bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2422: Early features of EMT in Abcb4−/
−-cholangiocytes: A novel cellular model for testing antimetastatic drugs
Authors: Arbizu Amaia , Gil-Puig Carmen , Cabello Juan , Lecanda Jon 
Published: August 2012

Abstract
Discovering novel drugs for epithelial tumors remains a challenge since cellular events underlying the onset of carcinoma progression are largely unknown. We previously reported the therapeutic effects of oral 5′-methylthioadenosine in the Abcb4−/− mouse (Latasa et al, PLoS ONE 2010: e15690), a clinically relevant model of chronic liver disease leading to carcinoma development. Aiming to gain insight into malignant cellular traits, we then generated primary cultures of intrahepatic bile duct cells from this Abcb4−/− mouse model. We found that Abcb4−/−-cholangiocytes exhibit a fibroblastoid-like appearance which is accompanied by diminished expression of epithelial hallmarks (CK19), and a concomitant up-regulation of mesenchymal markers such as Snail1. The trans-epithelial-electrical-resistance analyses indicated that whereas confluent monolayers of normal cholangiocytes retained the epithelial polarity, Abcb4−/−-cholangiocytes fail to repolarize. Abcb4−/−-cholangiocytes proliferated at reduced growth rates (p&lt;0.05), formed a higher number of colonies in soft agar (p&lt;0.01) and were less sensitive to antiproliferative effect of TGFβ1 (p&lt;0.05). Consistent with EMT characteristics, Abcb4−/−-cholangiocytes induced TGFβ isoforms and were more sensitive to TGFβ1-signaling. Collectively, this data suggests that Abcb4−/− cholangiocytes acquire EMT features that may be largely regulated in vivo by TGFβ1. This original bile ductular cell line of Abcb4−/−-cholangiocytes will be useful for testing compounds that may interfere with metastatic malignancy of EMT.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2422. doi:1538-7445.AM2012-2422
Abstract 2427: The stress response controls the interorgan glutathione/interleukin-6 cycling activity: A systemic signaling mechanism promoting metastases growth.
Authors: Estrela Jose M. , Obrador Elena , Mena Salvador , Rodriguez Maria L. , Pellicer Jose A. , Asensi Miguel , Vallés Soraya L. , Benlloch Maria 
Published: August 2012

Abstract
B16 melanoma F10 (B16-F10) cells with high glutathione (GSH) content show very high metastatic activity in vivo. An intertissue flow of GSH, where the liver is the main reservoir, increases GSH content in metastatic cells and promote their growth. We studied possible tumor-derived molecular signals that could activate GSH release from hepatocytes. GSH efflux increases in hepatocytes isolated from mice bearing liver or lung metastases, thus suggesting a systemic mechanism. Fractionation of serum-free conditioned medium from cultured B16-F10 cells and monoclonal antibody-induced neutralization techniques facilitated identification of interleukin (IL)-6 as a tumor-derived molecule promoting GSH efflux in hepatocytes. IL-6 activates GSH release through a methionine-sensitive/organic anion transporter polypeptide 1- and multidrug resistance protein 1-independent channel located on the sinusoidal site of hepatocytes. Specific siRNAs were used to knock down key factors in the main signaling pathways activated by IL-6, which revealed a STAT3-dependent mechanism. Our results show that IL-6 (mainly of tumor origin) facilitates GSH release from hepatocytes and its interorgan transport to metastatic growing foci. Metastatic tumor activated the hypothalamic-pituitary-adrenal axis, thus increasing expression of hypothalamic corticotropin releasing factor and plasma levels of adrenocorticotropin hormone, corticosterone, and cathecolamines. Corticosterone and norepinephrine increased IL-6 expression and synthesis in metastatic cells, thus promoting the interorgan GSH/IL-6 cycling activity. Our results suggest possible mechanisms of cross-talk between metastases and the central nervous system of the host.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2427. doi:1538-7445.AM2012-2427
Abstract 2431: 89Zr-bevacizumab PET as an early biomarker for response to everolimus treatment in an ovarian cancer xenograft model
Authors: van Scheltinga Anton G.T. Terwisscha , van der Bilt Arne R.M. , Timmer-Bosscha Hetty , Schröder Carolien P. , Pot Linda , Kosterink Jos G.W. , van der Zee Ate G.J. , Hooge Marjolijn N. Lub-de , de Jong Steven , de Vries Elisabeth G.E. , Reyners An K.L. 
Published: August 2012

