariano Sebastian Viapiano. Tumor promoting role of NF-kappa B in the glioma environment. [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 4864. doi:10.1158/1538-7445.AM2014-4864
Abstract 4980: Inhibiting carbonic anhydrase IX targets hypoxic small cell lung cancer cells
Authors: Bryant Jennifer L. , Meredith Suzanne L. , Gieling Roben G. , Telfer Brian A. , Babur Muhammad , Supuran Claudiu T. , Williams Kaye J. , White Anne 
Published: May 2015

Abstract
Small-cell lung cancer (SCLC) is an extremely aggressive disease, exhibiting acquired resistance to therapy and poor patient prognosis. Therapy resistance can in part be attributed to tumor hypoxia. Hypoxic SCLC cells up-regulate carbonic anhydrase IX (CA IX) in order to survive. CA IX is involved in pH maintenance of cells and presents a novel therapeutic target for SCLC. This study aimed to investigate the potential of inhibiting CA IX in SCLC as a novel therapeutic target.
Hypoxic conditions (0.1% O2) increased CA IX expression over 24 hours in both COR-L24 and DMS 79 SCLC cells in culture. S4 belongs to a sulfamate class of carbonic anhydrase inhibitors and has shown anti-metastatic properties in breast cancer xenografts. Treatment with 30μM and 100μM S4 significantly decreased CA IX protein levels in hypoxic COR-L24 and DMS 79 SCLC cells, respectively (p&lt;0.05 for both treatments). Exposure to S4 for 24 hours resulted in predominantly hypoxic cell death in both cell lines (p&lt;0.05). Combining S4 with etoposide (0.3µM) and cisplatin (0.5µM) chemotherapeutic agents resulted in additional cell death, which was also seen under normoxic conditions (20% O2). Sub-cutaneous xenograft tumors were grown in nude mice using either COR-L24 or DMS 79 SCLC cells. Resultant tumors (1000mm3) expressed CA IX largely adjacent to regions of necrosis. Treating mice with 50mg/kg S4 on two consecutive days each week resulted in greater necrosis than saline controls, coupled with up-regulation of CA IX. Analyzing tumors for characteristic neuroendocrine (pro-opiomelanocortin) and epithelial (cytokeratin) markers revealed heterogeneous expression; however, this did not correlate with CA IX expression and is not altered in response to treatment.
In summary, CA IX is upregulated in hypoxic SCLC cells and tumors. Inhibition of CA IX resulted in hypoxic cell death and had an additive effect to the response observed with chemotherapy treatment alone. This suggests that directly targeting hypoxic SCLC cells via CA IX inhibition holds promise in improving treatment outcome for this aggressive disease.
Citation Format: Jennifer L. Bryant, Suzanne L. Meredith, Roben G. Gieling, Brian A. Telfer, Muhammad Babur, Claudiu T. Supuran, Kaye J. Williams, Anne White. Inhibiting carbonic anhydrase IX targets hypoxic small cell lung 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 4980. doi:10.1158/1538-7445.AM2014-4980
Abstract 5063: PSCA as a potential therapeutic and prognostic biomarker for common cancer
Authors: Matsuda Koichi , Tanikawa Chizu , Nakamura Yusuke 
Published: May 2015

Abstract
SNP rs2294008 in PSCA was shown to be associated with bladder and gastric cancer risk among European and Asian. PSCA was upregulated in various cancer tissues, and PSCA expression level was associated with tumor stage and poor prognosis. Thus PSCA is consider as promising therapeutic target of cancers. Our group revealed that T allele of rs2294008 encodes a translation initiation codon upstream of the reported site and changes protein localization from the cytoplasm to the cell surface. To further investigate the role of this variation in Japanese population, we genotyped using bladder and lung cancer samples. As a result, we found the significant association with bladder and lung cancer risk (OR=1.20 and 1.09 with P-value of 0.0092 and 0.0126). In addition, we found that T allele was associated with higher level of mRNA expression and T type of PSCA protein was secreted into the culture medium. These finding suggest that PSCA genotype and serum PSCA protein would be good biomarkers of disease risk, prognosis, and response to treatment using anti-PSCA antibody, implicating the clinical usefulness of genomic analysis for the treatment of common cancer.
Citation Format: Koichi Matsuda, Chizu Tanikawa, Yusuke Nakamura. PSCA as a potential therapeutic and prognostic biomarker for common 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 5063. doi:10.1158/1538-7445.AM2014-5063
Abstract 5151: A687V EZH2 is a driver of histone H3 lysine 27 (H3K27) hyper-trimethylation
Authors: Ott Heidi , Graves Alan , Pappalardi Melissa , Kruger Ryan , Tummino Peter , Creasy Caretha , McCabe Michael T. 
Published: May 2015

