bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1509: Modulation of stromal reaction by PDGF-R tyrosine kinase inhibitor in an orthotopic mice model of gastric carcinoma
Authors: Kitadai Yasuhiko , Onoyama Mieko , Shinagawa Kei , Ohnishi Mayu , Ohara Eiji , Tanaka Shinji , Yasui Wataru , Chayama Kazuaki 
Published: August 2012

Abstract
Recent studies in molecular and cellular biology have shown that tumor growth and metastasis are not determined by cancer cells alone but also by a variety of stromal cells. Many human tumors secrete platelet-derived growth factor (PDGF) ligands, and PDGF receptors (PDGF-Rs) are expressed by various stromal cell populations, including carcinoma-associated fibroblasts (CAFs). We reported recently that, in a mice model of colon cancer, bone marrow-derived mesenchymal stem cells (MSCs) traveled to tumor stroma, where they differentiated into CAF-like cells. In the present study, we examined PDGF-B and PDGF-Rβ expression in relation to clinicopathologic features of human gastric carcinomas. We also examined the effects of PDGF-R tyrosine kinase inhibitors (imatinib, nilotinib) on tumor stroma in an orthotopic nude mouse model of human gastric carcinoma. Five gastric carcinoma cell lines and 38 surgical specimens of gastric carcinoma were used. Under culture conditions, gastric cancer cell lines expressed PDGF-B at various levels but not PDGFR-β. When cells from these lines were implanted orthotopically into the gastric wall of nude mice, cells with high PDGF-B expression resulted in tumors with abundant stroma. In contrast, cells with low PDGF-B expression resulted in medullary tumors with little stromal reaction. In surgical specimens, we found PDGF-B expression to be associated with stromal reaction. PDGF-B and PDGF-Rβ mRNA expression was significantly higher in patients with lymph node metastasis than in those without and also significantly higher in diffuse-type carcinoma than in intestinal-type carcinoma. In surgical specimens and orthotopic tumors, tumor cells expressed PDGF-B, but PDGF-Rβ was expressed predominantly by stromal cells, including CAFs, pericytes, and lymphatic endothelial cells. Treatment with PDGF-R tyrosine kinase inhibitors did not inhibit tumor growth but did significantly decrease the stromal reaction, lymphatic invasion, lymphatic vessel area, and pericyte coverage of tumor microvessels. In addition, tumor tropism of MSCs was also inhibited by treatment with PDGF-R inhibitors in vivo and in vitro. The PDGF/PDGF-R signaling pathway appears to regulate cancer-stromal cell interaction, and target molecule-based inhibition of the stromal reaction may hold promise as an effective anti-tumor 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 1509. doi:1538-7445.AM2012-1509
Abstract 151: Advancing pathway analysis using bioluminescent reporters
Authors: Robers Matthew B. , Binkowski Brock , Karassina Natasha , Stecha Pete , Eggers Chris , Cheng Jey , Zimmerman Kris , Fan Frank , Cong Mei 
Published: August 2012

Abstract
To enable investigation of key cellular signaling pathways, Promega has developed a portfolio of bioluminescent reporter gene assays using Firefly and Renilla luciferases. In combination with best-in-class luciferase detection reagents, these genetic reporter systems enable interrogation of important cellular responses involved in cancer, inflammation, and CNS disease. To address specialized customer needs in our industrial and research markets, Promega has a new custom assay service team dedicated to applying these enabling technologies through strategic external research collaborations. The performance of this technology portfolio is presented, including novel applications of luciferase reporters to interrogation of cytokine, stress, and toxicity pathway responses.
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 151. doi:1538-7445.AM2012-151
Abstract 1516: HB-EGF and PDGF mediate reciprocal interactions of carcinoma cells with cancer-associated fibroblasts to support progression of uterine cervical cancers
Authors: Murata Takuya , Enomoto Takayuki , Ueda Yutaka , Yoshino Kiyoshi , Yagi Shigeo , Hoffman Robert M. , Mizushima Hiroto , Kimura Tadashi , Mekada Eisuke 
Published: August 2012