Abstract
The mammalian target of rapamycin (mTOR) pathway is activated in the majority of ovarian cancers and is involved in tumor angiogenesis. Inhibitors of mTOR, like everolimus, are potentially interesting drugs as they can exert antitumor activity in part through reducing downstream vascular endothelial growth factor-A (VEGF-A) production. We investigated whether early effects of everolimus treatment could be monitored with 89Zr-bevacizumab positron emission tomography (VEGF-PET). Methods: The effect of everolimus on VEGF-A secretion was determined in three human ovarian cancer cell lines and in A2780luc+ ovarian cancer cells xenografted subcutaneously in BALB/c mice. Mice received daily everolimus (10 mg/kg intraperitoneally) for 14 days. PET scans with the tracer 89Zr-labeled bevacizumab were performed to monitor tumor VEGF-A expression before (baseline) and after treatment. Images were obtained 6 days after tracer injection. Tracer uptake was quantified and expressed as mean standardized uptake values (SUVmean). For ex vivo 89Zr-bevacizumab biodistribution and correlative tissue analyses, control animals were sacrificed after the baseline scans. Tumor VEGF-A levels were measured with ELISA in tumor lysates and mean vascular density (MVD) was determined with immunohistochemistry. Results: Everolimus treatment lowered VEGF-A levels in the supernatant of all cell lines. Everolimus lowered 89Zr-bevacizumab tumor uptake by 21.7 ± 4.0% (SUVmean 2.26 ± 0.18 versus 2.89 ± 0.20, p &lt; 0.01). Ex vivo 89Zr-bevacizumab biodistribution showed less tracer uptake in the tumors of treated compared to control animals (7.78 ± 0.84 %ID/g versus 14.02 ± 1.68 %ID/g, p &lt; 0.01), while no differences were observed for other tissues. VEGF-A protein levels in tumor lysates were lower in treated versus untreated tumors (p = 0.04), as was the MVD (p &lt; 0.01). Conclusion: 89Zr-bevacizumab PET showed reduced tumor VEGF-A levels in vivo in response to everolimus therapy, coinciding with inhibition of tumor angiogenesis. Currently there are 2 clinical trials ongoing to study the value of 89Zr-bevacizumab PET to monitor tumor VEGF-A levels as an early biomarker of response to mTOR inhibitor therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2431. doi:1538-7445.AM2012-2431
Abstract 2434: A genetically engineered mouse for imaging of apoptosis in a tissue specific manner
Authors: Galbán Stefanie , Jeon Yong Hyun , Sharkey Lisa M. , Hoff Benjamin A. , Galban Craig J. , Ross Brian D. , Rehemtulla Alnawaz 
Published: August 2012

Abstract
The importance of the apoptotic machinery is exemplified in a number of disease processes. For example, inhibition of apoptosis can result in a number of cancers, autoimmune diseases, inflammatory diseases, and viral infections. Cancer is characterized by dysregulated cell proliferation and altered cell death, which constitutes a common basis for neoplastic evolution. The most implicit and clinically attractive anticancer strategies, therefore, consist of eliminating tumor cells by preventing their expansion and ultimately inducing apoptotic cell death. We have developed a transgenic mouse model wherein Caspase 3 mediated cell death can be imaged in real time and non-invasively utilizing a luciferase based biosensor. Upon Cre-mediated recombination, transgene expression containing the Caspase 3 biosensor is achieved in a cell or tissue specific manner. Here we show that expression of the Caspase 3 biosensor can be achieved in several tissues. In addition, we demonstrate in mouse models of cancer, that the ability to dynamically and sensitively image the activation of the Caspase 3 provides an opportunity to understand the dynamics of cell death in response to specific drugs or combination therapies. We also provide results demonstrating the utility of the technology in evaluating the efficacy of cancer therapeutics in cancer stem cells, a population that is rare and transient.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2434. doi:1538-7445.AM2012-2434
Abstract 244: Characterization of a candidate tumor suppressor gene DIRAS1 in esophageal squamous cell carcinoma
Authors: Zhu Yinghui , Chen Polly Leilei , Fu Li , Liu Haibo , Xie Fajun , Guan Xin-Yuan 
Published: August 2012

Abstract
Loss of 19p is one of the most frequent alterations in many malignancies including esophageal squamous cell carcinoma (ESCC), suggesting the existence of a tumor suppressor gene (TSG) within the frequently deleted region. In this study we describe the identification and characterization of one candidate TSG, DIRAS family, GTP-binding RAS-like 1 (DIRAS1), at 19p13.3. DIRAS1 downregulation occurred in 34 of 75 (43.33%) primary ESCCs and 5/9 (55.6%) of the ESCC cell lines. Immunohistochemistry detection demonstrated that the down-regulation DIRAS1 expression was an independent prognostic factor of ESCC and associated with poor survival in ESCC. Functional studies showed that Ectopic expression of DIRAS1 in ESCC cells inhibited cell proliferation, foci formation, and tumor formation in nude mice. The tumor-suppressive mechanism of DIRAS1 was associated with its proapoptotic role in a mitochondrial-dependent manner by down-regulation of phosphorylated BAD and activating caspase-9, caspase3 and PARP via ERK- and p38-dependent signaling pathway. In addition, down-regulation of DIRAS1 protein was significantly correlated with ESCC lymph node metastasis (P = 0.003), which was associated with its function in inhibiting cell migration and invasion by down-regulation of MMP-2 and MMP-9 via ERK- and p38-dependent signaling pathway. In conclusion, our findings suggest that DIRAS1 plays an important suppressive role in the development and progression of ESCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 244. doi:1538-7445.AM2012-244
Abstract 2450: Optimization of spontaneous metastasis incidence and quantification in human tumor xenograft models using bioluminescence imaging
Authors: Meade Mary Anne , Baugher Meridith , Baranski Jeni , Castorena Jeremy , Trachet Erin , Lister Deanne R. , Leopold Dick , McConville Patrick 
Published: August 2012

