bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4796: Chronic exposure to nitric oxide drives human breast epithelial cells to malignant-like features
Authors: Cheng Yuk Sing Robert , Anderson Stephen K. , McVicar Daniel W. , Wink Daivd A. , Ridnour Lisa A. 
Published: July 2017

Abstract
The small endogenous signaling molecule, nitric oxide (NO) influences numerous physiological conditions including cancers. We have previously shown that different steady state NO levels activate pro-tumor signaling cascades. In this study, we explored the effect(s) of chronic NO exposure on breast epithelial cells as defined by changes in genomic stability, RNA and protein expression, and mostly importantly altered cell phenotype. Human breast epithelial cells (MCF10A) were chronically exposed to various concentrations of the NO donor DETA/NO for a three weeks. Distinct patterns of genomic alteration in the target genes (TP53, KRAS & PIK3CA) of exposed cells as compared to the background mutations were observed. In addition, quantitative real time PCR revealed increased expression of cancer stem cell (CSC) markers including NANOG, CD44, CXCR4 and OCT4 at 300 μM DETA/NO exposure. While altered cell morphology was observed in cells chronically exposed to 300-500 μM DETA/NO, increased motility occurred in cells cultured in 100 μM DETA/NO. Strikingly, these 100 μM NO-exposed cells grew in serum-free media; selected clonal populations as well as pooled cells formed colonies in soft agar that were disorganized and resembled cancer-like-clusters. In conclusion, these results implicate a precise tuning of microenvironmental NO levels that shift non-transformed breast epithelial cells toward cancerous phenotypes. The elucidation of underlying mechanisms may lend a new perspective regarding therapeutic approaches that redirect the cellular response(s) of tumor cells.
Citation Format: Yuk Sing Robert Cheng, Stephen K. Anderson, Daniel W. McVicar, Daivd A. Wink, Lisa A. Ridnour. Chronic exposure to nitric oxide drives human breast epithelial cells to malignant-like features [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4796. doi:10.1158/1538-7445.AM2017-4796
Abstract 4798: Genetically engineered mouse models of proliferative C5 high grade serous ovarian cancer
Authors: Scott Clare L. , Ho Gwo Y. , Lieschke Elizabeth E. , Kondrashova Olga , Drapkin Ronny , Bowtell David , Wakefield Matthew J. 
Published: July 2017

Abstract
Introduction: High-grade serous ovarian cancer (HGSOC) can be divided into four subgroups based on molecular characteristics1,2. The proliferative/C5 subgroup is defined by MYCN-pathway activation and may be associated with stem cell-like behavior3. The majority of HGSOC originate from the secretory cells of the fallopian tube (FT), with both tumours and secretory cells characterised by PAX8 expression4. We have developed pre-malignant C5 sub-type Genetically Engineered Mouse Models (GEMM) to characterise key molecular events in the initiation of this sub-type and to provide an immune-competent model for testing therapeutics.
Methods: We have generated independent GEMM with p53 dysfunction (p53lsl-R172H knock-in5) and over-expression of the MYCN-pathway, using either lsl-MYCN or lsl-lin28b transgenes6 directed by the doxycycline-inducible PAX8 promoter. Murine FT were harvested following two-weeks of transgene activation. One FT was harvested en bloc and paraffin embedded for analysis by H&E and immunohistochemistry for the presence of pre-malignant tubal lesions. The contralateral FT was macro-dissected into distal/mid-FT, which were snap frozen for analysis of gene expression by qRT-PCR and RNAseq. As mice with PAX8-directed expression of oncogenes (±MYCN/lin28b overexpression) developed enlarged kidneys due to renal tubular adenomata, for alternate mice, the mid/distal FT tissue was implanted into the bursae of wild-type CBA/nu mice for observation and later analysis.
Results: FT were harvested from twelve p53lsl-R172H/lsl-lin28b mice and from ten p53lsl-R172H/lsl-MYCN mice (including relevant control mice). Dysplastic lesions were observed in a subset of p53lsl-R172H/lsl-MYCN or lsl-lin28b FT and not in controls. MYCN pathway activation was demonstrated by qRT-PCR analysis.
Conclusion: Over-expression of the MYCN-pathway can drive FT epithelial dysplasia in the presence of p53 dysfunction. RNASeq analysis is being performed to elucidate early genetic events in dysplastic FT. Mice are now being harvested after eight-weeks of doxycycline activation to determine whether more advanced pre-malignant change occurs. CRISPR guides deleting relevant genes including p53, PTEN, Nf1 or Rb1 were generated to delete additional genes in MYCN pathway-transgenic FT, followed by implantation for observation of tumourigenesis.
Note: This abstract was not presented at the meeting.
Citation Format: Clare L. Scott, Gwo Y. Ho, Elizabeth E. Lieschke, Olga Kondrashova, Ronny Drapkin, David Bowtell, Matthew J. Wakefield. Genetically engineered mouse models of proliferative C5 high grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4798. doi:10.1158/1538-7445.AM2017-4798
Abstract 4802: Immune dysfunction and fungal infection contribute to esophageal carcinogenesis
Authors: Zhu Feng , Willette-Brown Jami , Song Na-young , Zhang Peilin , Hu Yinling 
Published: July 2017

