bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2509: Blockage of angiotensin II type 1 receptor (AGTR1) inhibits epithelial-mesenchymal transition (EMT) and tumor growth in breast cancer
Authors: Kim Ji Young , Oh Eunhye , Kim Yoon-Jae , Sung Daeil , Cho Tae-Min , Jang Seojin , Seo Jae Hong 
Published: August 2018

Abstract
The angiotensin II type I receptor (AGTR1) has been implicated in diverse aspects of human disease, from the regulation of blood pressure and cardiovascular homeostasis. A recent study has reported pathogenic overexpression of the angiotensin II type 1 receptor (AGTR1) in breast cancers. We sought to investigate the effect of losartan, an angiotensin II receptor blocker on cell proliferation, epithelial-mesenchymal transition (EMT), angiogenesis and tumor growth in breast cancer. Overexpression of AGTR1 was associated with accelerated cell proliferation, concomitant with increased expression of survival factors including poly(ADP-ribose) polymerase (PARP) and X-linked inhibitor of apoptosis (XIAP), as well as extracellular signal-regulated kinase (ERK) activation. AGTR1-overexpressing MCF7 cells were more aggressive than their parent line, with significantly increased activity in migration and invasion assays. These observations were associated with changes in EMT markers, including reduced E-cadherin expression and increased p-Smad3, Smad4 and Snail levels. Treatment with the AGTR1 antagonist losartan attenuated these effects in vitro. To confirm the physiological relevance of our in vitro observations, we examined the effect of losartan on tumor growth using a mammary fat pad xenograft model with the AGTR1-overexpressing cells. Losartan administration resulted in a significant reduction in tumor growth and a significant decrease in the number of Ki-67-positive cells in the AGTR1-overexpressing xenograft tumors. Losartan administration notably upregulated E-cadherin and suppressed vimentin expression. Furthermore, microvessel density analysis revealed that the number of CD31-positive microvessels in both the peritumoral and intratumoral areas was significantly decreased in the losartan-treated groups. Our findings support the notion that AGTR1 is a potentially useful diagnostic marker and its inhibition may provide an effective therapeutic strategy for breast cancer treatment.
Citation Format: Ji Young Kim, Eunhye Oh, Yoon-Jae Kim, Daeil Sung, Tae-Min Cho, Seojin Jang, Jae Hong Seo. Blockage of angiotensin II type 1 receptor (AGTR1) inhibits epithelial-mesenchymal transition (EMT) and tumor growth in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2509.
Abstract 2510: Clinicopathologic significance of fibroblast growth factor 2 type IIIb and type IIIc in gastric cancer
Authors: Kuroda Kenji , Yashiro Masakazu , Masuda Go , Miki Yuichiro , Okuno Tomohisa , Togano Shingo , Toyokawa Takahiro , Tanaka Hiroaki , Muguruma Kazuya , Hirakawa Kosei , Ohira Masaichi 
Published: August 2018

Abstract
[Background]Fibroblast Growth Factor Receptor 2(FGFR2) amplification occuers flequently in undifferentiated gastric cancer(GC), and accounts for 3-10% of primay GC. FGFR2 shows two isoforms, IIIb-type expressed in epithelial cells, and IIIc-type expressed in mesenchymal cells. The aim of this study is evaluating clinicopathological significance of FGFR2-IIIb and IIIc expression on GC cells.
[Method]562 patients who had undergone GC surgery were retrospectively examined. Immunohistochemistry of resected specimen was used to investigate the expression of FGFR2-IIIb and IIIc.
[Result]FGFR2-IIIb and FGFR2-IIIc were positive in 28 cases (4.9%) and 4 cases (0.7%) of 562 gastric cancers. All of FGFR2-IIIc positive tumors were also positive for FGFR2-IIIb in a same tumor, but both were not positive in same cells. 5-year overall survival rate of FGFR2 positive group is significantly poorer (p=0.0011, log-lank) than that of FGFR2 negative. Moreover, the prognosis of FGFR2-IIIc positive group was significantly poorer (p=0.003, log-lank) than that of FGFR2-IIIb positive group. In univariate analysis, the overall survival was significantly correlated to FGFR2-IIIb positive, FGFR2-IIIc positive, invasion depth, macroscopic type, histological type, lymph node metastasis, peritoneal dissemination, lymphatic invasion, and cytology. In multivariate analysis, FGFR2IIIc was significantly correlated to overall survival (p=0.045)
[Conclusion] The expression of FGFR2IIIc and/or FGFR2IIIb was observed in 5% of gastric cancer. FGFR2 amplification is associated with poor overall survival. As a result, treatment targeting FGFR2 amplification has the potential to provide clinical benefit for FGFR2 positive GC.
Citation Format: Kenji Kuroda, Masakazu Yashiro, Go Masuda, Yuichiro Miki, Tomohisa Okuno, Shingo Togano, Takahiro Toyokawa, Hiroaki Tanaka, Kazuya Muguruma, Kosei Hirakawa, Masaichi Ohira. Clinicopathologic significance of fibroblast growth factor 2 type IIIb and type IIIc in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2510.
Abstract 2524: A new mTOR-independent effect of rapamycin: Transcriptional regulation of TRIB3
Authors: Stefanovska Bojana , Vicier Cécile , Scott Véronique , Meurice Guillaume , André Fabrice , Fromigué Olivia 
Published: August 2018

