bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4010: Significant roles of p120 catenin and MUC1 in promoting invasive behavior of pancreatic cancer cells
Authors: Liu Xiang , Yi Chunhui , Hollingsworth Michael A. 
Published: June 2012

Abstract
Pancreatic cancer is highly lethal in part because the tumors have metastasized at the time of diagnosis. We are investigating the hypothesis that interactions between the cell surface mucin MUC1 and p120 catenin (p120ctn) modulate cell adhesion, invasion and metastatic properties of pancreatic cancer cells. MUC1 is overexpressed in pancreatic cancer and is known to modulate the invasive and metastatic properties of tumor cells by influencing cell surface adhesion properties directly and by signaling through the MUC1 cytoplasmic tail that reprogram transcription of invasion and metastasis associated genes. Downregulation or mislocalization of p120ctn is correlated with high grade and poor survival in human pancreatic cancer. E-cadherin, which is normally stabilized by p120 catenin in the cell membrane, is frequently lost or downregulated in various human cancers, resulting in the emergence of malignant characteristics, such as loss of epithelial morphology, and gain of invasiveness and metastatic potential. We hypothesized that MUC1 competed with binding of E-cadherin to p120ctn, which enhanced E-cadherin internalization, thus promoting epithelial to mesenchymal transition (EMT). We report here that several p120 catenin isoforms are expressed in human pancreatic cancer and that MUC1 cytoplasmic tail interacts with armadillo repeats of p120ctn. Overexpression of MUC1 resulted in alterations in expression of different p120ctn isoforms, increased nuclear localization of p120ctn, and a decrease in p120ctn association with E-cadherin, as detected by western blotting, co-immunoprecipitations, and confocal microscopy analysis of Capan1 and MIAPACA-2 pancreatic cancer cell lines. Our data support the hypothesis that MUC1 overexpression decreases the association of p120 catenin with E-cadherin, which increases E-cadherin turn over. We also detected colocalization of MUC1 and p120ctn in the nucleus, raising the possibility that this association constitutes a novel signaling pathway mediated by MUC1 and p120ctn that contribute to the reprograming of gene expression during EMT, invasion and metastasis. This research provides novel insight that enable opportunities to develop an effective therapy to prevent pancreatic tumor invasion and metastasis. Supported by grant R01CA57362 from the NCI.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4010. doi:10.1158/1538-7445.AM2011-4010
Abstract 402: The role of IL-6 in communication of pancreatic carcinoma cells with fibroblasts
Authors: Kamohara Hidenobu , Kinoshita Kouichi , Kurashige Junji , Tanaka Youhei , Baba Hideo 
Published: June 2012

Abstract
&lt;INTRODUCTION&gt; Pancreatic cancer shows high mortality rates in gastroenterogical neoplasms, and there are difficulties in early diagnosis and aggressive progression. IL-6 has pleiotropic function and are produced by various immunnocompetent cells, as well as cancer cells. Some studies have been demonstrated IL-6 play an important role in evading host immune surveillance in tumor microenvironment, but interactions of fibroblasts has not been fully understood. Therefore, the aim of this study is to reveal role of fibroblasts in pancreatic tumor microenvironment. Especially, we evaluate induction and biologicial function of IL-6 in pancreatic carcinoma cells after the stimulation with various cytokines and fibroblast associated factors.
&lt;METHODS and RESULTS&gt; Firstly, we examined IL-6 and its receptors expression by RT-PCR and Northern blotting. All 7 tested cell lines expressed gp130 and IL-6R alpha mRNA, 2 cell lines (Hs7667 and Capan1) expressed IL-6 mRNA in serum free condition. To clarify the effect of proinflammatory cytokines on IL-6 expression in Hs766T cells, cells were stimulated with or without cytokines. Northern blotting revealed TNFα and IL-1β upregulated IL-6 mRNA, but not IL-6, IL-8 and LIF. IL-6 did not affect cell proliferation by WTS assay in 7 pancreatic carcinoma cells. In contrast, IL-6 promoted cell motility significantly by gold particles phagocytosis assay (P&lt;0.05) and cell invasion significantly by matrigel insert chamber assay (P&lt;0.05). IL-6 induces phosphorylation of STAT3 in Hs-766T cells, but not AKT. To identify IL-6 expression by interaction between pancreatic carcinoma cells and fibroblasts, we used two established fibroblastic cell lines (MRC-9 and WI-38) isolated from human embryonal lung tissues. Serum free conditioned medium (CM) were collected after incubation for indicated periods. Hs766T originated CM (Hs766T-CM) induced IL-6 and IL-8 mRNA in MRC-9 and WI-38 cells. MRC-9 CM and WI-38-CM did not affect in Hs-766T cells. Co-culture between Hs-766T and MRC-9 cells induced IL-8 mRNA dratically. IL-6 promotes miR-146a and miR155 expression in Hs-766T cells.
&lt;CONCLUSIONS&gt; Communication of pancreatic carcinoma cells with fibroblasts affect IL-6 expression and it could contribute to pancreatic cancer progression. Regulation of IL-6 expression in tumor microenvironment would be important for pancreatic cancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 402. doi:10.1158/1538-7445.AM2011-402
Abstract 4026: Id4 acts as a tumor suppressor by regulating c-Myc and MDM2 in prostate cancer
Authors: Evans Ashley L. , Carey Jason WP , Glymph Shanora E. , Chaudhary Jaideep 
Published: June 2012