Abstract
Human esophageal cancer is the sixth leading cause of cancer death worldwide. More than 90% of esophageal cancer is esophageal squamous cell carcinoma (ESCC). While the etiological causes remain unclear, esophageal mucosal fungal infection is very common in esophageal cancer patients, including patients with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) who have more than 20-fold risk of ESCC when compared to the healthy population. Here, we report that kinase-dead Ikka knock-in mice (hereafter referred to as mutant mice) develop APECED-like autoimmune disease due to developmental defects in thymus and lack of central tolerance. Similar to human APECED patients who develop esophageal mucosal fungal infection on average at the age of five, mutant mice develop fungal infection in oral cavity and esophagus as early as seven weeks old. About 20% of mutant mice develop ESCC during aging, which exhibits specific molecular signatures observed in human ESCC, such as p16 gene silencing, elevated EGFR phosphorylation and PD-L1 expression, etc. Autoreactive T cell depletion, or central tolerance reconstitution and/or normal T cell transfer prevents fungal infection and ESCC development in mutant mice. Importantly, antifungal drug treatment inhibits inflammation and ESCC development in mutant mice. However, oral inoculation of Clasdosporium, one of the major fungal species isolated from mutant mice, increases the tumor incidence from 20% to 63% in mutant mice. These results reveal that immune dysfunction and fungal infection is associated with ESCC development, which sheds new light on ESCC etiological factors, prevention and treatment.
Citation Format: Feng Zhu, Jami Willette-Brown, Na-young Song, Peilin Zhang, Yinling Hu. Immune dysfunction and fungal infection contribute to esophageal carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4802. doi:10.1158/1538-7445.AM2017-4802
Abstract 4807: Braf mutations initiate the development of rat gliomas induced by postnatal exposure to N-ethyl-N-nitrosourea (ENU)
Authors: Satomi Kaishi , Wang Qi , Oh Ji Eun , Hutter Barbara , Brors Benedikt , Diessl Nicolle , Liu Hai-Kun , Wolf Stephan , Wiestler Otmar , Kleihues Paul , Koelsch Bernd , Kindler-Rohrborn Andrea , Ohgaki Hiroko 
Published: July 2017

Abstract
Purpose
A single dose of N-ethyl-N-nitrosourea (ENU) during late prenatal or early postnatal development induces a high incidence of malignant schwannomas and gliomas in rats. Although T -&gt; A mutations in the transmembrane domain of the neu (c-ErbB-2) gene are the driver mutations in ENU-induced malignant schwannomas, the molecular basis of ENU-induced gliomas was unknown. The objectives of this study were to identify driver mutations in ENU-induced rat gliomas.
Methods
We performed whole-genome sequencing of gliomas that developed in three BDIV and two BDIX rats exposed to a single dose of 80 mg ENU/kg body weight on postnatal day one.
Results
T:A-&gt;A:T and T:A-&gt;C:G mutations, which are typical for ENU-induced mutagenesis, were predominant (41-55% of all somatic single nucleotide mutations). T-&gt;A mutations were detected in all 5 rat gliomas at Braf codon 545 (V545E), which corresponds to the human BRAF V600E. Additional screening revealed that 33 gliomas in BDIV rats and 12 gliomas in BDIX rats all carried a Braf V545E mutation, while peritumoral brain tissue of either strain (n=16) had the wild-type sequence. The gliomas were immunoreactive to BRAF V600E antibody.
Conclusions
Braf mutation is a frequent early event in the development of rat gliomas caused by a single dose of ENU.
Citation Format: Kaishi Satomi, Qi Wang, Ji Eun Oh, Barbara Hutter, Benedikt Brors, Nicolle Diessl, Hai-Kun Liu, Stephan Wolf, Otmar Wiestler, Paul Kleihues, Bernd Koelsch, Andrea Kindler-Rohrborn, Hiroko Ohgaki. Braf mutations initiate the development of rat gliomas induced by postnatal exposure to N-ethyl-N-nitrosourea (ENU) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4807. doi:10.1158/1538-7445.AM2017-4807
Abstract 4810: Loss of Cav-1 is associated with manifestation of stem cell-like properties via Src-mediated phosphorylation in human breast MDA-MB-231 cancer cells
Authors: YOON Hyo-Jin , KIM Do-Hee , CHA Young-Nam , SURH Young-Joon 
Published: July 2017

