bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2382: IGFBP-3 regulates angiogenesis through upregulation of TSP-1
Authors: Torng Pao-Ling , Shih Ho-Jun , Huang Su-Cheng , Lin Chin-Tarng 
Published: February 2011

Abstract
Insulin growth factor binding protein-3 (IGFBP-3) has been postulated to be a mediator of growth suppression signal. In our previous study, IGFBP-3 was found as an invasion suppressor gene in ovarian endometrioid carcinoma (OEC) (Oncogene 2008;27:2137-47). It was silenced through IGFBP-3 promoter methylation, which was associated with cancer progression (Mol Cancer, in press). Through microarray analysis, we further identified that IGFBP-3 expression was associated with an elevation of thrombospondin-1 (TSP-1), which is an endogenous inhibitor of angiogenesis. We established a tetracyclin-inducible IGFBP-3 expressing OEC cell line using pBIG2i plasmid (OVTW59 P4-D-I: pBIG2i-hIGFBP3). This cell line showed 4-fold increase in IGFBP-3 expression 2 hours after tetracyclin treatment, associated with an paraellel increase in TSP-1. Expression of IGFBP-3 decreases cell migration and capillary tube formation, which was reversed after anti-TSP-1 treatment. By chick embryo chorioallantoic membrane (CAM) assay, IGFBP-3 expression showed a significant decrease in capillary formation. Heterotransplantation of IGFBP-3-transfectants significantly decrease in tumor growth 5 days after IGFBP-3 induction. Such dormancy state of tumor growth persisted for about 10 days. Xenograft tumors during this period showed a decrease in microvessel density and an increase in tumor apoptosis. In conclusion, we have identified a novel association between IGFBP-3 expression and TSP-1 elevation that consequently results in a decrease in angiogenesis. Such impairment in angiogensis could be associated with the dormancy state of cancer growth and may represent a major function of the oncosupressor IGFBP-3 in ovarian cancer pathogenesis.
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 2382.
Abstract 2383: MicroRNA-519c suppresses HIF-1α expression and tumor angiogenesis
Authors: Cha Shih-Ting , Chen Pai-Sheng 
Published: February 2011

Abstract
Hypoxia-inducible factor (HIF)-1α is widely considered to be one of the key regulators of tumor angiogenesis. The upstream regulation is complex and involves several growth factors, cytokines and hypoxia. Herein, we identified miR-519c as a hypoxia independent regulator of HIF-1α, acting through direct binding to HIF-1α 3′UTR and leading to reduced tumor angiogenesis. Over expression of miR-519c resulted in a significant decrease of HIF-1α protein levels and reduced the tube formation of HUVEC cells and similarly, antagomir inhibition of miR-519c increased the level of HIF-1α protein and enhanced angiogenic activity, suggesting an important role of miR-519c in HIF-1α-mediated angiogenesis. In consistence with the over-expression of miR-519c in cancer patients with better prognosis, mice injected with miR-519c over-expressing cells exhibited dramatically reduced HIF-1α level, followed by suppressed tumor angiogenesis, growth, and metastasis. In addition, we found that hepatocyte growth factor (HGF), a known HIF-1α inducer, reduced miR-519c levels in an Akt-dependent pathway. This regulation is post-transcriptional and may mediate by suppressing miR-519c maturation. Taken together, our findings provide the first evidence that miR-519c is a pivotal regulator of tumor angiogenesis and, moreover, micro environmental HGF contributes to regulating miR-519c biogenesis in cancer cells.
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 2383.
Abstract 2387: Characterization the role of leukocyte cell-derived chemotaxin 2 (LECT2) in angiogenesis
Authors: Chi-Kuan Chen , Chung Wan-Chin , Wu Yu-Ling , Yang Ching-Yao , Chang Jia-Ming , Kuo Ming-Lian 
Published: February 2011

Abstract
Leukocyte Cell-Derived Chemotaxin 2 (LECT2) protein is expressed preferentially in the liver in a constitutive manner and secreted into bloodstream. Recently studies indicate that LECT2 potentially associated with the liver injury, repair, and regeneration, but other functions are still unknown. Angiogenesis is a process of new blood vessel formation which has essential roles in development, repair, tumor growth, invasion, and metastasis. In our pervious studies, we have recently identified LECT2 as a potential tumor suppressor, correlating with decreased vascular invasion in hepatocellular carcinomas (HCC). In this study, we evaluated the function of recombinant LECT2 (rLECT2) proteins on angiogenesis by using human umbilical vein endothelial cells (HUVEC). We demonstrated a selective and significant inhibition of VEGF165-induced angiogenic activity in HUVEC by rLECT2 protein through inhibiting the proliferation, migration, and tube formation. The rLECT2 protein also suppressed VEGF165-induced angiogenesis in CAM assay and matrigel plug assay. In conclusion, we for the first time found that LECT2 played an important role in anti-angiogenesis. Moreover, the LECT2 might have broad therapeutic applications in diseases characterized by excessive angiogenesis.
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 2387.
Abstract 2392: Transcriptional repression of VEGF by Znf24, a C2H2 zinc finger protein
Authors: Jia Di , Loureiro Robyn , D'Amore Patricia , Rodig Scott , Moses Marsha 
Published: February 2011