Abstract
Tumor stroma drives the growth and progression of cancers. A heparin-binding epidermal growth factor-like growth factor, HB-EGF, is an EGF receptor ligand that stimulates cell growth in an autocrine or paracrine fashion. While elevated expression of HB-EGF in cancer cells and its contribution to tumor progression are well documented, the effects of HB-EGF expression in the tumor stroma have not been clarified. Here, we show that HB-EGF is expressed in stromal fibroblasts where it promotes tumor cell proliferation. In uterine cervical cancers, HB-EGF was detected immunohistochemically in the stroma proximal to the cancer epithelium. Proliferation of cervical cancer cells in vitro was enhanced by coculture with fibroblasts isolated from tumor tissues of patients with cervical cancer. Inhibition of HB-EGF function or treatment with platelet-derived growth factor (PDGF) inhibitors abrogated cancer cell growth enhanced by cervical cancer-associated fibroblast (CCF) coculture. Furthermore, tumor formation in a mouse xenograft model was enhanced by cotransplantation of CCF or mouse embryonic fibroblasts but not with embryonic fibroblasts from HB-EGF-deficient mice. Conversely, conditioned medium from cancer cells induced HB-EGF expression in CCF and mechanistic investigations established that PDGF was the primary factor responsible. Together, our findings indicate that HB-EGF and PDGF reciprocally mediate the interaction of cancer cells with cancer-associated fibroblasts, promoting cancer cell proliferation in a paracrine manner that has implications for novel combinatorial cancer.
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 1516. doi:1538-7445.AM2012-1516
Abstract 1558: Innovative biotherapy for brain tumors: Myxoma virus accelerates NK clearance of malignant gliomas
Authors: Ogbomo Henry , Lun Xueqing , Zhang Jiqing , Zemp Franz J. , Mcfadden Grant , Mody Christopher H. , Forsyth Peter A. 
Published: August 2012

Abstract
Innovative biotherapeutic approaches for experimental malignant gliomas (MGs) and brain tumor stem cells (BTSCs) include using oncolytic viruses such as Myxoma Virus (Myxv) or immune cells such as Natural Killer (NK) cells. In this study, we combined the individual strengths of using NK cells and Myxv to treat MGs with a view of overcoming the potential limitations posed when each is used as monotherapy. All MGs (U87, U251) and BTSCs (25EF and 48EF) investigated expressed varying levels of NK ligands including inhibitory MHC-I, activating ULBP1-3, MICA/B, and co-activating nectin-2, poliovirus receptor. Infection of MGs and BTSCs with Myxv resulted in the downregulation of MHC-I expression both on the cell surface and intracellularly. No effect was observed on the expression of NK activating ligands except for the downregulation of nectin-2. The downregulation of MHC-I and nectin-2 by Myxv was specifically mediated by M153 gene of Myxv as loss of M153 restored MHC-I and nectin-2 expression. Subsequently, NK cell degranulation and killing of MGs was enhanced in Myxv-infected cells. Loss of M153 inhibited NK degranulation and lysis of MGs. In vivo, using luciferase-expressing U87 cells in a mouse intracranial model, Myxv accelerated tumor size reduction/clearance by NK cell lysis. Combined intratumoral treatment with Myxv and NK of established U87 tumor accelerated tumor clearance when compared with single treatment with Myxv or NK. Tumor in 66% of mice (4 out of 6 mice) were cleared or significantly reduced within 14 days following combination treatment with Myxv and NK. No significant effect was observed in Myxv or NK singly-treated mice within the same time frame. Clearance of tumors was only first observed in 50% (2 out of 4) of Myxv-treated mice after 25 days Myxv treatment. In NK treated mice, the tumor size rather increased. The enhanced tumor clearance in the combined Myxv and NK treated mice was possibly due to the down-regulation of MHC-I by Myxv since combined treatment with NK cells and mutant Myxv (gene M153 which is responsible for MHC-I down-regulation was deleted) did not result in clearance of tumors.
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 1558. doi:1538-7445.AM2012-1558
Abstract 156: Screening and characterization of inhibitors of G-protein coupled receptor kinase GRK6 as potential therapeutics for multiple myeloma
Authors: Griffin Carly , Subramanian Ratheesh , Zaidi Hassan S. , Marcellus Richard , Joseph Babu , Isaac Methvin , Uehling David , Leung-Hagesteijn Chungyee , Tiedemann Rodger , Al-awar Rima 
Published: August 2012

