bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5703: Up-regulation of miR-146a contributes to the inhibition of invasion of pancreatic cancer cells
Authors: Li Yiwei , VandenBoom Timothy , Wang Zhiwei , Kong Dejuan , Ali Shadan , Philip Philip A. , Sarkar Fazlul H. 
Published: February 2011

Abstract
Pancreatic cancer (PC) is an aggressive malignancy with high mortality primarily due to its highly invasive and metastatic behavior. Over-expression of EGFR and activation of NF-κB are frequently observed in PC associated with high metastatic capacity. Emerging evidence also suggest the critical role of microRNAs (miRNAs) in the regulation of various biological and pathological processes including metastasis. Moreover, miR-146a has been found to be lost in metastatic prostate cancer and its expression reduces the metastatic potential of breast cancer cells through repression of IRAK1 (interleukin 1 receptor-associated kinase 1) and subsequent inhibition of NF-κB activity. In the present study, we assessed the expression pattern of miRNAs in the normal pancreatic duct epithelial cells and pancreatic cancer cells. We also investigated whether the treatment of PC cells with either B-DIM (BioResponse formulated 3,3′-diinodolylmethane with greater bioavailability) or G2535 (a mixture of genistein and other isoflavones) could alter the expression of miRNAs and their targets that are involved in the processes of invasion and metastasis. We found lower expression of miR-146a in PC cells compared to normal pancreatic duct epithelial cells. Interestingly, re-expression of miR-146a inhibited the invasive capacity of Colo357 and Panc-1 PC cells with concomitant down-regulation of EGFR and IRAK-1. Mechanistic studies including miR-146a re-expression, anti-miR-146 transfection, and EGFR knock-down experiment showed that there was a crosstalk between EGFR, MTA-2, IRAK-1, IκBα, and NF-κB. Most importantly, we found that the treatment of PC cells with B-DIM or G2535 could increase the expression of miR-146a and consequently down-regulated the expression of EGFR, MTA-2, IRAK-1, and NF-κB, resulting in the inhibition of invasion of Colo357 and Panc-1 cells. These results provide experimental evidence in support of the role of DIM and isoflavone as a potential non-toxic agent as regulators of miRNA, which could be useful for the inhibition of cancer cell invasion and metastasis, suggesting that these agents could be important for designing novel targeted strategy for the treatment of PC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5703.
Abstract 5719: Epigallocatechin-3-gallate, a green tea polyphenol, reactivates silenced tumor suppressor gene by modifying DNA methylation and histones in human skin cancer cells
Authors: Vaid Mudit , Nandakumar Vijayalakshmi , Katiyar Santosh K. 
Published: February 2011

Abstract
Epigenetics, the heritable processes that modulate gene activity without changes in the DNA sequence, have gained considerable interest in cancer development and molecular targets of cancer treatment. Cancer epigenetics deal with important processes like DNA methylation and histone modification patterns that can either activate oncogenes or inactivate tumor suppressor genes, the crucial steps in tumor development. Accumulating data suggest that dietary factors may alter cancer risk by modifications of epigenetic processes in the cancer cell. Therefore, the present study was designed to investigate whether (−)-epigallocatechin-3-gallate (EGCG), a most potent polyphenol from green tea which has anti-carcinogenic activity, would alter epigenetic events to regulate methylation-silenced tumor suppressor genes in human skin cancer cells. DNA methylation, histone modification and gene expression profile were studied using human epidermoid carcinoma A431 cells and melanoma cells as an in vitro model after EGCG treatment using RT-PCR, western blot analysis, cytostaining, southwestern dot-blot analysis, chromatin immunoprecipitation, enzymatic activity assays and fluorescence activated cell sorting (FACS) analysis of apoptotic cell death. Our study shows that treatment of A431 cells for 3 or 6 days with EGCG at lower concentrations (5, 10 and 20 μg/ml) resulted in DNA demethylation and reduction in the mRNA and protein levels of DNA methyltransferases (DNMTs) 1 and 3a and 3b and the activity of DNMTs in A431 cells in a dose- and time-dependent manner. EGCG also increased the levels of acetylated lysine 9 and lysine 14 on histone H3 (H3-Lys 9, H3-Lys 14), but decreased levels of methylated H3-Lys 9. Under identical conditions, EGCG re-expressed mRNA and protein levels of tumor suppressor genes, p16INK4a and p21WAF1/CIP1, in A431 cells in a dose-dependent manner. Re-expression of p16INK4a and p21 by EGCG treatment of the A431 cells leads to the inhibition of cell proliferation and induction of apoptosis of A431 cells. Together, our study demonstrates that EGCG can epigenetically modulate DNA and histones to activate methylation-silenced tumor suppressor genes. These epigenetic modifications by EGCG may contribute to skin cancer prevention/treatment strategies in humans.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5719.
Abstract 5755: Molecular mechanisms of small cell lung carcinoma development using preclinical mouse models
Authors: Park Kwon-Sik , Sage Julien 
Published: February 2011