Abstract
The EZH2 methyltransferase silences gene expression through methylation of histone H3 on lysine 27 (H3K27). Recently, EZH2 mutations have been reported at Y641, A677, and A687 in non-Hodgkin's lymphoma. While the Y641F/N/S/H/C and A677G mutations exhibit clearly increased activity with substrates di-methylated at lysine 27 (H3K27me2), the A687V mutant has been shown to prefer a mono-methylated lysine 27 (H3K27me1) with little gain of activity toward H3K27me2. Herein, we demonstrate that despite this unique substrate preference, A687V EZH2 still drives increased H3K27me3 when transiently expressed in cells. However, unlike the previously described mutants which dramatically deplete global H3K27me2 levels, A687V EZH2 retains normal levels of H3K27me2. Sequencing of B-cell derived cancer cell lines identified a cell line harboring this mutation. Similar to exogenous expression of A687V EZH2, this cell line exhibited elevated H3K27me3 while possessing H3K27me2 levels higher than Y641 or A677 mutant lines. Treatment of A687V EZH2 mutant cells with GSK126, a selective EZH2 inhibitor, induced global H3K27me3 demethylation, robust gene activation, caspase activation, and decreased proliferation. These findings suggest that A687V EZH2 likely increases global H3K27me3 indirectly through increased catalytic activity with H3K27me1 and cells harboring this mutation are highly dependent on EZH2 activity for their survival.
Citation Format: Heidi Ott, Alan Graves, Melissa Pappalardi, Ryan Kruger, Peter Tummino, Caretha Creasy, Michael T. McCabe. A687V EZH2 is a driver of histone H3 lysine 27 (H3K27) hyper-trimethylation. [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 5151. doi:10.1158/1538-7445.AM2014-5151
Abstract 5205: CCND1 is a miR-193b target in prostate cancer
Authors: Tuppurainen Kirsi M. , Rauhala Hanna E. , Scaravilli Mauro , Vessella Robert L. , Visakorpi Tapio 
Published: May 2015

Abstract
Prostate cancer is the most frequent cancer of men in Western countries and causes second most of the cancer-related deaths. In addition to genetic changes also epigenetic alterations and micro-RNAs (miRNAs) are important in prostate cancer development. Our group has previously shown that miR-193b is hypermethylated in 22Rv1 prostate cancer cell line and that it is putative tumor suppressor in prostate cancer. In melanoma and hepatocellular carcinoma, it has been shown that CCND1, encoding cyclin D1 protein, is among the target genes of miR-193b. The aim of this project was to study if CCND1 is a target of miR-193b in prostate cancer.
According to qRT-PCR and microarray analyses, the expression of CCND1 and miR-193b were inversely correlated in prostate cancer cell lines (PC-3, VCaP, 22Rv1, LAPC4, DU145, LNCaP) and in LuCaP xenografts. Using a luciferase reporter gene assay in 22Rv1 cells, we showed that miR-193b targets CCND1 3′UTR. In 22Rv1 cells with low endogenous miR-193b expression, transient pre-miR-193b transfection reduced CCND1 mRNA levels and cyclin D1 and phospho-RB protein levels. By rescue experiment we confirmed that the downregulation of cyclin D1 and phospho-RB proteins is due to miR-193b. When prostate cancer cell lines were treated with cdk4/6 inhibitor, 22Rv1 and VCaP cells with low miR-193b and high CCND1 expression showed significant growth retardation. In contrast, the inhibitor did not have any effect on the growth of PC-3 and DU145 cells with high miR-193b and low CCND1 expression. Furthermore, immunohistochemical analysis of 337 specimens showed that cyclin D1 is expressed significantly higher in castration resistant compared to hormone-naïve prostate cancers. Therefore, we conclude that CCND1 is one of the miR-193b targets in prostate cancer.
Citation Format: Kirsi M. Tuppurainen, Hanna E. Rauhala, Mauro Scaravilli, Robert L. Vessella, Tapio Visakorpi. CCND1 is a miR-193b target in prostate 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 5205. doi:10.1158/1538-7445.AM2014-5205
Abstract 5268: The expression of lemur tyrosine kinase-3 in high grade pediatric tumors
Authors: Mazarakis Nektarios K. , Smith Stuart , Vraka Aikaterini , Macarthur Donald , Grundy Richard , Stebbing Justin , Giamas George 
Published: May 2015