Abstract
A subpopulation of cancer cells, termed cancer stem cells (CSCs), has self-renewal and differentiation potential, which contributes to cancer recurrence and tumor resistance. Caveolin-1 (Cav-1), the major structural protein of flask-shaped plasma membrane invaginations called caveolae, functions as a tumor suppressor or an oncogene depending on the tumor type and the grade. Caveolae participate in various cellular functions, such as vesicle trafficking, cholesterol homeostasis, signal transduction, and tumor progression. In the present study, we investigated the role of Cav-1 on the stemness of human breast cancer (MDA-MB-231) cells. A sphere formation assay has been widely used to enrich for CSCs through serial passaging. A level of Cav-1 protein expression decreased in third-generation mammospheres as compared to parent MDA-MB-231 cells. Under the same experimental conditions, however, there was no concurrent decrease in the Cav-1 mRNA level. Therefore, it is likely that stability of Cav-1 protein is decreased during mammosphere formation. Recently, it has been reported that sustained phosphorylation of Cav-1 promotes its ubiquitination and degradation by the proteasomes. We observed that PP2, an inhibitor of Src, suppressed phosphorylation of Cav-1 in MDA-MB-231-derived mammosphere cells, which in turn increases its protein stability. Breast CSCs are enriched in cells with enhanced expression of phenotypic markers, such as CD44+/CD24-. We found that Cav-1 gene silencing using siRNA enhanced the proportion of CD44+/CD24- MDA-MB-231 cells. In addition, Cav-1 knockdown increased the number and the size of secondary mammospheres, and this was accompanied by enhanced expression of Bmi-1 and Sox-2, which are representative self-renewal markers. Moreover, epithelial-mesenchymal transition (EMT) was decreased by knockdown of Cav-1 in MDA-MB-231 cells. Taken together, these findings suggest that loss of Cav-1 protein stability facilitates the formation of mammospheres through upregulation of self-renewal and EMT markers in breast CSCs.
Citation Format: Hyo-Jin YOON, Do-Hee KIM, Young-Nam CHA, Young-Joon SURH. Loss of Cav-1 is associated with manifestation of stem cell-like properties via Src-mediated phosphorylation in human breast MDA-MB-231 cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4810. doi:10.1158/1538-7445.AM2017-4810
Abstract 4813: In vivo modeling of high grade glioma for oncology drug development
Authors: Krona Cecilia , Kundu Soumi , Holmberg-Olausson Karl , Islam Riasat , Ramachandra Rashmi , Elfineh Ludmila , Nelander Sven 
Published: July 2017