Abstract
Small cell lung carcinoma (SCLC) is a neuroendocrine subtype of lung cancer with a 5-year survival rate of less than 10%. A mouse model for human SCLC has been developed based on the fact that the RB and p53 tumor suppressor genes are mutated in more than 90% of human SCLC tumors. Rb/p53 mutant mouse lung tumors closely resemble human SCLC at the cellular and molecular levels, providing a model to probe the mechanisms underlying the development and the maintenance of SCLC in vivo.
Based on preliminary evidence in a small number of human samples and tumor cell lines, we have examined the possibility that SCLC tumors may rely on the Hedgehog (Hh) signaling pathway for their growth. Hh signaling plays a key role during normal lung development and response to injury but normally has low activity in the lung epithelium. In contrast, when we crossed Rb/p53 mutant mice to Ptch1lacZ/+ reporter mice, we found that Hh signaling was active in all the SCLCs that developed. Experiments with cell lines derived from mouse tumors also indicated that the activation of Hh signaling in these cells was cell-autonomous. Constitutive activation of the Hh pathway using a mutant allele of Smo was sufficient to enhance SCLC development in vivo. Inhibition of the Hh pathway with Cyclopamine and GANT61 reduced the survival of SCLC cells in culture and of primary tumors in vivo, indicating that activation of the Hh pathway is also necessary for the expansion of these tumor cells. Thus, the Hh pathway is active in SCLC cells and plays an intrinsic role in the initiation and the maintenance of SCLC. These observations in a pre-clinical model suggest that inhibition of this signaling pathway may provide a novel means to treat SCLC patients.
Emerging evidence in patients and mouse models also suggests that p130, a gene related to RB, may act as a tumor suppressor in SCLC cells. To test this idea, we used conditional mutant mice to delete p130 in combination with Rb and p53 in adult lung epithelial cells. We found that loss of p130 resulted in increased proliferation and significant acceleration of SCLC development, indicating that p130 plays a key tumor suppressor role in SCLC and providing an improved mouse model for SCLC. We are currently using this triple knock-out mouse model to identify the cell(s) of origin for SCLC as well as to elucidate the mechanisms behind the high metastatic potential of this tumor type.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5755.
Abstract 5765: Tumor-elicited myeloid progenitors promote metastasis through induction of mesenchymal to epithelial transition
Authors: Gao Dingcheng , Joshi Natasha , Choi Hyejin , Ryu Seongho , Hann Mary , Mittal Vivek 
Published: February 2011