Abstract
Background: Mechanistic Target of Rapamycin (mTOR), a key component of the PI3K/Akt signaling pathway, coordinates various cellular processes such as metabolism, growth, cell proliferation and cell cycle progression. Dysregulations affecting mTOR frequently occur in cancer, and mTOR inhibitors/rapalogs are used as monotherapy or a part of combination therapy in breast or kidney metastatic cancer. Despite this, response rate is modest. Several mechanisms of resistance have been reported, but do not fully characterize insensitive tumor cells. Purpose: This study investigated new target genes of rapamycin/rapalogs. Methods: Expression levels of target genes were evaluated in a panel of cancer cell lines by transcriptomic analyses, real-time qPCR and western blot. Transcriptional regulation was investigated by in silico analyses of the promoter region, gene reporter assays using site-directed mutagenesis, and ChIP. Stably silenced cell lines were established by lentiviral transduction of shRNA sequences. Results: We identified one gene: TRIB3 (Tribbles Pseudokinase 3), whose expression is downregulated in the presence of rapamycin in a panel of cancer cell lines and in PBMCs isolated from cancer patients. This gene encodes for a pseudokinase involved in a glucose-induced insulin resistance in Type 2 Diabetes by inhibiting the activation of Akt1/2. We observed that silencing mTOR did not mimic rapamycin downregulation of TRIB3, suggesting an mTOR-independent effect of rapamycin. We identified a binding site for the transcriptional repressor GCF2/LRRFIP1 in the promoter region of TRIB3, and confirmed that the presence and the binding of GCF2 to TRIB3 promoter are required for TRIB3 downregulation by rapamycin. Finally, we identified FKBP3 (FK506-Binding Protein 3), a protein that can bind rapamycin with high affinity, as a GCF2 partner, confirming the direct effect of rapamycin on TRIB3 promoter. Conclusions: Taken together, our investigations identified a novel transcriptional target gene of rapamycin: TRIB3. We also characterized the molecular mechanism of regulation by rapamycin through a FKBP3/GCF2-dependent repression of TRIB3 promoter activity, and independently of mTOR signaling. Such variations in TRIB3 expression level in cancer cells could be linked to rapamycin sensitivity, and may represent a valuable therapeutic target.
Citation Format: Bojana Stefanovska, Cécile Vicier, Véronique Scott, Guillaume Meurice, Fabrice André, Olivia Fromigué. A new mTOR-independent effect of rapamycin: Transcriptional regulation of TRIB3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2524.
Abstract 2537: Regulation of LMO2 oncogene expression in high-risk B-cell acute lymphoblastic leukemia
Authors: Ding Yali , Payne Jonathon L. , Kane Shriya , Dovat Elanora , Soliman Mario , Song Chunhua , Dovat Sinisa 
Published: August 2018

