bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2271: Dabigatran etexilate blocks breast cancer progression in vitro and in a 4T1 breast cancer tumor model in mice
Authors: DeFeo Karen , Hayes Candace S. , Ryn Joanne Van , Gilmour Susan K. 
Published: February 2011

Abstract
Introduction: Coagulation proteases and the generation of thrombin are increased in tumors. Thrombin can modify tumor cell behavior directly through the activation of protease-activated receptors (PAR) or indirectly by generating fibrin matrices.
Aim: To test the hypothesis that dabigatran etexilate (Pradaxa®), an oral direct thrombin inhibitor, can prevent the progression of tumor cells in experimental models.
Materials and Methods: The effect of dabigatran on invasiveness of MDA-MB-231 breast carcinoma cells was evaluated in vitro by invasion across Matrigel-coated membranes and in vivo using a tracheal xenotransplant invasion assay in athymic nude mice. To evaluate the effect of dabigatran on the development of metastatic foci, 4T1 tumor cells were injected orthotopically in the mammary fat pads of syngeneic Balb/c mice. Tumor growth and metastasis was monitored weekly. Dabigatran etexilate was administered twice daily at a dose of 45 mg/kg over 4 weeks in all in vivo models.
Results: Whereas dabigatran had no effect on the proliferation index of cultured tumor cells, it inhibited invasiveness of MDA-MB-231 cells across Matrigel-coated membranes. In vivo evaluation of invasiveness of MDA-MB-231 cells in tracheal xenotransplants in mice administered dabigatran for 3 and 4 weeks demonstrated significantly less penetration of tumor cells through the tracheal wall. Dabigatran treatment had a modest inhibitory effect on growth of the primary 4T1 mammary carcinoma (∼50% reduction in tumor volume at 4 weeks) in syngeneic Balb/c mice, and it reduced both 4T1 tumor cells in the blood and liver micrometastases by 50-60%. Dabigatran treatment resulted in no weight loss in mice.
Conclusion: Oral administration of the direct thrombin inhibitor, dabigatran etexilate, inhibits both invasion and metastasis of malignant breast tumors, suggesting that dabigatran may be beneficial in not only preventing thrombotic events in cancer patients, but also as adjunct therapy to treat malignant tumors. (Supported by funds from Boehringer Ingelheim Pharma)
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 2271.
Abstract 2278: Tumor microenvironment might be more important than pro-angiogenic chemotactic factors for tumor angiogenesis
Authors: Lee Myungjin , Chang Hyo Won , Nam Hae Yun , Lee Hyangju , Han Myung Woul , Kim Seong Who , Kim Sang Yoon 
Published: February 2011

Abstract
During angiogenesis, many different tumor cytokines have been known to be involved in the regulation of chemotactic endothelial cell migration. Among those, a vascular endothelial growth factor (VEGF) is one of the most essential pro-angiogenic factors and the blockage of VEGF action through competitive inhibition on its receptor or by using of neutralizing antibody such as avastin has been considered as a promising anti-cancer approach to treat several solid tumors. However, despite their ability of releasing VEGF, some cancers show scarce angiogenesis and resistance to avastin treatment.
To explore key factors deciding tumor angiogenesis apart from well-known pro-angiogenic cytokines, we compared the pro-angiogenic capability of the AMC-HN9 head and neck cancer cell line (HN9) which has a low degree of angiogenesis in vivo and are reluctant to avastin treatment with that of the highly angiogenic AMC-HN3 cancer cell line (HN3). Of interest, in vitro cytokine assay of HN9 culture media revealed no difference in the secretion profile of pro-angiogenic cytokines such as VEGF, PlGF, FGF2 and PDGF compared with those of HN3. In addition, HN9 media could strongly promoted tubular formation of HUVECs and migration of fibroblasts in vitro as much as HN3 could. Next, we proceeded to HN9 xenograft co-injected with ECM molecules including fibronectin, collagen III or matrigel. In the co-injected xenografts, density of CD34 positivity significantly increased and the tumor growth exceeded that of HN9 alone-injected ones. Moreover, prominent fibroblast infiltration adjacent to tumor vessels was detected in the co-injected xenografts.
Taken together, these results imply that the formation of extracellular matrix surrounding tumor cells and the presence of activated fibroblasts are pre-requisites and more decisive in angiogenesis than tumor secreted pro-angiogenic cytokine per se.
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 2278.
Abstract 228: Cucurbitacin-I (JSI-124) induces apoptosis in chronic lymphocytic leukemia (CLL) cells through inhibiting STAT3 activation and XIAP expression
Authors: Ishdorj Ganchimeg 
Published: February 2011