Abstract
In a multi-disciplinary project, patient derived glioblastoma stem-cell cultures (GSCs) have been established and characterized extensively with the goal of applying computational efforts to integrate results from high-throughput screens of drugs and RNAi with genomic and transcriptional profiling to predict the most successful therapy for individual glioma patients. The main goal of this study was to develop a platform for testing the tumor-initiating capacity of GSCs in mouse brain and to label the cells with GFP-luciferase to enable non-invasive quantification of tumor growth by in vivo bioluminescence imaging. Adherently grown GFP-luciferase labeled glioblastoma stem-cell cultures were dissociated and injected stereotactically into immunodeficient mice. Tumor growth was monitored by IVIS imaging for up to 40 weeks and brains were collected for histopathological and immunohistochemical stainings. Automatic quantification and growth pattern analysis of tumor cells in brain sections was set up based on human cell specific staining and a CellProfiler Analyst’s machine learning classifier with a manual observer correlation of 0.86. GSC xenograft tumors with a wide range of histopathological features and biological behaviors recapitulating high grade astrocytoma was confirmed in mice injected with 14 of the 29 glioblastoma cell cultures (48%). Glial lineage markers, such as Sox2, GFAP, and Olig2, were expressed both in patient tumors and patient derived xenografts. Individual glioblastoma cell cultures were either characterized by formation of condensed tumors (8/14, 57%) or diffuse infiltrative growth through the brain parenchyma (6/14, 43%). In summary, we present a valuable mouse model for preclinical studies of glioma. Integrative analysis of molecular profiles with growth pattern data has the potential to unravel genes that distinguish tumors with more infiltrative growth. Our biobank of luciferase labeled GSCs may be useful for longitudinal monitoring of tumor growth dynamics in the setting of therapies and provides a foundation for testing the effect of predicted drug vulnerabilites in orthotopic xenografts mouse models.
Citation Format: Cecilia Krona, Soumi Kundu, Karl Holmberg-Olausson, Riasat Islam, Rashmi Ramachandra, Ludmila Elfineh, Sven Nelander. In vivo modeling of high grade glioma for oncology drug development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4813. doi:10.1158/1538-7445.AM2017-4813
Abstract 483: Differential expression of miR-34b and androgen receptor pathway regulate prostate cancer aggressiveness between African Americans and Caucasians
Authors: Shiina Marisa , Hashimoto Yutaka , Kato Taku , Yamamura Soichiro , Tanaka Yuichiro , Majid Shahana , Saini Sharanjot , Varahram Shahryari , Kulkarni Priyanka , Dasgupta Prita , Sumida Mitsuho , Deng Guoren , Dahiya Rajvir 
Published: July 2017

Abstract
African-Americans are diagnosed with more aggressive prostate cancers and have worse survival than Caucasians, however a comprehensive understanding of this health disparity remains unclear. To clarify the mechanisms leading to this disparity, we analyzed the potential involvement of miR-34b expression in African-Americans and Caucasians. We found that miR-34b expression is lower in human prostate cancer tissues from African-Americans compared to Caucasians. DNA hypermethylation of the miR-34b-3p promoter region showed significantly higher methylation in prostate cancer compared to normal tissues. We found that AR and ETV1 genes are differentially expressed in MDA-PCa-2b and DU-145 cells after overexpression of miR-34b. Direct interaction of miR-34b with the 3’ untranslated region of AR and ETV1 was validated by luciferase reporter assay. We found that miR-34b downregulation in African-Americans is inversely correlated with high AR levels that lead to increased cell proliferation. Overexpression of miR-34b in cell lines showed higher inhibition of cell proliferation, apoptosis and G1 arrest in African-American cells (MDA-PCa-2b) compared to the Caucasian cell line (DU-145). Taken together, our results show that differential expression of miR-34b and AR are associated with prostate cancer aggressiveness in African-Americans.
Citation Format: Marisa Shiina, Yutaka Hashimoto, Taku Kato, Soichiro Yamamura, Yuichiro Tanaka, Shahana Majid, Sharanjot Saini, Shahryari Varahram, Priyanka Kulkarni, Prita Dasgupta, Mitsuho Sumida, Guoren Deng, Rajvir Dahiya. Differential expression of miR-34b and androgen receptor pathway regulate prostate cancer aggressiveness between African Americans and Caucasians [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 483. doi:10.1158/1538-7445.AM2017-483
Abstract 4837: Development of an in vitro 3D glioblastoma model system for patient-specific drug response profiling
Authors: DesRochers Teresa , Clark Ashley , O'Donnell Lauren , Guo Qi , Holmes Lillia , Dobrolecki Lacey , Lewis Michael , Schammel David , Edenfield Jeff , Kanos Charles , Nelson Fred , Gardner Steve , Lynn Michael , Hodge Philip , Corless Christopher , Clark Paul , Crosswell Hal E. , Kuo John 
Published: July 2017