Abstract
Multiple myeloma (MM) is one of the most common hematological malignancies, but current therapy options are limited to high-dose chemotherapy or high-risk stem-cell transplantation. It is clear that the development of more selective and less toxic treatments for MM is greatly needed. In a recent kinome-wide RNAi study by Tiedemann and colleagues (2010), the G-protein coupled receptor kinase-6 (GRK6) was identified as a critical kinase required for survival of MM cells. This study also suggests that MM cells, but not other cell types, are dependent on GRK6; and that gene silencing by shRNA or siRNA of GRK6, but not other GRKs, results in decreased survival. At present, the G-protein coupled receptor (GPCR) signaling mediated by GRK6 in MM cells is not well understood. Our current research aims to identify the important GPCRs phosphorylated by GRK6 and the signaling proteins/pathways implicated in survival of multiple myeloma cells. Through gene silencing techniques and expression of either the wild-type or kinase-dead form of GRK6 protein, we have determined that a functional GRK6 kinase domain is required for survival of MM cells. We have also demonstrated that the signaling pathway downstream of CXCR4 phosphorylation by GRK6 is defective in cells expressing the kinase-dead GRK6-mutant protein. This loss of signaling by the GRK6-mutant protein was observed for other GPCRs found to be important for survival of MM cells. These findings helped to validate that the kinase domain of GRK6 is a potential target for MM, and spurred the identification of small molecule kinase inhibitors of GRK6. Compounds with high potency in preliminary biochemical assays were screened against MM and non-MM cell lines to evaluate their activity and specificity in vivo. Small molecule inhibition of GRK6 kinase activity is a novel approach to the treatment of MM, as it specifically targets a protein found to be critical for survival of these cells through an unbiased RNAi study. Treatment options for patients with MM are limited and based on our preliminary findings small molecule inhibitors of GRK6 offer an alternative therapeutic approach to the treatment of MM.
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 156. doi:1538-7445.AM2012-156
Abstract 1561: Leukemia cell-derived exosomes targeted dendritic cells can induce more strong anti-leukemia response than exosomes alone
Authors: Sun Jing , Chen Linjun , Deng Xiaohui , Hao Siguo 
Published: August 2012

Abstract
Exosomes are the newest family number of ‘bioactive vesicles’ that play important roles in antigen presentation. Recent clinical trials about exosomes have shown minor clinical benefit. However, exosomes derived from leukemia cell lines were less studied, In this study, we investigated the biological properties and anti-leukemia immunity of leukemia cell-derived exosomes (LEX). The results showed that like other tumor cells, similarly, leukemia cells can release exosomes too. Transmission electron microscopy showed that exosomes derived from NB4 cell, a promyloblastic leukemia cell line and K562 cell, a chronic myeloid leukemia cell line were membrane vesicles with diameter about 50-100μm, and loading their specific moleculars such as RAR-α and ABL and adherent moleculars such as ICAM-1. Similarly, our data also demonstrated the presence of Hsp70 in these two leukemia cell-derived exosomes. The data from two-dimensional electrophoresis of K562 cell-derived exosomes showed that most of molecules expressing on leukemia cells were detected on their exosomes, indicating that LEX load most of proteins expressed on their original leukemia cells. Out data also demonstrated that LEX can induce anti-leukemia CTL response and LEX-targeted DC can induce more efficient anti-leukemia immunity compared with LEX alone. In conclusion, exosome-based therapies could be considered as a promising strategy to prolong disease-free survival in patients with leukemia after consolidation or hematopoietic stem cell transplantation. Note: This research work was supported by research grants from Shanghai Pujiang Project of Science and Technology Commission of Shanghai Municipality. Keywords: Exosome, leukemia cell, anti-leukemia immunity
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 1561. doi:1538-7445.AM2012-1561
Abstract 1566: Inhibition of TGF-β in tumor-draining lymph nodes can enhance the potency of dendritic cell-based vaccine immunotherapy
Authors: Teramoto Koji , Fujita Takuya , Hanaoka Jun , Tezuka Noriaki , Kontani Keiichi 
Published: August 2012