Abstract
Abstract AACR April-2010
Cucurbitacin-I (JSI-124) induces apoptosis in Chronic Lymphocytic Leukemia (CLL) cells through inhibiting STAT3 activation and XIAP expression.
Ganchimeg Ishdorj, James B Johnston and Spencer B Gibson
Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Canada
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in North America. Current therapies control the disease but eventually the disease recurs and becomes drug resistant. Phosphorylation of signal transducer and activator of transcription 3 (STAT3) plays a pivotal role in cell survival and induces proliferation, whereas deletion of STAT3 results in cell death. Constitutive phosphorylation of STAT3 on tyrosine 705 residues has been found in a number of solid tumors and hematologic malignancies. Unlike other tumors, STAT3 is constitutively phosphorylated (p) on serine 727 but not on tyrosine residues in CLL. These observations lead to investigation of the effect of STAT3/JAK2 inhibitor Cucurbitacin-I (JSI-124) in CLL cells. We proposed that the targeting STAT3 phosphorylation may induce apoptosis in CLL cells. We studied B-cell lines (BJAB, I-83, NALM-6) and primary B-cells from patients with CLL using immunoprecipitation and found that JSI-124 suppressed serine pSTAT3 and induced apoptosis of these cells as determined by FACS analysis and membrane permeability assay. Using western blotting analysis, caspase-8 activation was observed in these cells after JSI-124 treatment. Since the activation of caspases are inhibited by members of the inhibitor of apoptosis (IAP) and Bcl-2 protein families and STAT3 has been shown to regulate their expression, we investigated anti-apoptotic members of these families. JSI-124 treatment led to downregulation of IAP protein XIAP, while Bcl-xL and Mcl-1 levels remained unchanged. In addition, JSI-124 selectively induced activation of JNK signaling pathways in CLL cells. Taken together, our results indicate that JSI-124 causes apoptosis through alterations in signal transduction pathways and could be a useful treatment in CLL.
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 228.
Abstract 2285: Epigenetic silencing of SOD3 contributes to the malignant phenotype in human lung cancer
Authors: Fitzgerald Matthew P. , Teoh Melissa LT , Madsen Joshua M. , Domann Frederick E. 
Published: February 2011

Abstract
Extracellular SOD (EcSOD), encoded by the SOD3 gene, scavenges superoxide in the extracellular space. EcSOD is highly expressed in the lung where it comprises the majority of SOD activity in airway epithelial and vascular cells. The role of EcSOD in lung cancer, if any, has not yet been thoroughly studied. It has been reported, however, that EcSOD expression is lost in the lung cancer cell line A549 and that the transcription factors SP1/SP3 that regulate expression in MRC-5 cells could neither bind the promoter nor stimulate EcSOD expression in A549 cells. We hypothesized that EcSOD loss in lung cancer could be due to epigenetic events. To test this hypothesis we analyzed the epigenotype of the SOD3 promoter in three normal cell types (airway epithelial, MRC-5, HMEC) and two EcSOD negative lung cancer cell lines (A549, H1650) as well as in normal lung versus five human lung tumors. We also re-expressed EcSOD in the A549 cell line to assess possible changes in malignant phenotype. We now report that EcSOD expression is highly correlated with SOD3 promoter methylation. In the normal airway epithelial and MRC-5 lung cells that express EcSOD, the promoter has an overall cytosine methylation of &lt;1% while in the non-expressing lung cancer cells and HMEC cells there was &gt;86% methylation at the 18 CpG sites examined. Treatment of cells with 5-aza-dC induced SOD3 mRNA, indicating that DNA methylation was causal, at least in part, to the gene silencing. Moreover, A549 and H1650 cells displayed a ∼25-fold reduction in chromatin accessibility of the SOD3 promoter compared to MRC-5 cells. In the five lung tumors, EcSOD mRNA expression was significantly decreased and the SOD3 promoter showed a significantly more methylated state in the tumors compared to normal lung tissue. Re-expression of EcSOD attenuated the malignant phenotype of A549 cells by increasing doubling time by 25 hours, decreasing matrigel invasion and clonogenic capacity by 65% and 70% respectively. Taken together, our findings indicate that loss of EcSOD expression in human lung cancer is highly correlated with aberrant SOD3 promoter methylation and a repressive chromatin structure, and that re-acquisition of EcSOD attenuates the malignant phenotype of lung cancer cells.
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 2285.
Abstract 2286: SPARC stimulates neuronal differentiation of medulloblastoma cells via the IL-6/STAT3 pathway
Authors: Bhoopathi Praveen , Chetty Chandramu , Gujrati Meena , Dinh Dzung H. , Rao Jasti S. , Lakka Sajani S. 
Published: February 2011