Abstract
Introduction: Spontaneous metastasis models are sought after in order to assess the potential of therapies aimed at prevention or treatment of primary tumor metastases. While some human tumor xenograft mouse models show spontaneous metastasis, few show high tissue specific incidence. Commonly the growth of the inherently more advanced primary tumor also limits the ability to characterize far less advanced metastases. Bioluminescence imaging provides a quantitative and convenient means for assessing location, incidence and progression of metastases using metastatic luciferase expressing tumor lines. However, substantially greater light signal from the primary tumor inhibits the ability to find and track much smaller metastasis signals. Several approaches to optimizing metastasis incidence and quantification, and controlling primary tumor growth were used and compared in a MDA-MB-231-luc-D3H2LN xenograft model. Methods: To assess both mouse strain dependence and implant site dependence of primary tumor metastasis, MDA-MB-231-luc-D3H2LN cells (2x106) were implanted in either the mammary fat pad, the sacral region or the quadriceps in several mouse strains, including outbred nu/nu, SHO and nd/bg/xid. To control primary tumor growth in order to facilitate metastasis quantification, both surgical excision and radiation based growth inhibition of of the primary tumors were used. In all cases, whole body bioluminescence imaging was used to quantify metastasis incidence and growth. Shileding of the primary tumor was used in order to characterize smaller metastases. Results and Discussion: While the MDA-MB-231-luc-D3H2LN mammary fat pad implant model has been shown the metastasize spontaneously, tissue specific incidence is generally &lt; 100% and the ability to quantify metastases severely limited by the substantially greater light signal overwhelming much smaller metastasis signals, even when primary tumor shielding is used. In this study, both surgical excision and radiation based primary tumor growth inhibition enhanced the ability to detect metastases in a variety of tissues, including lymph nodes and lungs. The mammary fat pad implant site and the SCID Beige strain provided the highest spontaneous metastasis incidence. Future work will test radiation timing and dose to further optimize metastasis quantification in this and other spontaneous metastasis models.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2450. doi:1538-7445.AM2012-2450
Abstract 2538: HIF1α regulated expression of XPA contributes to cisplatin resistance in lung cancer
Authors: Liu Yanbin 
Published: August 2012

Abstract
Factors regulating nucleotide excision repair (NER) likely contribute to the heterogenous response of advanced stage lung cancer patients to drugs such as cisplatin. Studies to identify the genes in the NER pathway most closely associated with resistance to cisplatin have not been conclusive. We hypothesized that Xeroderma pigmentosum complementation group A (XPA) because of its dual role in sensing and recruiting other DNA repair proteins to the damage template would be critical in defining sensitivity to cisplatin. Studies were conducted to identify factors regulating transcription of XPA, to assess its role in modulating sensitivity to cisplatin, and its expression in primary lung tumors. HIF1α was found to bind with strong affinity to a hypoxia response element sequence in the promoter of XPA. Modulating expression of HIF1α by siRNA or cobalt chloride markedly reduced or increased transcription of XPA in lung cancer cell lines, respectively. Protein levels of XPA were strongly correlated with sensitivity to cisplatin (r = 0.868; p &lt; 0.001) in cell lines and sensitivity could be increased by siRNA depletion of XPA. Expression of XPA determined in 54 primary lung tumors was increased on average 5.2-fold when compared to normal bronchial epithelial cells and correlated with levels of HIF1α (r = 0.58; p &lt; 0.01). Together, these studies identify XPA as a novel target for regulation by HIF1α whose modulation could impact lung cancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2538. doi:1538-7445.AM2012-2538
Abstract 254: Genome-wide shRNA screening identifies candidate proteins modulating the extrinsic apoptotic pathway
Authors: Kang Zhigang , Cao Liang 
Published: August 2012