Abstract
High grade gliomas are the most common primary brain tumors in adults, but also occur in childhood, with a poor prognosis in all age groups . Lemur tyrosine kinase 3 (LMTK3) is a transmembrane tyrosine kinase that seems to play a pivotal role in oncogenesis in breast cancer. It regulates the estrogen receptor alpha and is evolutionarily selected for in humans compared to non-human primates. LMTK3 expression levels were strongly associated with survival and therapy response.This study assesses the role of LMTK3 in pediatric high grade brain tumors at both the protein and mRNA levels.
We initially assessed by immunohistochemistry (IHC) the expression levels of LMTK3 in well described cohorts of patient specimens with brain cancer. First, we performed an IHC analysis using a brain tumor tissue microarray (TMA) purchased from US Biomax (#T175), in order to examine the LMTK3 levels in a variety of brain tumors.
Preliminary analysis revealed variable LMTK3 expression levels in brain tissue, scored as negative, low, moderate and high. We demonstrate that LMTK3 appears to be expressed at low levels at normal brain tissue samples and epithelial meningioma tissues (benign tumors). On the contrary, LMTK3 was expressed at different levels in cases with grade 2 or grade 4 gliomas. Further immunohistochemical analysis was therefore undertaken on a selection of TMAs containing pediatric high grade gliomas. Genome wide gene expression analysis (using the Affymetrix U133plus2 chip) previously undertaken on a cohort of pediatric high grade gliomas demonstrated measurable LMTK3 mRNA expression in many samples. Our preliminary analysis was correlated with various tumor characteristics that are available in Nottingham datasets (including demographic and overall survival data). In conclusion, LMTK3 is expressed in pediatric high grade gliomas and may have differential expression depending on the histological grade of the tumor. This work will lead to larger scale studies to elucidate the exact role of LMTK3 in high grade brain neoplasms.
Citation Format: Nektarios K. Mazarakis, Stuart Smith, Aikaterini Vraka, Donald Macarthur, Richard Grundy, Justin Stebbing, George Giamas. The expression of lemur tyrosine kinase-3 in high grade pediatric tumors. [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 5268. doi:10.1158/1538-7445.AM2014-5268
Abstract 5271: Homozygous deletion of the activin A receptor, type IB gene is associated with an aggressive cancer phenotype in pancreatic cancer
Authors: Togashi Yosuke , Sakamoto Hiroki , Hayashi Hidetoshi , Terashima Masato , Velasco Marco A. de , Fujita Yoshihiko , Kodera Yasuo , Sakai Kazuko , Tomida Shuta , Kitano Masayuki , Kudo Masatoshi , Nishio Kazuto 
Published: May 2015

Abstract
Background: Transforming growth factor, beta (TGFB) signal is considered to be a tumor suppressive pathway based on the frequent genomic deletion of the SMAD4 gene in pancreatic cancer (PC); however; the role of the activin signal, which also belongs to the TGFB superfamily, remains largely unclear.
Methods and Results: We found a homozygous deletion of the activin A receptor, type IB (ACVR1B) gene in 2 out of 8 PC cell lines using array-comparative genomic hybridization, and the absence of ACVR1B mRNA and protein expression was confirmed in these 2 cell lines. Activin A stimulation inhibited cellular growth and increased the phosphorylation level of SMAD2 and the expression level of p21CIP1/WAF1 in the Sui66 cell line (wild-type ACVR1B and SMAD4 genes) but not in the Sui68 cell line (homozygous deletion of ACVR1B gene). Stable ACVR1B-knockdown using short hairpin RNA cancelled the effects of activin A on the cellular growth of the PC cell lines. In addition, ACVR1B-knockdown significantly enhanced the colony formation abilities and cellular growth, compared with controls. In a xenograft study, ACVR1B-knockdown resulted in a significantly elevated level of tumorigenesis and a larger tumor volume, compared with the control. Furthermore, in clinical samples, 6 of the 29 PC samples (20.7%) carried a deletion of the ACVR1B gene, while 10 of the 29 samples (34.5%) carried a deletion of the SMAD4 gene. Of note, 5 of the 6 samples with a deletion of the ACVR1B gene also had a deletion of the SMAD4 gene.
Conclusion: We identified a homozygous deletion of the ACVR1B gene in PC cell lines and clinical samples and proposed that the deletion of the ACVR1B gene may mediate an aggressive cancer phenotype in PC. Our findings provide novel insight into the role of the activin signal in PC.
Citation Format: Yosuke Togashi, Hiroki Sakamoto, Hidetoshi Hayashi, Masato Terashima, Marco A. de Velasco, Yoshihiko Fujita, Yasuo Kodera, Kazuko Sakai, Shuta Tomida, Masayuki Kitano, Masatoshi Kudo, Kazuto Nishio. Homozygous deletion of the activin A receptor, type IB gene is associated with an aggressive cancer phenotype in pancreatic 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 5271. doi:10.1158/1538-7445.AM2014-5271