Abstract
LIM domain only protein 2 (LMO2) is an oncogene that is overexpressed in a subset of B-cell acute lymphoblastic leukemia (B-ALL). The mechanisms that regulate LMO2 expression in B-ALL are still unknown. Here, we show that transcription of LMO2 in B-ALL is regulated by Ikaros, a tumor suppressor protein, which is encoded by the IKZF1 gene, and whose deletion is associated with development of high-risk B-ALL. The use of global chromatin immunoprecipitation coupled with the next-generation sequencing (ChIP-seq) studies in primary human B-ALL cells and in cell lines revealed a strong Ikaros occupancy at the promoter of the LMO2 gene. Ikaros binding to the LMO2 promoter was confirmed by quantitative chromatin immunoprecipitation (qChIP). We tested the role of Ikaros in regulating LMO2 transcription in B-ALL using gain-of-function and loss-of-function experiments. A luciferase reporter assay with the LMO2 promoter showed that Ikaros directly represses LMO2 transcription. Overexpression of Ikaros in B-ALL via retroviral transduction was associated with strongly reduced expression of LMO2. Furthermore, Ikaros knock-down with shRNA, resulted in increased transcription of LMO2 in B-ALL cells. These results suggest that Ikaros represses transcription of LMO2 in B-ALL. Since Ikaros' function in B-ALL is negatively regulated by pro-oncogenic Casein Kinase II (CK2), we tested whether CK2 inhibition affects Ikaros-mediated repression of LMO2. Both molecular inhibition with shRNA, and pharmacological inhibition of CK2 with a specific CK2 inhibitor, CX-4945, resulted in reduced expression of LMO2. Inhibition of CK2 was also associated with increased Ikaros occupancy at the LMO2 promoter. In high-risk B-ALL that have deletion of a single copy of the IKZF1 gene, Ikaros does not bind to the LMO2 promoter. Treatment of primary B-ALL cells that have IKZF1 haploinsufficiency restores Ikaros binding to the LMO2 promoter and results in reduced LMO2 expression. In conclusion, our data demonstrate that Ikaros and CK2 regulate transcription and overall expression of the LMO2 oncogene in B-ALL. Our results identify a novel mechanism of therapeutic action of CK2 inhibitors in high-risk B-ALL—repression of LMO2 expression via restoration of Ikaros' tumor suppressor function.
Citation Format: Yali Ding, Jonathon L. Payne, Shriya Kane, Elanora Dovat, Mario Soliman, Chunhua Song, Sinisa Dovat. Regulation of LMO2 oncogene expression in high-risk B-cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2537.
Abstract 2547: A potential new autologous mast cell cancer immunotherapy
Authors: Plotkin Jesse D. , Elias Michael G. , Daniels-Wells Tracy R. , Dellinger Anthony , Penichet Manuel L. , Kepley Christopher L. 
Published: August 2018

Abstract
Mast cells (MC) are important immune cells that reside in tissue and are most widely recognized for their role as mediators of Type I hypersensitivity reactions (allergies). In certain cancers, such as breast cancer, the presence of MC in the tumor microenvironment has been associated with favorable prognosis, which may be due to their ability to release, through activation of the high affinity IgE receptor FcεRI, anti-tumor mediators such as tumor necrosis factor alpha (TNF-α) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Thus, developing approaches to target autologous MC to tumor antigens is a potential new form of cancer immunotherapy. However, this concept has not been realized given that MC reside in tissue; thus, efficient removal, expansion ex vivo, and targeting to tumor sites has not yet been feasible. Previous attempts to generate MC from human progenitor cells have yielded cells that are often immature and not optimally functional. We report here, for the first time, the generation of functional human MC from adipose tissue in numbers sufficient for clinical applications. The adipose derived MC (ADMC) are phenotypically similar to connective tissue MC as evidenced through their expression of tryptase, chymase, c-kit, and FcεRI. The ADMC release several anti-tumor mediators through FcεRI activation. The ADMC, sensitized with an anti-HER2/neu IgE with human constant regions, bound to and were activated by HER2/neu-positive human breast cancer cells (SK-BR-3). ADMC sensitized in this way were observed to induce apoptosis in breast cancer cells when co-cultured. Importantly, breast cancer cell apoptosis was also observed after addition of media containing mediators released from activated ADMC. In conclusion, we present a novel method for the production of functional human MC from adipose tissue and demonstrate that these cells can be directed to target and eliminate breast cancer cells. It may now be possible to use them in conjunction with IgE antibodies targeting cancer cells for autologous mast cell cancer immunotherapy (AMCIT) as a new way to treat solid tumors such as those overexpressing HER2/neu for which new therapies are urgently need.
Citation Format: Jesse D. Plotkin, Michael G. Elias, Tracy R. Daniels-Wells, Anthony Dellinger, Manuel L. Penichet, Christopher L. Kepley. A potential new autologous mast cell cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2547.
Abstract 2578: Expression of epiregulin/amphiregulin associates with prognosis in recurrent/metastatic head and neck cancer treated with cetuximab
Authors: Kogashiwa Yasunao , Inoue Hitoshi , Kuba Kiyomi , Yasuda Masanori , Nakahira Mitsuhiko , Sugasawa Masashi 
Published: August 2018

