bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 864: Alternated activation of TGFβ pathway and differential expression of epithelial to mesenchymal transition transcription factors in relation to lymph node metastasis in two subtypes of breast cancer tumors
Authors: Ortega-Hernandez Victoria , Gajardo-Meneses Patricia , Fernandez Wanda , Carvallo Pilar 
Published: July 2017

Abstract
Breast cancer is the leading cause of cancer death among women worldwide, being distant metastases the main cause of death. Epithelial to mesenchymal transition (EMT) has been implicated in promoting cancer invasion and metastasis. This process can be induced by TGFβ through the expression of transcription factors: TWIST, SNAIL, SLUG and ZEB1, which expression may be promoted by different signaling pathways such as SMAD2/SMAD3, PI3K/AKT and ERK/MAPK. The expression of EMT transcription factors has been previously studied in several cancer cell lines, although no studies have been performed in breast cancer tumors. In this study, we analyzed by immunohistochemistry the expression of the four transcription factors, and the signal transduction key proteins p-SMAD2 (ser465/467), p-SMAD2L (ser245/250/,255) and p-AKT (ser473), in 107 breast cancer tumors. We found expression of at least one transcription factor in all triple negative tumors (n=24), while only 70% luminal tumors showed expression of at least one of these proteins. Expression of ZEB1, SNAIL and SLUG was observed in tumors with metastases to lymph node, whereas the majority of tumors expressing TWIST were negative for lymph node status. All triple negative tumors with an active state of the signal transduction pathway TGFβ/SMAD showed expression of at least one transcription factor, whereas 65% of luminal tumors with an active state of the same pathway showed no expression of these transcription factors. Active state of PI3K/AKT pathway was observed only for luminal tumors as it has been described. Sixty-three percent of tumors having this pathway active showed expression of at least one transcription factor. In conclusion we found differential expression of EMT transcription factors in relation to lymph node status and a differential active state of signaling pathways in relation to tumoral subtype of breast cancer tumors. Our results suggest a different mechanism of EMT induction by TGFβ in relation to two tumor’s subtypes and lymph node metastasis.
Citation Format: Victoria Ortega-Hernandez, Patricia Gajardo-Meneses, Wanda Fernandez, Pilar Carvallo. Alternated activation of TGFβ pathway and differential expression of epithelial to mesenchymal transition transcription factors in relation to lymph node metastasis in two subtypes of breast cancer tumors [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 864. doi:10.1158/1538-7445.AM2017-864
Abstract 868: GRK5 promotes a mesenchymal transition in prostate cancer
Authors: Black Joseph B. , Mahmud Iqbal , Purayil Hamsa Thayele , Daaka Yehia 
Published: July 2017

Abstract
Locally advanced and metastatic prostate cancer is incurable, despite decades of research targeting the activity of the androgen receptor (AR). Our lab previously identified G protein-coupled receptor 5 (GRK5) for its ability to regulate PCa progression, independent of AR activity. GRK5 partially partitions to the nucleus, wherein it has been shown to regulate the transcriptome in non-PCa models. To globally elucidate the mechanistic impact of GRK5 on PCa progression, we are investigating the impact of GRK5 on the PCa transcriptome. We hypothesize that GRK5’s regulation of the PCa transcriptome promotes tumor progression. To assay the effect of GRK5 on the PCa transcriptome, RNA sequencing was performed in two cell lines: PC3 Control (PC3 shGFP) and PC3 GRK5 Knockdown (PC3 shGRK5). Ontologic analysis identified the epithelial–mesenchymal transition (EMT) as being affected when GRK5 is depleted. The epithelial–mesenchymal transition (EMT) is highly associated with promoting PCa progression and chemoresistance, thus we selected this pathway for further investigation. Confirmatory western blot analysis and quantitative PCR (qPCR) validated that depleting GRK5 suppresses the expression of the mesenchymal markers Vimentin and N-Cadherin. Similarly, overexpression of GRK5 increases the expression of these mesenchymal markers. Stable overexpression of GRK5 promotes cells to develop a spindle-like morphology, indicative of a mesenchymal state. GRK5 mediates this mesenchymal transition through increasing the expression of the EMT transcription factor, Twist1. Further analysis identifies that GRK5 activity promotes in vitro invasion. Cell lines overexpressing GRK5 demonstrate an increase in resistance to docetaxel, the mainstay chemotherapy for advanced PCa. Overexpression of mutated forms of GRK5 that are relegated to the nucleus are able recapitulated all aforesaid changes, arguing that the nuclear activity of GRK5 mediates this effect. Collectively, this data presents a novel mechanism promoting PCa progression, independent of AR activity. Future work seeks to assay the ability of GRK5 to promote metastasis in vivo in mouse models.