Abstract
Vascular endothelial growth factor (VEGF) is a key regulator during the formation of new blood vessels during angiogenesis. It functions to promote the proliferation and migration of endothelial cells under both physiological conditions such as embryogenesis and pathological conditions such as tumor growth. VEGF has been shown to play an important role in the development and metastasis of breast as well as other human cancers. To date, many trans-activating factors of VEGF have been described, whereas transcriptional repression of VEGF remains less studied. We have previously reported the identification of a SCAN-domain containing C2H2 zinc finger protein, Znf24, which functions to repress the transcription of VEGF. In this study we explore the mechanism by which Znf24 represses VEGF transcription. We have generated a series of VEGF promoter constructs bearing deletions from the 5′ end. Reporter gene assays in the breast cancer cell line MDA-MB-231 have revealed a proximal region of the VEGF promoter essential for Znf24-induced repression. To determine whether Znf24 represses VEGF transcription through direct binding to the VEGF promoter, we have performed electrophoretic mobility shift assays (EMSA) using the VEGF proximal promoter region as a probe. We have found that Znf24 protein binds to this proximal region, suggesting that VEGF is a direct downstream target of Znf24. To begin to investigate Znf24 functions in vivo, we have conducted immunohistochemistry assays using human breast cancer tissue microarrays representing different stages of disease progression and tumor sizes, as well as matched normal breast tissues. We have determined that Znf24 protein levels are significantly decreased in malignant tissues compared to normal adjacent tissues. A potential negative correlation between Znf24 protein levels and tumor sizes is also observed, suggesting that Znf24 may serve as a negative regulator of tumor growth. Our data suggest that Znf24 represses VEGF transcription through direct binding to the VEGF promoter and that it may function as a negative regulator of tumor growth by inhibiting tumor angiogenesis. (Supported by NIH P01 CA045548 and the Simeon J. Fortin Charitable Foundation)
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 2392.
Abstract 2397: SSX-2 vaccines with enhanced MHC class I binding epitopes elicit anti-prostate tumor CTL
Authors: Smith Heath A. , McNeel Douglas G. 
Published: February 2011

Abstract
The tumor-associated antigen synovial sarcoma X breakpoint 2 (SSX-2) is classified as a cancer-testis antigen (CTA) based upon its tissue-restricted expression to germline cells and its frequent expression in a variety of malignancies. We have previously identified SSX-2 as a potential prostate cancer antigen that can be inducibly expressed in several prostate cancer cell lines. We have also previously identified two nonamer peptides from the amino acid sequence of SSX-2 that have significant affinity for HLA-A2 as assessed by in vitro T2 binding assay. These HLA-2-binding peptides were found to represent HLA-A2-restricted epitopes, able to induce peptide-specific immune responses in peptide- or DNA-immunized HHD-II (HLA-A2.1+/HLA-DR1+ transgenic) mice. Given these observations, the current study was conducted to determine if CTL generated in vaccinated HHD-II mice are capable of lysing HLA-A2+ prostate cancer cells and whether SSX-2 vaccine efficacy could be enhanced using an altered peptide ligand binding strategy. We found that peptides that were designed in silico to have increased or decreased HLA-A2+ affinity had enhanced and reduced HLA-A2 binding by in vitro T2 binding assay, respectively. Additionally, HHD-II mice immunized with modified SSX-2 vaccines developed increased or decreased frequencies of peptide-specific T cells in vivo, which could be detected by IFNγ ELISPOT assay and cytotoxicity assay. Animals immunized with enhancing modified SSX-2 vaccines generated CTL with cross-reactivity to the native SSX-2 epitopes. These CTL were capable of lysing target cells pulsed with both modified and native peptides and could also lyse an HLA-A2-expressing prostate cancer cell line. These results provide support for the further investigation of SSX-2 as an immunotherapeutic target for prostate cancer using vaccines modified to increase MHC class I binding.
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 2397.
Abstract 24: Labeling of oxidizable proteins with a photoactivatable analog of the antitumor agent DMXAA and evidence for redox signaling in its mode of action
Authors: Ching Lai-Ming , Wang Liang-Chuan S. , Brauer Romy , Bridewell David J.A , Henare Kimiora , Palmer Brian D. 
Published: February 2011