Abstract
Objectives: The anti-EGFR antibody cetuximab, combined with chemotherapy, is the standard therapy for recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). However, the response rate and survival benefit are limited. The purpose of this study was to investigate the expression of the epidermal growth factor receptor ligands epiregulin (EREG) and amphiregulin (AREG), as predictive prognostic markers for the efficacy of cetuximab combined with chemotherapy in R/M HNSCC.
Materials and methods: We conducted a retrospective analysis of 37 patients diagnosed with R/M HNSCC. Tumor samples from biopsy specimens or surgical specimens were analyzed for EREG and AREG mRNA gene expression, and clinical outcomes evaluated. Survival rates were estimated by Kaplan-Meier analysis. Cox proportional hazard regression was used to test the potential association between ligand expression, overall survival (OS), and progression free survival (PFS).
Results: Values of EREG ≤ 15.87 and AREG ≤ 11.80, determined by receiver operating characteristic (ROC) curve analysis, were associated with significantly longer OS (p=0.03 and p=0.01, respectively), as well as PFS (p=0.04 and p=0.04, respectively). EREG and AREG expression levels were significantly correlated (r=0.73, p&lt;0.01). Multivariate analysis revealed that AREG expression was significantly associated with OS and PFS.
Conclusion: R/M HNSCC patients with higher EREG and AREG gene expression appear to benefit more from cetuximab combined with chemotherapy than those with lower expression. The potential for these ligands as prognostic biomarkers for cetuximab-containing regimens requires further evaluation.
Citation Format: Yasunao Kogashiwa, Hitoshi Inoue, Kiyomi Kuba, Masanori Yasuda, Mitsuhiko Nakahira, Masashi Sugasawa. Expression of epiregulin/amphiregulin associates with prognosis in recurrent/metastatic head and neck cancer treated with cetuximab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2578.
Abstract 2589: Novel predictor of FGFR1 inhibition efficacy in non-small cell lung cancer
Authors: Quintanal-Villalonga Álvaro , Ferrer Irene , Marrugal Ángela , Ojeda-Márquez Laura , Zugazagoita Jon , García-Redondo Laura , López-Ríos Fernando , Montuenga Luis , Molina-Pinelo Sonia , Molina-Pinelo Sonia , Carnero Amancio , Paz-Ares Luis 
Published: August 2018

Abstract
Fibroblast growth factor receptor (FGFR)1 has been associated with tumorigenesis in a variety of tumors, including lung cancer. FGFR1 amplification is detected in up to 20% of lung squamous cell carcinomas, and was initially related to tumorigenesis and to response to FGFR inhibitors in preclinical models of this pathology. These data encouraged the establishment of FGFR1 amplification as the main eligibility criterion for inclusion of patients in FGFR inhibitors clinical trials. However, the use of FGFR inhibitors in FGFR1-amplified tumors has shown limited success, with only 5-10% of selected patients showing partial response, suggesting that this genomic aberration may not be a good predictive biomarker for the efficacy of these inhibitors. In this work, we provide in vitro and in vivo data showing that the oncogenic effects of FGFR1 expression depend on the expression of the adhesion molecule N-cadherin in non-small cell lung cancer (NSCLC). In line with these results, FGFR1 expression correlates with poorer prognosis only in tumors with high N-cadherin levels in two independent NSCLC patient cohorts. We observed that high FGFR1 expression alone is not sufficient to predict FGFR inhibition efficacy in lung cancer cell lines and patient-derived xenografts, with only high FGFR1- and high N-cadherin-expressing models responding to selective FGFR inhibitors. Altogether, our data show that the determination of the expression of FGFR1 alone is not sufficient to predict FGFR inhibition efficacy. The co-determination of N-cadherin expression may optimize patient selection for this therapeutic strategy.
Citation Format: Álvaro Quintanal-Villalonga, Irene Ferrer, Ángela Marrugal, Laura Ojeda-Márquez, Jon Zugazagoita, Laura García-Redondo, Fernando López-Ríos, Luis Montuenga, Sonia Molina-Pinelo, Sonia Molina-Pinelo, Amancio Carnero, Luis Paz-Ares. Novel predictor of FGFR1 inhibition efficacy in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2589.
Abstract 2621: Genomic determinants of progression and response to therapy in prospectively characterized glioma patients
Authors: Jonsson Philip , Lin Andrew L. , Ogilvie Shahiba L. , Chavan Shweta S. , McKeown Andrew T. , DiStefano Natalie M. , Rosenblum Marc , DeAngelis Lisa M. , Mellinghoff Ingo K. , Taylor Barry S. 
Published: August 2018