Note: This abstract was not presented at the meeting.
Citation Format: Joseph B. Black, Iqbal Mahmud, Hamsa Thayele Purayil, Yehia Daaka. GRK5 promotes a mesenchymal transition in prostate 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 868. doi:10.1158/1538-7445.AM2017-868
Abstract 87: Treatment schedules influence acquisition of Doxorubicin resistance through epigenetic mechanism in breast cancer cells
Authors: Ponnusamy Logeswari , Mahalingaiah Prathap Kumar S. , Singh Kamaleshwar P. 
Published: July 2017

Abstract
Breast cancer is the leading cause of cancer related mortality in women. Chemotherapy resistance is a major limitation in clinical treatment of breast cancer. Mounting evidence implicates the epigenetic aberrations in acquired chemoresistance. However, the influence of treatment schedules and associated epigenetic changes on acquisition of doxorubicin resistance in breast cancer is not clear. Therefore, objective of this study was to evaluate the impact of treatment schedules on acquisition of doxorubicin resistance and the molecular mechanistic basis of this process in breast cancer cells. To address this question, two different treatment strategies viz, continuous exposure and intermittent exposure were used to generate doxorubicin resistant cells lines from ER-positive MCF-7 and triple negative MDA-MB-231 breast cancer cell lines. The level of resistance against doxorubicin and the temporal sequence of molecular changes associated with the resistance phenotype were evaluated at 4 months and 18 months’ following exposure to doxorubicin. Results revealed that intermittent exposure to doxorubicin resulted in significantly higher level of resistance as compared to continuous exposure. ER-positive MCF-7 cells developed relatively earlier and high level of resistance when compared to MDA-MB-231 cells. Additionally, the resistance to doxorubicin-induced cytotoxicity was associated with transient acquisition of EMT and CSC-like phenotype in breast cancer cells around 4 months following doxorubicin. Gene and protein expression analysis further revealed temporal changes in the expression of epigenetic regulatory genes and histone modifications respectively. The temporal changes in expression of genes were positively correlated with doxorubicin exposure time during resistance development. In summary, the result of this study for the first time suggests that the treatment schedules influence the acquisition of doxorubicin resistance potentially through epigenetic mechanisms. The findings of this study will be helpful in chemotherapy of breast cancer to achieve the best clinical result
Note: This abstract was not presented at the meeting.
Citation Format: Logeswari Ponnusamy, Prathap Kumar S. Mahalingaiah, Kamaleshwar P. Singh. Treatment schedules influence acquisition of Doxorubicin resistance through epigenetic mechanism in breast 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 87. doi:10.1158/1538-7445.AM2017-87
Abstract 888: Volumetric reconstruction of targeted nanoparticles for superparamagnetic relaxometry
Authors: Thrower Sara L. , Mathieu Kelsey , Stefan Wolfgang , Aburto R. Romero , Lu Zhen , Bast Robert C. , Sovizi Javad , Fuentes David , Hazle John D. 