Abstract
DMXAA (5,6-dimethylxanthenone-4-acetic acid) is in late stages of clinical development as a tumor vascular disrupting agent. The signalling pathway(s) and molecular target(s) for this drug are still undefined. As an approach towards identifying potential targets for DMXAA, a tritiated azido-analog of DMXAA is used in the studies here to probe for cellular binding proteins. Unexpectedly, over 20 proteins were photo-affinity labelled from the cytosolic protein extracts from murine spleen cells and the RAW 264.7 murine macrophage-like cell line. While no protein domain, fold or binding site for a specific ligand was found to be shared by all the candidate proteins, almost all were noted to be oxidisable proteins, implicating a role for redox cycling in the action of DMXAA. Consistent with this hypothesis, we showed that DMXAA caused an accumulative increase in concentrations of reactive oxygen species (ROS) in RAW 264.7 cells over the first two hours. This increase in ROS was suppressed in the presence of the anti-oxidant, N-acetyl-L-cysteine, which also suppressed DMXAA-induced cytokine production in the RAW 264.7 cells with no effects on cell viability. SiRNA knock-down in RAW 264.7 cells of one of the photolabelled proteins, superoxide dismutase 1, an ROS scavenger resulted in an increase in tumour necrosis factor-alpha production in response to DMXAA compared with controls treated with transfection reagent alone, or with unrelated siRNA molecules. Knock-down of two other photoaffinity labelled proteins which do not have direct ROS scavenging properties, thioredoxin and protein disulfide isomerase 6, had no significant effect on tumour necrosis factor-alpha production. The results from these three lines of study have led us to speculate on a role of modulation of redox signalling in cytokine induction by DMXAA.
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 24.
Abstract 2412: Sorafenib can be effectively combined with GM-CSF secreting cellular immunotherapy in a mouse model of HER-2+ breast cancer
Authors: Edwards Justin P. , Leatherman James M. , Goding Steven R. , Erdinc Melek M. , Emens Leisha A. 
Published: February 2011

Abstract
Due to the complexities of the tumor microenvironment and the frequent emergence of drug resistance with treatment, it is increasingly evident that cancer therapy will have to hit multiple host and tumor targets simultaneously. We previously reported that DC101, an antiangiogenic monoclonal antibody specific for the vascular endothelial growth factor receptor-2 (VEGFR-2), can enhance tumor immunity by a T cell-dependent mechanism. Sorafenib, a small molecule that also disrupts angiogenesis, blocks signaling through multiple kinases that control tumor growth and progression. It has also been reported to inhibit both dendritic cell (DC) and T cell function. To further explore the intrinsic tumor- and host-based effects of sorafenib, we tested it against murine HER-2+ breast tumor cells (NT) in vitro, and in NT-tumor-bearing FVB/N (immune-competent) and neu-N (immune tolerant to HER-2) mice in vivo. Sorafenib inhibited the growth of NT tumor cells in vitro, inducing apoptosis. Western blot analysis revealed that Sorafenib interfered with ERK/MAPK, but not AKT, signaling pathways, both of which are constitutively activated when HER-2 is over-expressed. Single agent sorafenib effectively controlled the growth of established tumors in immune competent FVB/N mice, but did not result in complete tumor clearance. In contrast, sorafenib alone did not significantly impact the outgrowth of established tumors in neu-N mice, where tumor-specific immune tolerance is in play. Consistent with this observation, depletion studies conducted in immune competent FVB/N mice revealed that the control of tumor growth is in part dependent on T cells, but not macrophages or NK cells. While sorafenib treatment alone did not induce immunity specific for RNEU420–429 (the immunodominant HER-2 epitope), it did accelerate tumor clearance induced by vaccination with a granulocyte-macrophage colony-simulating factor (GM-CSF)-secreting, HER-2+ cellular vaccine in tumor-bearing FVB/N mice compared to either drug treatment or vaccination alone. Finally, sorafenib neither augmented nor inhibited the vaccine-induced T cell response specific for RNEU420–429 as measured by ELISPOT and intracellular cytokine staining. Overall, these findings suggest that vaccine-based immunotherapy can interact with kinase inhibitors by distinct mechanisms for enhanced therapeutic response.
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 2412.
Abstract 2415: Evaluation of a DNA vaccine and adjuvant construct for producing anti tumor immunity targeting IGFBP2
Authors: Holt Gregory E. , Gad Ekram , Dang Yushe , Disis Mary 
Published: February 2011