Abstract
Malignant primary tumor cells colonize in target organs to form dormant micrometastasis. In some cases, the micrometastases progress to macrometastasis resulting in more than 90% of human cancer related deaths. However, the cellular and molecular regulators of metastatic initiation and progression remains poorly understood. Using a variety of metastatic tumor models we show that recruited bone marrow-derived myeloid progenitor cells comprise a significant fraction of the metastatic lung as compared to the primary tumor that predominantly have infiltrated macrophages. Specific depletion of the myeloid progenitor cells did not affect primary tumor growth but significantly impaired lung metastases. Global gene expression profiling of the CD11b+GR1+ myeloid progenitor cells identified potential pro-metastatic mediators. We have characterized one such mediator that promotes lung metastasis via promoting mesenchymal to epithelial transition (MET) of disseminated tumor cells. Our data suggests that this transition favors enhanced proliferation and survival of disseminated tumor cells so that they can successfully form functional metastases. RNAi-mediated acute suppression of this mediator in the bone marrow markedly inhibited lung metastases. Taken together, these findings illustrate the critical roles of the myeloid progenitors in metastasis and suggest the potential impact of targeting bone marrow cells and MET pathways in metastatic disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5765.
Abstract 577: Combination therapy with arsenic trioxide and radiation in oral squamous carcinoma
Authors: Zhang Xinyan 
Published: February 2011

Abstract
Objective: As a cancer therapeutic drug, arsenic trioxide (As2O3) was originally developed for promyelocytic leukemia. The emerging importance As2O3 in other solid tumors prompted extensive studies of mechanism of action of As2O3 in other types of cancer. Radiation is a commonly used therapeutic treatment for oral squamous carcinoma, while high dose radiation treatment is invasive with unwanted side effects. The aim of this study was to investigate if combined treatments with As2O3 and low dose radiotherapy could enhance the anti-tumor effects. Materials and Methods: Human oral squamous cell lines KB and Tca8113 and Human umbilical vein endothelial cells (HUVEC) were irradiated in vitro with a dose of 7.5Gy with or without low to high doses of As2O3. Cell survival was assessed by MTT assay. Flow cytometry was performed for the analysis of apoptosis. Tumor cell colony formation assay was detected in KB and Tca8113 cells and endothelial tube formation assay was evaluated in HUVEC. Nude mice xenografted animal model with oral cancer cells was established to evaluate the combination treatment efficacy of As2O3 and radiation. Results: As2O3 was able to enhanced radiation-induced tumor cell apoptosis and enhance radiation-induced inhibition of tumor cell proliferation and colony formation and endothelial cell tube formation. In vivo study, the combination treatment efficacy of As2O3 and radiation attained a significant decrease in the incidence of tumor development and tumor volume in nude mice. Conclusions: All these results suggested that As2O3 could enhance the therapeutic efficacy of low dose radiation treatment in vitro and in vivo in oral squamous carcinomas.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 577.
Abstract 5771: Molecular radiation therapy: Targeting DNA damage response proteins
Authors: Bart Cornelissen , Kersemans Veerle , Darbar Sonali , Smart Sean , Vallis Katherine A. 
Published: February 2011