Published: July 2017

Abstract
Superparamagnetic relaxometry (SPMR) is an emerging technology that uses the unique magnetic properties of superparamagnetic iron oxide nanoparticles (SPIONs) to detect cancer cells. In order to estimate tumor locations from raw MRX data, we developed an L1 reconstruction algorithm under the assumption that early stage disease is sparsely distributed throughout the anatomy. The approach was previously validated in phantom datasets of known signal locations. Advantages of our method are that the solver does not require the user to input prior information regarding the expected number of tumors or their approximate locations. Additionally, the solver reconstructs a volumetric distribution of detected sources within the field of view. To validate the algorithm for use in preclinical settings, SPMR was performed on SKOV3 ovarian tumor bearing mice (n = 3) with the MRX device over time following an intratumoral injection of anti-Her2 antibody-conjugated 25nm SPIONs (Senior Scientific LLC). The SPMR data was reconstructed with our sparse solver and was found to be highly correlated (r = 0.9978) with the results generated by the commercial software that accompanies the MRX instrument (MSA). Additionally, segmentation of the reconstruction revealed a strong signal (2.0·106 pJ/T) in the area of the tumor and almost no signal in areas outside of the tumor (0.077 pJ/T) at four hours after injection. This result was consistent with our prior observations which have revealed that a large fraction of intratumorally-injected nanoparticles remain localized within the tumor for several hours after injection. Furthermore, these results were consistent with SPMR data collected by measuring tissue samples excised 24 hours after injection, of which the tumor had the highest signal. Thus, our sparse reconstruction algorithm was able to return the expected results without prior information regarding the location of nanoparticles. Future work will focus on quantifying the uncertainty in our reconstruction method, as well as characterizing its stability with increasingly complex nanoparticle distributions and detectability limits. In conclusion, this work represents an important advancement of the SPMR technology by allowing for volumetric reconstructions of bound nanoparticles from in vivo data.
Citation Format: Sara L. Thrower, Kelsey Mathieu, Wolfgang Stefan, R. Romero Aburto, Zhen Lu, Robert C. Bast, Javad Sovizi, David Fuentes, John D. Hazle. Volumetric reconstruction of targeted nanoparticles for superparamagnetic relaxometry [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 888. doi:10.1158/1538-7445.AM2017-888
Abstract 900: Tumor Treating Fields (TTFields) affect human glioma cell migration, invasion and adherence properties in vitro
Authors: Garcia-Carracedo Dario , Schneiderman Rosa S. , Zeevi Einav , Shteingauz2 Anna , Giladi Moshe , Voloshin Tali , Porat Yaara , Munster Mijal , Blat Roni , Kirson Eilon D. , Weinberg Uri , Palti Yoram 
Published: July 2017

Abstract
TTFields, an approved treatment modality for glioblastoma, are delivered via continuous, noninvasive application of low intensity, intermediate frequency alternating electric fields. The antimitotic effects of TTFields have been extensively investigated. We investigated other processes that may be affected by TTFields such as human glioma cell migration and cellular invasion properties. Four human glioma cell lines were treated with TTFields using the inovitro system. Cell migration rates were measured using wound healing assays. Invasion assays were performed using a modified Matrigel coated Boyden chamber. Cell adhesion assays were performed during TTFields treatment and compared to untreated controls. At the end of TTFields’ treatment, adhered cells were trypsinized and counted. A cells de-adhesion assay was performed following 24 and 72 hours of TTFields application with the outcome being the number of cells removed after varying times of trypsinization. Application of TTFields in-vitro led to a significant reduction in cell migration velocity compared with untreated control cells. Furthermore, comparison of the anti-migratory efficacy of TTFields applied from 2 directions vs. a single direction revealed that the single direction approach applied perpendicularly to the course of migration was more effective than TTFields applied in 2 directions or in a single parallel direction. Glioma cells invasion was significantly reduced compared to untreated cells in all tested cell lines. Cell adhesion to the substrate (fibronectin) was significantly reduced when exposed to TTFields. On the other hand, cell de-adherence following TTFields treatment took significantly longer time of trypsinization. Our results suggest that human glioma cell motility is impaired by exposure to TTFields. Both alterations in cells adherence and de-adherence during exposure to TTFields may contribute to reduction in cell motility. Further studies are needed to elucidate the mechanism by which TTFields disrupts cellular motility in glioma cancer cells.