Abstract
Transforming growth factor-β (TGF-β), an immunosuppressive cytokine, produced in the tumor microenvironment will flow into tumor-draining lymph nodes where are primary priming sites for generation of anti-tumor immune responses, and play a critical role in suppressing anti-tumor immune responses. We focused on TGF-β-mediated immunosuppression in tumor draining lymph nodes, and examined whether local inhibition of TGF-β there could enhance the potency of dendritic cell (DC) -based vaccine immunotherapy in tumor-bearing mice. C57BL/6 mice bearing Lewis lung carcinoma (LLC1) subcutaneously were vaccinated with DCs loaded with LLC1-derived antigen. In order to inhibit TGF-β in tumor-draining lymph nodes, those mice were administered the plasmid DNA encoding the extracellular domain of TGF-β type II receptor fused to the human IgG heavy chain (TGFR DNA) near the established tumor intramuscularly. As results, the level of TGF-β in tumor-draining lymph nodes was decreased by administrations of TGFR DNA near the established tumor. In tumor-draining lymph nodes, the proliferative activity of FoxP3+ regulatory T cells was eliminated, whereas tumor antigen-specific CD8+ cells producing interferon-α were increased as compared with those in mice administered DC vaccine alone. In spleen, tumor antigen-specific cytotoxic as well as natural killer activity were augmented in mice administered DC vaccine with TGFR DNA. Subsequently, growth of the established tumor was suppressed effectively. In conclusion, inhibition of TGF-β-mediated immunosuppression in tumor-draining lymph nodes can significantly enhance the potency of DC vaccine. This animal model provides for a novel rationale with DC vaccine immunotherapy.
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 1566. doi:1538-7445.AM2012-1566
Abstract 1817: Characterisation of CCT251455, a novel, selective and highly potent Mps1 kinase inhibitor
Authors: Faisal Amir , Naud Sebastian , Schmitt Jessica , Westwood Isaac , Hayes Angela , Gurden Mark , Bavetsias Vassilios , Berry Teeara , Mak Grace , Innocenti Paolo , Cheung Jack , Sheldrake Peter , Atrash Butrus , Sun Chongbo , Matijssen Berry , Burke Rosemary , Baker Ross , McAndrew Craig , Rowlands Martin , Workman Paul , Eccles Suzanne A. , Hoelder Swen , Raynaud Florence I. , vanMontfort Rob , Blagg Julian , Linardopoulos Spiros 
Published: August 2012

Abstract
Monopolar spindle 1 (Mps1, also known as TTK) is a dual-specificity, cell cycle-regulated kinase required for the establishment and maintenance of the spindle assembly checkpoint during mitosis. Aneuploid tumour cells possess a weak spindle checkpoint to allow onset of anaphase and cell division. Our hypothesis is that a complete inhibition of an already weakened mitotic checkpoint of cancer cells will cause gross chromosomal abnormalities leading to aneuploid cell death. We have shown that depletion of Mps1 by siRNA induces cell death selectively in aneuploid and PTEN-deficient cancer cell lines. We have demonstrated that Mps1 depletion inhibits MAD2 localisation to the kinetochores. We have developed biochemical and cellular assays for Mps1 activity and a high throughput screening of our Institute's compound library delivered multiple hit series. Medicinal chemistry in combination with X-ray crystallography led to the development of CCT251455, a small molecule inhibitor of Mps1 kinase activity. CCT251455 selectively inhibits Mps1 kinase with an IC50 of 0.003 μM, inhibits growth of a panel of human tumour cell lines with GI50 between 0.06 - 1 μM and is particularly potent in PTEN-deficient cell lines. Cells treated with CCT251455 abrogate nocodazole-induced mitotic arrest and reduce the time spent in mitosis. Mps1-inhibited cells contain aberrant numbers of chromosomes and the majority of cells divide their chromosomes without proper alignment. CCT251455 is orally bioavailable (F = 82%) and shows modulation of biomarkers in vivo.
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 1817. doi:1538-7445.AM2012-1817
Abstract 1819: A MUC1-C oncoprotein soluble decoy receptor effectively suppresses the growth of human breast cancer cells
Authors: Panchamoorthy Govind , Raina Deepak , Rehan Hala , Kharbanda Surender , Kufe Donald 
Published: August 2012