Abstract
DNA damage is an early event after exposure of cells to many anti-cancer agents. Auger electron-emitting radiopharmaceuticals that localize at sites of DNA-double strand breaks (dsb) cause added damage, thus stimulating the formation of their own target and converting sublethal DNA lesions into irreparable damage. The histone H2A variant, H2AX, is phosphorylated on Ser139 (γH2AX) and forms foci at DNA-dsb. γH2AX foci are generally more numerous and resolve more slowly in cancer cells which are genomically unstable compared to normal cells. The aim of this study was to target γH2AX foci for molecular radiation therapy.
Methods: Anti-γH2AX (aγH2AX) or anti-mouse IgG (amIgG) monoclonal antibodies were modified by addition of a nuclear localizing signal (NLS)-containing cell penetrating peptide, TAT, through N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide/N-hydroxysuccinimide (EDC/NHS) coupling. Cyclic diethylenetriaminepentaacetic dianhydride (cDTPA) was added for radiolabeling with 111-indium. Fluorophore AlexaFluor 488-labelled variants of both radioimmunoconjugates (RICs) were also prepared.
Results: Using confocal microscopy, AF488-aγH2AX-TAT but not AF488-amIgG-TAT was found to colocalize with γH2AX-foci in cells exposed to X-Ray irradiation (IR) (4 Gy). To evaluate cellular retention of RICs, MDA-MB-468 or MDA-MB-231/H2N human breast cancer cells were treated with 111In-aγH2AX-TAT or 111In-amIgG-TAT (0.5 µg, 0.1 MBq/µg) and exposed to IR (4 Gy) or bleomycin (20 µg/mL). 111In was retained 16-fold longer in IR- or bleomycin-treated cells exposed to 111In-aγH2AX-TAT compared to control cells exposed to 111In-aγH2AX-TAT. 111In-aγH2AX-TAT (6 MBq/µg) caused amplification of both IR-induced DNA-dsb (evaluated by γH2AX foci number and the neutral comet assay [NCA]) and clustered DNA damage (evaluated by NCA plus glycosylases). In clonogenic assays, the combination of 111In-aγH2AX-TAT plus IR or bleomycin was significantly more cytotoxic than either agent alone and more cytotoxic than 111In-amIgG-Tat plus IR or bleomycin alone. In in vivo experiments, uptake of 111In-aγH2AX-TAT, but not 111In-amIgG-TAT, was up to 6-fold greater in MDA-MB-231/H2N xenografts exposed to IR (4 or 10 Gy) and in bleomycin-treated mice compared to untreated controls. The volume doubling time of MDA-MB-231/H2N xenografts increased 13-fold (p &lt; 0.05) in animals treated with IR (10 Gy) plus 111In-aγH2AX-TAT (10 µg, 6 MBq/µg) compared to those exposed to IR or 111In-αγH2AX-TAT alone.
Conclusion: 111In-aγH2AX-TAT is a novel radiopharmaceutical that amplifies DNA-damage and enhances the cytotoxicity of IR and chemotherapy in vitro and in vivo.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5771.
Abstract 591: Host cell DNA damage and inflammation responses determine oncolytic adenovirus efficacy in ovarian cancer
Authors: Salako Michael A. , Connell Claire M. , Shibata Atsushi , Graupner Vilma , Lockley Michelle , Balkwill Frances R. , McNeish Iain A. 
Published: February 2011

Abstract
Introduction. Oncolytic adenoviruses show promise as a cancer treatment, by replicating selectively within malignant cells. Viral replication requires multiple cell cycle checkpoints to be overcome. Ovarian cancer sensitivity to viral cytotoxicity varies greatly, even between cells with similar infectivity and intracellular virion production. Viruses also generate acute inflammatory responses with production of cytokines, especially TNF-α. We investigated the role of cellular DNA damage in efficacy of adenovirus dl922-947 in ovarian cancer and also whether inhibition of TNF-α augments activity.
Methods. Host DNA damage and repair pathways were assessed in ovarian cancer lines, TOV21G, IGROV1 and A2780CP, which cover three-log range of virus sensitivity. The ATR-chk1 pathway was inhibited using siRNA and UCN-01 treatment. In addition, inflammatory cytokine responses to dl922-947 were assessed in vitro and in xenograft models. TNF-α was inhibited using shRNA and monoclonal antibodies.
Results. Oncolytic adenovirus cytotoxicity is associated with extensive genomic DNA damage. Following infection, sensitive, but not resistant, ovarian cancer cells activate cdc25a and over-replicate genomic DNA, creating extensive double-strand breaks. Inhibition of ATR-chk1 in resistant cells augments cdc25a activity and increases genomic DNA over-replication. This enhances cytotoxicity without increasing E1A expression or viral replication. In addition, dl922-947 induces transcription of TNF-α, IL-6 and IL-8 in ovarian cancer cells and xenograft-bearing mice prior to any viral gene expression and host NF-κB activation. Both RNAi-mediated TNF-α knockdown and anti-TNF-α monoclonal antibody treatment increase virus cytotoxicity in vitro and in IGROV1 intraperitoneal xenografts. The increased efficacy results from suppression of cIAP1 transcription in malignant cells and a consequent increase in caspase-mediated apoptosis.
Conclusions. A phase I trial of dl922-947 in women with relapsed ovarian cancer is planned for 2011. Host cell DNA damage is a key determinant of oncolytic adenoviral activity, whilst TNF-α acts as a survival factor in infected cells. Inhibiting both repair of DNA damage and TNF-α could improve anti-tumour activity in future clinical trials.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 591.
Abstract 595: Single adenovirus-mediated simultaneous expression of p53 and the artificial microRNAs targeting anti-apoptotic p53 target genes
Authors: Idogawa Masashi , Sasaki Yasushi , Imai Kohzoh , Shinomura Yasuhisa , Tokino Takashi 
Published: February 2011