Citation Format: Dario Garcia-Carracedo, Rosa S. Schneiderman, Einav Zeevi, Anna Shteingauz2, Moshe Giladi, Tali Voloshin, Yaara Porat, Mijal Munster, Roni Blat, Eilon D. Kirson, Uri Weinberg, Yoram Palti. Tumor Treating Fields (TTFields) affect human glioma cell migration, invasion and adherence properties in vitro [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 900. doi:10.1158/1538-7445.AM2017-900
Abstract 919: Identification of stem cells in stomach corpus and antrum
Authors: Matsuo Junichi , Yamamura Akihiro , Yeoh Khay Guan , Osato Motomi , Ito Yoshiaki 
Published: July 2017

Abstract
Gastric cancer is still relatively poorly understood, because of the lack of knowledge on stem cells in stomach. By radio-labeling experiments and electron microscopy, rapidly proliferating stem cells have been suggested in isthmus of both corpus (which is just below pit cell zone) and antrum (which is a quarter above the base) (1). In addition, there have been reports indicating the proliferation capacity under certain conditions in a subset of chief cells present at the base in corpus (2). We reported earlier that 270 bp Runx1 enhancer element (termed aR1) that drives the expression of Runx1 in hematopoietic stem cells (3). We found that eR1 also marks the cells in these three locations of stomach (4). In antrum, the stem cell marker, Lgr5, has been reported to mark the cells at the base of antrum but not in corpus (5). eR1+ and Lgr5+ stem cell in antrum appears to be different. It will be interesting to find out the difference between these two types of stem cells. Transgenic mouse was generated that harbors eR1 linked to heterologous promoter and Cre recombinase (eR1-CreERT2). By treating the mouse with tamoxifen, we showed lineage tracing from eR1+ cells in the isthmus of both corpus and antrum that replenish entire glands. We expressed K-rasG12D in eR1+ cells in isthmus and observed antralization of corpus epithelium that is similar to precancerous lesion in human stomach after H pylori infection. On the other hand, eR1+ chief cells rarely multiply. However, they robustly proliferate after tissue damage or oncogene expression. When K-rasG12D is activated in eR1+ chief cells, they show retrodifferentiation to show SPEM (spasmolytic polypeptide expressing metaplasia) phenotype. eR1+ chief cells appear to be reserve stem cells that can replace cells after tissue damage. We now have capability to activate or inactivate genes of interest in the stomach stem cells. We are examining stepwise carcinogenesis in stomach. From eR1+ cells in isthmus of both corpus and antrum, we are generating organoids. We will describe interesting difference in the properties of organoids generated from eR1+ cells from corpus and those from antrum. &lt;Reference&gt; (1) Karam and Leblond., The Anatomical Record 1993; 236: 259-273. (2) Goldenring et al., Gastroenterology 2011; 138: 2207-2210. (3) Ng et al., Stem Cells 2010; 28: 1869-81. (4) Matsuo et al., Gastroenterology 2016; PMID: 27670082. (5) Barker et al., Cell Stem Cell 2010; 6: 25-36.
Citation Format: Junichi Matsuo, Akihiro Yamamura, Khay Guan Yeoh, Motomi Osato, Yoshiaki Ito. Identification of stem cells in stomach corpus and antrum [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 919. doi:10.1158/1538-7445.AM2017-919
Abstract 92: Acquisition of temozolomide resistance: Identification of a new drug tolerant stage in glioblastoma cells
Authors: Rabé Marion , Janati Hicham , Dumont Solenne , Thibault-Carpentier Christelle , Clairambault Jean , Vallette François M. , Gratas Catherine 
Published: July 2017

Abstract
Glioblastoma multiforme (GBM) are the most aggressive and common brain tumors in adults. Despite surgery and combined radio-chemotherapy with temozolomide (TMZ), tumor reccurence always occurs. The median survival time for patients diagnosed with GBM is about 14 months with less than 5% survival at 5 years. Today the main marker of TMZ resistance is the methylation status of MGMT promoter. Patients with a methylated promoter usually have a better response to treatment than patients with an unmethylated promoter. Indeed MGMT is an enzyme involved in DNA repair mechanisms that abrogates TMZ effects. However, in clinical trials targeting the MGMT enzyme, median survival of patients was not improved. It is thus essential to decipher the mechanisms involved in the acquisition of TMZ resistance to identify new therapeutic targets. To achieve this goal TMZ resistant cells were generated by continuous treatment of the U251 human glioblastoma cell line. These cells are sensitive to TMZ and do not express MGMT. We performed transcriptomic analysis by RNA-Seq on U251 treated with TMZ (50µM) for different time and selected differentially expressed genes. We also evaluated target genes expression in single cells by RT-qPCR using C1-HD-Biomark technology (Fluidigm). Transcriptome profiling allowed to identify a transient phase with TMZ tolerant cells before acquisition of complete resistance. These cells are characterized by a modified morphology and a no proliferative state. In this population we identified a subset of genes with the same transient overexpression. Similar results were observed in other glioblastoma cell lines and under other stress conditions. In contrast, stable expression of MGMT appeared later with the emergence of the TMZ resistant population. Interestingly single cell qPCR showed that MGMT expression in the resistant cells could not be explained by clonal selection of MGMT positive cells. Drug screening on the TMZ tolerant cells revealed a potent killing activity of histone deacetylating agents (HDAC inhibitors). In conclusion, we have shown that glioblastoma cells become resistant after a transient state of TMZ tolerance. Identification of this singular population highlights new molecular targets and a new therapeutic window. Targeting these tolerant cells could avoid emergence of resistance and tumor recurrence, thereby patients survival could be improved.