Abstract
Secreted Protein Acidic and Rich in Cysteine (SPARC), a 37-kDa glycoprotein, participates in the regulation of morphogenesis and cellular differentiation through its modulation of cell-matrix interactions. We have reported previously that SPARC expression significantly impairs medulloblastoma tumor growth in vivo. In this study, we show that the ectopic expression of SPARC induces neuronal differentiation in medulloblastoma cells. Adenovirus-mediated expression of SPARC cDNA (Ad-DsRed-SP) elevated the expression of neuronal markers NeuN, Nestin and MAP-2 in medulloblastoma cells. SPARC expression decreased STAT3 phosphorylation and constitutive expression of STAT3 reversed SPARC-mediated neuronal differentiation. Moreover, our results show that SPARC expression not only inhibited interleukin (IL)-6 but also attenuated IL-6-mediated STAT3 phosphorylation in medulloblastoma cells. Taken together, our results suggest that SPARC induced neuronal differentiation of medulloblastoma tumor cells through its inhibitory effect on IL-6-mediated STAT3 signaling. Immunohistochemical analysis of tumor sections from mice treated with Ad-DsRed-SP showed increased staining for the neuronal markers NeuN, Nestin and MAP-2. Overall, our results demonstrate that SPARC promotes neuronal differentiation and inhibits tumor growth, thereby further supporting the potential use of SPARC as a therapeutic target for medulloblastoma.
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 2286.
Abstract 2293: ZEB1 and ZEB2 promote EMT and invasion in esophageal squamous cell carcinoma
Authors: Naganuma Seiji , Ohashi Shinya , Kimura Sotai , Natsuizaka Mitsuteru , Gimotty Phyllis , Klein-Szanto Andres J. , Itoh Hiroshi , Nakagawa Hiroshi 
Published: February 2011