Abstract
The Mucin 1 (MUC1) transmembrane glycoprotein is aberrantly overexpressed by most human breast carcinomas and contributes to the malignant phenotype. MUC1 is expressed as two subunits (MUC1-N and MUC1-C) that form a stable heterodimer at the cell surface. MUC1-N is shed to contribute to a protective physical barrier, leaving the oncogenic MUC1-C subunit at the cell surface as a putative receptor for signaling the presence of stress to the interior of the cell. As shown for the VEGF receptor TRAP, aflibercept, a potential approach for blocking MUC1-C function is to generate a soluble decoy receptor by fusing the MUC1-C extracellular domain to an Ig constant (Fc) region. The present studies demonstrate that in vitro treatment of human ZR-75-1 breast carcinoma cells with the MUC1-C soluble decoy receptor is associated with a dose-dependent induction of cell death. Similar findings were obtained with human MCF-7 breast cancer cells. To explore the potential of the MUC1-C soluble decoy receptor as an anti-cancer agent, we evaluated its ability to block the growth of breast cancer cells in subcutaneous tumor xenograft models growing in nude mice. Administration of the MUC1-C soluble decoy receptor to nude mice bearing established ZR-75-1 breast tumor xenografts was associated with a dose-dependent loss of tumorigenicity and prolonged tumor regressions after completing therapy. Taken together, these findings demonstrate that targeting the MUC1-C oncoprotein with a soluble decoy receptor is effective in inducing death of human breast cancer cells in vitro and in tumor 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 1819. doi:1538-7445.AM2012-1819
Abstract 1826: Anti-tumorigenic effects by targeted functional disruption of the Sin3 PAH-2 domain
Authors: Ariztia Edgardo V. , Das Tirtha K. , Farias Eduardo F. , Leibovitch Boris , Petrie Kevin , Gil Veronica , Zelent Arthur , Zhou Ming-Ming , Cagan Ross L. , Waxman Samuel 
Published: August 2012

Abstract
The Sin3 A/B adapter proteins function as structural scaffolds for repressor/activator complexes that regulate transcription through the specific association with histone modifying enzymes and a number of transcription factors. Sin3 contains four paired amphipathic α-helices (PAH domains). We have reported earlier that targeted disruption of the PAH2 domain with a SID (Sin3 Interaction Domain) peptide decoy in triple negative (TN) breast cancer cells leads to cytoskeletal reorganization, loss of anchorage independent growth and 3D invasive morphology and decreased cell adhesion and invasion. There is epigenetic reprogramming of silenced genes such as CDH1, ESR1 and RARA which are re-expressed and together contribute to a SID decoy induced switch from basal to a more differentiated luminal phenotype (Farias, et. al., PNAS, 2010, 107:11811-6). Computerized screening coupled with such assays as Duolink, GST pull downs and mammalian two hybrid identified small molecule inhibitors (SMI) that mimic the effects of the SID decoy peptide. SMI inhibit cellular invasion at nanomolar range and in in vivo mouse myc TN breast cancer prolong latency, decrease local invasion and metastasis. Tumors recovered showed evidence of re-expression of E-cadherin and estrogen receptor. Early effects of SID decoy in TN breast cancer cells include inhibition of invasion that is associated with a significant decrease in Src phosphorylation within 2-4hr of treatment. Recovery of phosphorylation after SID decoy washout is coupled with recovered invasion at 24hr. These effects occurred prior to measurable increase in E-cadherin expression, suggesting a non-transcriptional effect. In Drosophila larval breast cancer models with activated Src/Ras, overexpression of SID inhibited (60%) tumor growth in the eye imaginal disc, and was eradicated by the addition of a MEK inhibitor (AZD-6244), indicating a strong synergy between SID and AZD-6244. In the adult fly SID expression greatly inhibited RetMEN2B induced eye tumors (90%). These data demonstrate that SID decoys have a potential to be effective agents in the treatment of TN breast cancer by promoting basal phenotype reversal, inhibiting invasion and metastasis, and could be synergistic with specific inhibitors of signal transduction targets. Moreover, SID decoys can overcome profound oncogenic stimulus such as Ras, Src and Ret suggesting that they have a potential greater role than just in the treatment of TN breast cancer.
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 1826. doi:1538-7445.AM2012-1826