Abstract
Gene transfer involving p53 is viewed as a potentially effective cancer therapy, but does not result in a good therapeutic response in all human cancers. Several p53 target genes have an inhibitory effect on p53-mediated apoptosis. Therefore, if the induction of these genes by p53 is selectively suppressed, the therapeutic effectiveness would be improved. In previous study, we constructed a replication-deficient recombinant adenovirus that encoded co-cistronic p53 and artificial microRNAs (miRNAs) targeting p21, a representative p53 target gene which have an anti-apoptotic effect, resulting in p53 expression and the suppression of p21 induction simultaneously. In colorectal and hepatocellular carcinoma cells, infection with the adenovirus vector augmented apoptosis and suppressed tumor growth as compared to an adenovirus that expressed p53 alone in vitro and in vivo. In this study, we additionally inserted miRNA sequences targeting other anti-apoptotic genes such as MDM2 to the vector and evaluated the therapeutic effectiveness of p53 expression in combination with the suppression of several anti-apoptotic p53 target genes. Infection with the vector suppressed the induction of anti-apoptotic target genes and induced apoptosis more efficiently in cancer cells. These results suggest that adenovirus-mediated transduction of p53 and miRNAs targeting anti-apoptotic p53 target genes is useful for therapy of human cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 595.
Abstract 628: A novel SND1-BRAF fusion confers resistance to the cMet inhibitor PF-04217903 in GTL16 cells
Authors: Lee Nathan V. , Ching Keith , Lira Maruja , Pavlicek Adam , Dillon Roslyn , Srinivasa Sreesha P. , Nilsson Carol , Greig Michael , North Michael , Rejto Paul , Christensen James G. 
Published: February 2011

Abstract
The hepatocyte growth factor receptor (HGFR/cMET) signaling pathway is a driver of tumorigenesis in a variety of tumor types, and a number of agents targeting cMet, including PF-04217903, are under investigation in clinical trials. Tumor types exhibiting an amplified MET gene locus such as gastric, NSCLC, or esophageal cancers are of particular interest for clinical development of c-Met inhibitors. While inhibition of other receptor tyrosine kinases (RTKs) such as ErbB2, EGFR, or KIT have proven to be effective treatments for cancer patients, most tumors become refractory to respective targeted therapies due to the emergence of resistance mechanisms associated with drug targets or upregulation of compensatory pathways. To identify potential mechanisms of resistance to c-Met inhibitors, a gastric carcinoma line (GTL16) was placed under selective pressure by culturing cells in increasing concentrations of PF-0421703 in vitro and resistant clones were isolated. Resistant clones were characterized for changes in signaling, gene expression, and DNA copy number variation as compared to parental GTL16 cells. These studies resulted in the identification of genomic rearrangements at the 7q32 and 7q34 loci which produce a novel SND1-BRAF fusion protein in resistant cells. The fusion protein includes the BRAF kinase domain and is both constitutively active and overexpressed relative to parent cells as determined by gene expression array, immunoblot, and mass spectrometry. In addition, phosphoproteomic analyses demonstrated enrichment of phosphopeptides associated with the MAPK pathway signaling proteins relative to wildtype cells. Cells expressing the fusion protein exhibited resistance to multiple c-Met inhibitors whereas treatment of resistant cells with a combination of c-Met and BRAF inhibitors or a MEK inhibitor (PD325901) reversed the resistance phenotype by reestablishing inhibition of MAPK signaling and restoring growth inhibition. Together, these data provide an unique example of a mechanism where MAPK activation, through BRAF amplification/rearrangement, confers resistance to a RTK/cMET inhibitor. Furthermore, the results suggest the importance of MEK/ERK signaling downstream of c-Met and that a potential combination strategy for c-Met inhibitors with BRAF or MEK inhibitors could be employed to delay onset or circumvent potential resistance mechanisms.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 628.