Abstract
Introduction: Epithelial-mesenchymal transition (EMT) promotes tumor invasion and metastasis. Amongst transcription factors essential in EMT, zinc finger E-box binding proteins ZEB1 and ZEB2 (ZEB) are upregulated in several tumor types due to loss of the miR-200 family. However, the role of ZEB in esophageal squamous cell carcinoma (ESCC) remains to be elucidated. Methods: ESCC cell lines were grown. Immortalized human esophageal cells EPC2-hTERT were retrovirally co-transduced with EGFR and mutant p53 (p53R175H), early genetic lesions common in ESCC, leading to transformation as described previously (Genes Dev. 2007; 21:2788). Short hairpin RNA was expressed by lentivirus to knockdown ZEB1 and ZEB2. Epithelial cells were grown in organotypic 3-D culture, a form of tissue engineering. Laser capture microdissection (LCM) was performed to isolate RNA for gene expression profiling in the invasive cells in 3-D culture as well as microRNA determination in archived paraffin embedded primary ESCC tissue samples. Real-time RT-PCR, Western blotting and immunohistochemistry were done to determine gene expression. Senescence-associated β-galactosidase activity was determined. Results: In primary ESCC, ZEB expression was found upregulated in tumor cells at the invasive front with increased Vimentin and decreased E-cadherin expressions. Moreover, LCM documented a significant downregulation of the miR-200 family in the invasive tumor cells consistent with EMT. ZEB upregulation and concomitant loss of the miR-200 family were also found in two out of 11 ESCC cell lines, exhibiting EMT corroborated by spindle-shaped cell morphology as well as an E-cadherin to N-cadherin class switch. EGFR overexpression and p53 mutation in EPC2-hTERT cells resulted in ZEB upregulation and a significantly augmented susceptibility to EMT, where robust induction of ZEB and suppression of the miR-200 family were observed upon TGF-β treatment. In 3-D culture, the cells co-transduced with EGFR and mutant p53 markedly invaded into the underlying stroma compartment. The invasive cells had a gene signature compatible with EMT along with ZEB upregulation. Finally, knockdown of either ZEB1 or ZEB2 not only prevented TGF-β from inducing EMT, but also TGF-β-mediated massive senescence in EPC2-hTERT cells transformed by EGFR and mutant p53. Conclusions: Our data indicate that ZEB1 and ZEB2 are negatively regulated by the miR-200 family and induced upon invasion in ESCC. ZEB may regulate senescence and EMT in concert with TGF-β signaling, thus contributing to esophageal carcinogenesis and tumor progression.
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 2293.
Abstract 23: Sanguinarine suppresses survivin expression and inhibits the growth of prostate cancer cells
Authors: Sun Meng , Chun Jae Yeon , Lou Wei , Gao Allen C. 
Published: February 2011

Abstract
Background: Prostate cancer is a frequently occurring disease and is the second leading cause of cancer related deaths of men in the United States. Current treatments have proved inadequate in curing or controlling prostate cancer and a search for agents for the management of this disease is urgently needed. Survivin plays an important role in both progression of castration-resistant prostate cancer and resistance to chemotherapy. Altered expression of survivin in prostate cancer cells is associated with cancer progression, drug/radiation resistance, poor prognosis and short patient survival. Methods: We performed a cell based rapid screen of the Prestwick Chemical Library consisting of 1120 FDA-approved compounds with known safety and bioavailability in humans to identify potential inhibitors of survivin and anti-cancer agents for prostate cancer. Results: Sanguinarine, a benzophenanthridine alkaloid derived primarily from the bloodroot plant, was identified as a novel inhibitor of survivin that selectively kills prostate cancer cells over “normal” prostate epithelial cells. We found that sanguinarine inhibits survivin protein expression through protein degradation via the ubiquitin-proteasome system. Sanguinarine induces apoptosis and inhibits tumor formation and growth of human prostate cancer cells. Administration of sanguinarine, beginning 3 days post ectopic implantation of DU145 human prostate cancer cells, reduces both tumor weight and volume by more than 70% compared to the control treated mice with no apparent toxicity. In addition, sanguinarine sensitized prostate cancer cells to paclitaxel-mediated growth inhibition and apoptosis, offering a potential therapeutic strategy for overcoming taxol resistance. Conclusions: These results suggest that sanguinarine may be developed as an agent either alone or in combination with taxol for treatment of castration-resistant prostate cancer overexpressing survivin.
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 23.
Abstract 230: LMP1 function in NK/T-cell lymphoma
Authors: Nuri Kim 
Published: February 2011