Abstract
Glioblastoma (GBM) has a median survival of less than 2 years due to intra-tumoral and inter-patient heterogeneity, diffuse infiltration of adjacent brain tissue, and absence of effective therapies. Development of more efficacious therapies will require better GBM models for the testing and identification of novel agents; traditional 2D cell culture lacks biologic and clinical fidelity and orthotopic xenograft models are costly, low throughput, and time consuming. We have developed a complex, patient-specific 3D cultured GBM model to assay drug response that combines high-throughput drug response determination with neurosphere formation and next-generation sequencing (NGS). Neurosphere formation and the presence/quality of glioblastoma stem cells (GSCs) has been validate through limited dilution growth in vivo. Our 3D model system has been validated against the primary patient GBM tissue and/or patient-derived xenografts (PDX) and consists of histology, epigenetic and mRNA expression analysis, and comparison of in vivo drug response. This strategy enabled examination of MGMT methylation in relation to temozolomide response, and possible actionable genetic mutations with candidate targeted therapies. Using our 3D model, we have observed EGFR-amplified GBM sensitivity to the EGFR inhibitor afatanib, and PTEN mutant GBM sensitivity to dual PI3K/mTOR inhibitor dactolisib. These data suggest validation of clinical and molecular correlation with this new in vitro, patient-derived 3D GBM model for drug response profiling. Our data supports the further development and use of complex 3D models, neurosphere formation, and NGS profiling for patient-specific GBM analysis. This model system is currently being considered for preclinical assessment of novel therapies and may be a useful adjunct in future precision medicine applications to improve patient outcomes.
Citation Format: Teresa DesRochers, Ashley Clark, Lauren O'Donnell, Qi Guo, Lillia Holmes, Lacey Dobrolecki, Michael Lewis, David Schammel, Jeff Edenfield, Charles Kanos, Fred Nelson, Steve Gardner, Michael Lynn, Philip Hodge, Christopher Corless, Paul Clark, Hal E. Crosswell, John Kuo. Development of an in vitro 3D glioblastoma model system for patient-specific drug response profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4837. doi:10.1158/1538-7445.AM2017-4837
Abstract 4850: Overexpression of P62/IMP2 promotes metastasis in hepatocellular carcinoma via inhibition of E-cadherin expression
Authors: Xing Mengtao , Li Pei , Li Jitian , shi Jianxiang , Dai Liping , Francia Giulio , Zhang Jianying 
Published: July 2017

Abstract
Hepatocellular carcinoma (HCC) is one of the most common type of cancer and the third leading cause of cancer related death in worldwide. Insulin-like growth factor 2 mRNA binding protein 2 (p62/IMP2/IGF2BP2) was originally reported as an autoantigen in HCC which belongs to IMPs family. The IMPs family contains three members: IMP1, IMP2 and IMP3, which share similar protein structure. IMPs are oncofetal proteins, which are expressed during embryogenesis and lost in most tissues in adults. Therefore, p62/IMP2 can be used as a potential biomarker for early diagnosis of HCC. We have evaluated the expression of p62/IMP2 protein both in human tissues and HCC cell lines by immunohistochemistry and western blotting analysis, and found that p62/IMP2 protein is overexpressed in human HCC tissues compared with normal human liver tissues (score= 10.30, n=40 vs. score =5.23, n=30, p&lt;0.05). The expression of p62/IMP2 was scored by immune-staining intensity and positively immune-staining cell numbers. At the same time, we found that p62/IMP2 was also overexpressed in several HCC cell lines. Stable p62/IMP2 overexpression and depletion SNU449 human HCC cell line was made by using p62/IMP2 cDNA transfection and lentivirus mediated knockdown approaches, and it was further confirmed by western blotting analysis. Wound healing assay has shown that overexpression of p62/IMP2 can significantly enhance the cell migration ability in SNU449 cells. On the contrary, the depletion of p62/IMP2 can reduce the migration ability in SNU449 cells (p&lt;0.05). Moreover,MTT assay has also shown p62/IMP2 overexpressed cells may have a higher rate of proliferation at 72h(p&lt;0.05). In addition, we have observed that overexpression of p62/IMP2 can significant inhibit the expression of E-cadherin in western blotting analysis. In summary, our data would suggest that overexpression p62/IMP2 may promote metastasis via inhibition of E-cadherin expression in HCC.
Citation Format: Mengtao Xing, Pei Li, Jitian Li, Jianxiang shi, Liping Dai, Giulio Francia, Jianying Zhang. Overexpression of P62/IMP2 promotes metastasis in hepatocellular carcinoma via inhibition of E-cadherin expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4850. doi:10.1158/1538-7445.AM2017-4850