Abstract
Apoptosis is a highly regulated process critical for embryonic development, and tissue and organ homeostasis. Deregulation of apoptosis is a common occurrence in cancer. Emerging oncology therapeutic agents designed to engage apoptosis are currently undergoing clinical investigations. To identify unknown proteins that modulate the sensitivity to death receptor DR5 targeted agent drozitumab and to uncover predictive biomarkers, we perform a genome-wide screening of 18,000 genes by using pooled short hairpin RNA libraries, followed by the next generation sequencing for candidate identification. We have identified and confirmed candidate shRNA constructs and target genes that resulted in selective desensitizing of the cells to drozitumab. The roles and mechanisms of action of the newly identified proteins in modulating the extrinsic apoptotic pathway will be presented.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 254. doi:1538-7445.AM2012-254
Abstract 2542: EXO1 is required for SN1 methylator-induced DNA damage response
Authors: Izumchenko Eugene G. , Brown Kevin D. 
Published: August 2012

Abstract
SN1 methylating agents are therapeutics that methylate the O6 position of guanine (O6meG) forcing mispairing with thymine during DNA replication. The mismatch repair (MMR) system recognizes O6meG:T mispairs and activates DNA damage response (DDR). Exonuclease I (EXO1) functions during MMR by excising the damaged strand; however, how MMR mechanistically contributes to DDR activation and if EXO1 is required to activate MMR-dependent response remains unknown. Here we show that Exo1 knockdown in mouse embryonic fibroblasts (MEFs) results in decreased G2/M arrest and checkpoint response (ie, Cdc2/Chk1 phosphorylation), and increased cell proliferation and viability following exposure to the SN1 methylator MNNG. Moreover, ectopic expression of full-length human hEXO1 restored normal response to MNNG. We next examined gamma-H2AX foci formation as a surrogate marker of MMR-dependent DNA repair. 12h after MNNG treatment, 40% of MEFs scored positive for multiple gamma-H2AX foci and this population further increased with prolonged treatment. In contrast, Exo1 depleted MEFs displayed a significantly diminished number of gamma-H2AX foci-positive cells following MNNG. Increased association of Msh2/Msh6 with chromatin was observed in MNNG treated MEFs; however, Exo1 depletion resulted in no upregulation of MMR proteins within the chromatin fraction. Furthermore, MNNG-induced Msh2/Chk1 association was disrupted upon Exo1 depletion. Taken together, we conclude that Exo1 is required to activate DDR following SN1 methylator exposure. Data gathered suggests that Exo1 functions in activating MMR-dependent DNA repair, promoting assembly of MMR complexes with alkylated chromatin, and enhancing the association of MMR components with critical checkpoint mediators. Experiments designed to determine if Exo1 functions in a structural (ie, scaffolding) or catalytic (ie, nucleolytic) manner during SN1 methylator-induced DDR are currently underway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2542. doi:1538-7445.AM2012-2542
Abstract 2543: A dual-fluorescent reporter system facilitates identification of thiol compounds that suppress oxidative frameshift mutations
Authors: Chang Christina L. , Li I-Chen , Chiu Chien-Yuan , Chi Jhih-Ying , Jian Siao-Ru , Wu Chang-Lin 
Published: August 2012

Abstract
DNA mismatch repair (MMR) system corrects replicative errors, especially in microsatellites, and minimizes mutations caused by DNA-damaging agents. Patients with chronic and cancer-associated inflammation display microsatellite instability (MSI), indicative of an inactivated MMR system. MMR-deficient patients also display frameshift mutations in coding microsatellites of many genes, including oncogenes and tumor suppressors. We previously reported that oxidative stress, which occurs in the inflammatory settings, not only inactivates the MMR function but also increases accumulation of frameshift mutations. However, it remains unclear whether oxidative frameshift mutations are preventable due to the lack of a sufficiently sensitive detection assay. Here, we developed and characterized a dual-fluorescent system, utilizing RFP harboring the (CA)13 microsatellite as a reporter and GFP for normalization, in near-isogeneic human colorectal cancer cell lines. By flow cytometry, the new reporter sensitively detected a low level of H2O2-induced frameshift mutations in MMR-proficient cells. Without a functional MMR system, 0.5 mM H2O2 increased frameshift mutations by approximately 10 folds in the cells. In MMR-deficient cells, our reporter revealed that 5 mM glutathione or N-acetylcysteine suppressed oxidative frameshift mutations by approximately 75% or 90% respectively, without affecting cell viability. In contrast, 0.5 mM ascorbic acid augmented H2O2-induced frameshift mutations by two folds, whereas 1 mM aspirin had no effects. Glutathione and N-acetylcysteine also partially suppressed oxidative frameshift mutations in coding microsatellites of endogenous hMSH6 and CHK1 genes, determined by a fluorescinated PCR-based assay. The new utility of these thiol compounds is potentially valuable for preventing oxidative frameshift mutations in the inflammatory settings. The dual-fluorescent reporter system with improved sensitivity will facilitate identification of additional compounds that modulate frameshift mutations relevant to cancer initiation and progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2543. doi:1538-7445.AM2012-2543