Abstract
BACKGROUND:
Because NK/T-cell lymphoma was closely associated with EBV LMP1 (latent membrane protein-1) which can directly activate NF-κB-mediated oncoproteins, therefore, in this study determined whether bortezomib (proteasome inhibitor) alone or combined with irradiation affect cytotoxicity and related mechanism in NK/T-cell lymphoma and malignant lymphoid cell lines. Beside, recently LMP1 has been introduced ambivalent function, because it's also up-regulation of Fas signaling. However, lack of information when these are activated by various stimulations. Therefore, in this study, we showed that bortezomib can enhance up-regulation of LMP1 as pro-apoptotic protein in EBV LMP1 expressed cell lines.
MATERIAL & METHOD:
Human NK/T-cell lymphoma cells (Hank-1), NK-cell lymphoma (NK-92), T-cell lymphoma cells (Jurkat), and Burkitt lymphoma cells (Raji and Jijoye) were used. Bortezomib and irradiation were treated alone or combined, and tumor cell growth and apoptosis were measured by MTT assay and FACS respectively. Apoptosis and its associated protein expression levels were measured by Western blot assay. Interaction of LMP1 and Fas were evaluated by immuno-precipitation and protein ligation assay.
RESULTS:
Cell death by combining of bortezomib and irradiation synergistically inducing in LMP1 expressed Hank-1 than no LMP1 expressed NK-92 cells. To understand the mechanism of bortezomib regulated LMP1 and Fas, we examined that activated LMP1 by bortezomib enhanced effect of irradiation inducing cytotoxicity. Combined treatment of bortezomib and irradiation up-regulated LMP1 and Fas which composed binding complex, activating Fas-related molecules. In this regard, LMP1 may have paradoxal behavior. These results provided that combination of bortezomib and irradiation enhanced LMP1 as pro-apoptotic function, leading to degradation of NF-κB and resulted caspase activation in EBV LMP1 expressed cancer cell lines.
CONCLUSION:
LMP1 is able to inducing NF-κB in normal condition as oncoprotein, however bortezomib could up-regulate LMP1, its binding with Fas in EBV LMP1 expressed lymphoid cancer cell lines. Therefore, combination of bortezomib and irradiation is suggested as potential therapy not only in NK/T-cell lymphoma but also LMP1 expressed lymphoma and tumors.
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 230.
Abstract 2300: Overexpression of Snail induces epithelial-mesenchymal transition and cancer stem cell-like phenotypes in CRC cells
Authors: Fan Fan , Evans Kurt W. , Mani Sendurai A. , Zhou Yunfei , Samuel Shaija , Lu Jia , Xia Ling , Sceusi Eric , Tozzi Federico , Ye Xiang-Cang , Ellis Lee M. 
Published: February 2011

Abstract
Background: Epithelial-to-mesenchymal transition (EMT) is a critical process providing tumor cells with the ability to migrate and escape from the primary tumor and metastasize to distant sites. Recently, EMT has been shown to be associated with the cancer stem cell (CSC) phenotype in breast cancer. Snail is a transcriptional factor that mediates EMT in a number of tumor types. Its aberrant expression has been found in various cancers including colorectal cancer (CRC). The role of Snail in mediating EMT and CSC function in CRC has not yet been fully elucidated.
Methods: The human CRC cell lines HT29 and KM12L4 were transduced with a retrovirus containing the pBabe-puro-Snail expression construct or the empty vector. The Snail expressing cells and controls were selected with the medium containing 2µg/ml puromycin. Changes in cell proliferation and chemo-sensitivity were determined by MTT assay. Migration and invasion were determined using in vitro wound healing assay and modified Boyden Chamber assays, respectively. EMT makers (E-cadherin, vimentin) and the putative CSC marker CD133 was analyzed by Western blotting. ALDH1 enzyme activity was analyzed by the Aldefluor assay.
Results: Overexpression of Snail in CRC cells induced an EMT phenotype with elevated expression of vimentin and reduced expression of E-cadherin. Snail-induced EMT did not alter cell proliferation but showed enhanced cell motility, in which Snail-expressing cells were 5- to 6-fold more migratory than the control cells. Snail also promoted the CSC-like phenotype demonstrated by increased expression of the CSC markers CD133. The aldefluor positive cell population in the Snail-expressing cells was increased ∼4 fold. Moreover, the Snail-expressing CRC cells showed increased chemoresistance to 5FU by 50%.
Conclusion. High level of Snail expression confers the EMT and CSC phenotype in CRC cells, which enhanced cancer cell invasion and chemoresistance. Our data suggest that Snail may be a potential therapeutic target in metastatic colorectal 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 2300.