Abstract
While the genomic landscape of low- and high-grade gliomas has been characterized and incorporated into further disease classification, its relationship to disease progression and treatment response remains poorly understood. To address this question, we integrated prospective clinical sequencing of 1,007 primary and recurrent tumors from 924 glioma patients with clinical and treatment phenotypes. Genomic alterations in effectors of cell cycle progression were a biomarker of aggressive disease in 1p19q intact IDH-mutant disease, arising preferentially in enhancing and recurrent tumors. When present at recurrence, the lesions were associated with rapid disease progression. These alterations were also present in all astrocytic tumors that ultimately relapsed with alkylating therapy-associated hypermutation. Analysis of matched pre-treatment and post-progression tumors indicated that cell cycle alterations preceded the emergence of hypermutation. In total, 391 patients (42%) harbored a potentially therapeutically actionable lesion in their tumor of which 73 patients (19%) received a diversity of targeted therapies. Both the type of mutation and its clonality were associated with therapeutic sensitivity in this cohort. For instance, RAF dimer-dependent BRAF hotspot mutations arose predominantly in IDH-wildtype glioblastomas, were subclonal, and affected patients did not respond to MAPK-directed therapy. In contrast, BRAF V600 hotspot mutations arose clonally in histologically distinct gliomas, both low- and high-grade, and responded to MAPK-directed therapy (either RAF, MEK or ERK inhibition). Collectively, these data reveal previously unrecognized genomic determinants of disease progression and treatment response in diverse types of glioma and serve as a rationale for utilizing genomic information in clinical care of patients with glioma.
Citation Format: Philip Jonsson, Andrew L. Lin, Shahiba L. Ogilvie, Shweta S. Chavan, Andrew T. McKeown, Natalie M. DiStefano, Marc Rosenblum, Lisa M. DeAngelis, Ingo K. Mellinghoff, Barry S. Taylor. Genomic determinants of progression and response to therapy in prospectively characterized glioma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2621.
Abstract 263: Effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on hepatoma cell lines and liver tumorigenesis
Authors: Shirakami Yohei , Obara Koki , Kubota Masaya , Sakai Hiroyasu , Tanaka Takuji , Shimizu Masahito , Seishima Mitsuru 
Published: August 2018

Abstract
Obesity, diabetes mellitus, and their related metabolic abnormalities are associated with increased risk of hepatocellular carcinoma (HCC). Anti-diabetic agents sodium glucose cotransporter (SGLT)-2 inhibitors are expected to ameliorate the abnormalities associated with metabolic syndrome including non-alcoholic fatty liver disease (NAFLD). In this study, we investigated the effects of the SGLT2 inhibitor tofogliflozin on the development of NAFLD-related liver tumorigenesis in C57BL/KsJ-+Leprdb/+Leprdb (db/db) obese and diabetic mice. The direct effects of tofogliflozin on human hepatoma cell lines were also evaluated. Male db/db mice were administered diethylnitrosamine-containing water for two weeks and were then treated with tofogliflozin throughout the experiment. Tofogliflozin was kindly provided by Kowa Co., Ltd. and the chemical structure will be disclosed at the time of presentation at the meeting. In mice treated with tofogliflozin, the development of hepatic pre-neoplastic lesions, foci of cellular alterations, was markedly suppressed, and hepatic steatosis and inflammation significantly reduced, as evaluated using the NAFLD activity score (NAS), in comparison to those in the control mice. Serum levels of glucose and free fatty acid and mRNA expression levels of pro-inflammatory markers in the liver were reduced by tofogliflozin treatment. Conversely, the proliferation of SGLT2 protein-expressing hepatoma cells was not inhibited and the insulin signaling in those cells was not altered by this agent. These findings suggest that tofogliflozin suppressed the early phase of obesity- and NAFLD-related liver carcinogenesis by attenuating chronic inflammation and steatosis in the liver, while the agent had no significant direct effect on the proliferation of hepatoma cells. Therefore, SGLT2 inhibitors may have a chemopreventive effect on obesity-related HCC.
Citation Format: Yohei Shirakami, Koki Obara, Masaya Kubota, Hiroyasu Sakai, Takuji Tanaka, Masahito Shimizu, Mitsuru Seishima. Effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on hepatoma cell lines and liver tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 263.