Citation Format: Marion Rabé, Hicham Janati, Solenne Dumont, Christelle Thibault-Carpentier, Jean Clairambault, François M. Vallette, Catherine Gratas. Acquisition of temozolomide resistance: Identification of a new drug tolerant stage in glioblastoma 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 92. doi:10.1158/1538-7445.AM2017-92
Abstract 920: ICAM-1(CD54) is involved in the osteogenic differentiation of mesenchymal stem cells and affects the progression of osteosarcoma cells
Authors: Zhang Yidan , Piperdi Sajida , Zaphiros Nikolas , Koirala Pratistha , Ren Tingting , Roth Michael , Gill Jonathan , Hoang Bang , Geller David , Yang Rui , Zhang Wendong , Du Xiuquan , Zhang Jinghang , Gorlick Richard 
Published: July 2017

Abstract
Purpose: The aim of this study is to validate the relationship between the expression of ICAM-1(CD54), a cell surface glycoprotein, and osteogenic differentiation of mesenchymal stem cells (MSCs) and the role of ICAM-1 in the progression of osteosarcoma (OS) cells.
Experimental Design: To compare the gene expression profiles between MSCs and MSCs after osteogenic induction, a microarray analysis was first performed. The differences in expression of specific genes including ICAM-1 were confirmed using western blot and flow cytometry. MSCs were sorted into two groups of cells by CD105+CD44+CD54+ and CD105+C44+CD54- and properties of these cells were compared. Expression of ICAM-1 among tumor cell lines and xenograft OS cells were tested at the protein level. ICAM-1 was stably, constitutively overexpressed in multiple cell types. Differences in osteogenic differentiation potential between normal cell lines and transformed cell lines were studied using alizarin red S staining. Motility, proliferation and invasion as well as the metastatic potential of the transformed and normal cells were evaluated.
Results: The initial microarray analysis revealed that ICAM-1 expression was significantly increased in MSCs after osteogenic induction for 15 days (p=0.042). Consistent results were achieved in western blot and flow cytometry analysis. Further microarray analysis between CD105+CD44+CD54+ and CD105+C44+CD54- groups determined that NF-kB signaling pathway was differentially activated. As for OS cells, ICAM-1 is not expressed at high level among OS tumor cell lines and is inconsistently expressed in xenograft OS cells. Enhanced osteogenic differentiation potential was observed in ICAM-1 overexpressing cells. Although there were no major difference in in vitro motility, proliferation or invasion tests, substantially less lung nodules occurred with transformation as compared to the normal control.
Conclusions:
ICAM-1 is involved in the osteogenic differentiation of mesenchymal stem cells and its down regulation may be involved in the progression of osteosarcoma cells.
Citation Format: Yidan Zhang, Sajida Piperdi, Nikolas Zaphiros, Pratistha Koirala, Tingting Ren, Michael Roth, Jonathan Gill, Bang Hoang, David Geller, Rui Yang, Wendong Zhang, Xiuquan Du, Jinghang Zhang, Richard Gorlick. ICAM-1(CD54) is involved in the osteogenic differentiation of mesenchymal stem cells and affects the progression of osteosarcoma 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 920. doi:10.1158/1538-7445.AM2017-920