Abstract
DNA based vaccines offer the advantage of stability, low cost, and longer duration of antigen exposure than protein based vaccines. We sought to evaluate strategies to augment the anti tumor potency. Using three immunogenic peptides from the ovarian cancer antigen, human insulin-like growth factor binding protein-2 (IGFBP2) we created a DNA epitope construct that encodes these three peptides in sequence and vaccinated mice with the epitope vaccine or an admixture of the peptides or plasmids expressing either the full length human or mouse genes. Mice received three vaccinations separated by two weeks followed fourteen days later by a lethal injection of syngeneic MMC tumor cells known to express IGFBP2. The DNA epitope vaccine produced a greater level of protection than any of the other constructs proving it to be the best formulation for inducing protective anti tumor responses. Full length human and mouse IGFBP2 DNA constructs induced a similar level of protection as the peptide based vaccine. This IGFBP2 epitope DNA vaccine was then tested in conjunction with plasmids encoding murine GM-CSF and IL-12 either alone or in combination in an identical vaccination strategy. Each genetic adjuvant either alone or in combination improved the level of protection induced by the IGFBP2 DNA epitope vaccine though no difference in tumor protection was seen between adjuvants used either alone or together. Evaluation of the inoculation site revealed a persistence of CD11c+ dendritic cells and CD3+ T cells fourteen days after final vaccination predominantly in mice who received plasmids containing the cytokines versus those who received soluble protein. These data support the use of epitope based DNA vaccines in conjunction with genetic adjuvants for the production of anti tumor efficacy.
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 2415.
Abstract 2420: Modified vaccinia Ankara (MVA) expressing survivin combined with gemcitabine generates specific antitumor effects in a murine pancreatic carcinoma model
Authors: Ishizaki Hidenobu , Manuel Edwin , Srivastava Tumul , Song Guang-Yun , Diamond Don J. , Ellenhorn Joshua D.I. 
Published: February 2011

Abstract
Survivin is overexpressed by 70-80% of pancreatic cancers, and is associated with resistance to chemotherapy and a poor prognosis. Gemcitabine has been a standard treatment for patients with advanced pancreatic cancer for a decade. Recent reports have demonstrated that gemcitabine treatment attenuates the tumor-suppressive environment by eliminating CD11b+/Gr-1+ myeloid derived suppressor cells (MDSCs). It may also enhance the effect of cancer vaccines. The highly attenuated strain of vaccinia, modified vaccinia Ankara (MVA) has been employed as a vaccine vector to deliver a tumor associated antigen, and MVA vaccines have demonstrated safety, immunogenicity, and evidence of clinical benefit in patients with cancer. We hypothesize that a cancer vaccine targeting survivin can achieve enhanced efficacy when use in combination with gemcitabine. In this study, we tested this hypothesis using an MVA expressing full-length murine survivin. The poorly immunogenic mouse pancreas adenocarcinoma cell line, Pan02, which express murine survivin and syngeneic to C57BL/6, was used for this study. To develop an established tumor model, mice were challenged with 2.5 × 105 Pan02 cells by subcutaneous injection. When the tumors were palpable and reached 4 to 5 mm in diameter, mice were immunized twice at a 1-week interval with 5 × 107 pfu of MVA-survivin or control MVA. Immunization with MVA-survivin resulted in a modest therapeutic antitumor effect on established Pan02 tumors. Gemcitabine (60mg/kg) was administrated 48 hours before first immunization. Mice treated with a control MVA or PBS with gemcitabine all died of progressive tumor by day 35. When administered with gemcitabine, MVA-survivin immunization resulted in significant tumor regression and prolonged survival. The enhanced vaccine efficacy is in part due to decreased CD11b+/Gr-1+ MDSCs. To analyze the survivin specific immune response to MVA-survivin immunization, we utilized a peptide library of 15mers with 11 residues overlapping from full-length murine survivin. Splencytes from mice immunized with MVA-survivin produced intracellular γ-interferon in response to in vitro stimulation with the overlapping peptide library. These data suggest that vaccination with MVA-survivin in combination with gemcitabine represents an attractive strategy to overcome tumor-induced peripheral immune tolerance, and this effect may be associated with a clinical benefit in pancreatic cancer.
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 2420.