Abstract
PURPOSE: Id proteins (Id1, Id2, Id3, and Id4) function as dominant negative regulators of basic helix loop helix transcription factor family. They share the conserved HLH domain but lack the DNA binding basic domain. This domain configuration allows the Id proteins to dimerize with bHLH proteins. The Id-bHLH dimer therefore fails to bind the E box consensus sequence and activate transcription. In general Id1 and Id3 promote proliferation and inhibit differentiation and thus their expression is generally high in many cancers. The function of Id4 appears to be unique as compared to Id1-Id3. Recent studies have demonstrated that Id4 is epigenetically silenced in many cancers suggesting that Id4 may in fact act as a tumor suppressor. The present study was carried out to determine the molecular mechanism by which Id4 acts as a tumor suppressor in prostate cancer. DESIGN METHODS: Initial studies were carried out on DU145 cells in which Id4 is epigenetically silenced. Over-expression of Id4 decreased proliferation and promoted epithelial like morphology in DU145 cells. A proteomics based approach suggested that MDM2 is a potential downstream target of Id4. The upstream regulators and downstream targets of MDM2 were then evaluated to understand the mechanism and functional significance of Id4-MDM2 cross talk. RESULTS: A combination of expression and immuno-localization studies demonstrated that c-Myc and p14ARF, the upstream regulators of MDM2 expression are down-regulated in the presence of Id4. Id4 also significantly up-regulated the expression and nuclear localization of CDKNIs p21and p27. Unexpectedly, the expression of p53 a known target of MDM2 was decreased both at the transcript and protein level. CONCLUSIONS: Although MDM2 was discovered as a potential downstream target, our pathway analysis suggests that c-Myc could also be a downstream target of Id4. The de-repression of CDKNI appears to be c-Myc dependent but p53 independent primarily because in DU145 cells, p53 is mutated. Alternatively, decreased MDM2 could promote p21 stability resulting in increased nuclear localization and expression. Taken together our data support the role of Id4 as a potential tumor suppressor that is unique and opposite to the oncogenic properties of other HLH members Id1, Id2 and Id3.
Supported by: NIH/NCI R01CA128914 and NIH/NCRR/RCMI G12RR03062.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4026. doi:10.1158/1538-7445.AM2011-4026
Abstract 404: Proinflammatory cytokine IL-1β stimulates IL-8 synthesis in mast cells via a leukotriene B4 receptor 2-linked pathway, contributing to angiogenesis
Authors: Lee Jin-Wook , Kim Hyunju , Wei Jun-Dong , Seo Ji-Min , Park Soo Young , Park Geun-Soo , Lee A-Jin , Kim Jae-Hong 
Published: June 2012

Abstract
Recent studies have suggested that mast cells have critical roles in angiogenesis. However, the detailed mechanism by which mast cells contribute to angiogenesis is not yet clearly understood, especially in response to proinflammatory cytokines. In this study, we showed that the proinflammatory cytokine IL-1β induces the synthesis of IL-8, a potent angiogenic factor, in human mast cells via the leukotriene B4 receptor (BLT)2. We also characterized the BLT2 downstream signaling pathway and determined that BLT2-mediated IL-8 synthesis involves the upregulation of Nox1, a member of the NADPH oxidase family, Nox1-dependent reactive oxygen species generation and the subsequent activation of the redox-sensitive transcription factor NF-κB. For instance, knockdown of BLT2 and Nox1 with specific small interfering RNA, treatment with a specific BLT2 antagonist, LY255283, or treatment with a potential Nox inhibitor, diphenylene iodonium, suppressed IL-1β-induced IL-8 synthesis. We found that the conditioned media collected from IL-1β-treated human mast cell line HMC-1 had significantly enhanced angiogenic activity that could be dramatically attenuated by either small interfering RNA knockdown of BLT2 or treatment with neutralizing Ab to IL-8. Finally, the experiments were repeated using human primary cord blood-derived mast cells, and the results were clearly reproduced. Taken together, our results suggest that BLT2-Nox1-reactive oxygen species-dependent pathway plays a role in promoting the secretion of IL-8 from human mast cells in response to the proinflammatory cytokine IL-1β, thus contributing to angiogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 404. doi:10.1158/1538-7445.AM2011-404
Abstract 4040: Goyazensolide, a sesquiterpene lactone from Piptocoma rufescens inhibits tumor development in hollow fiber
Authors: Shen Qi , Matthew Susan , Wittwer Jennifer A. , Ren Yulin , Kinghorn A. Douglas , Carcache de Blanco Esperanza J. , Swanson Steven M. 
Published: June 2012

Abstract
Goyazensolide (C19H20O7) is a rare sesquiterpene lactone isolated from Piptocoma rufescens Cass. (Asteraceae). Goyazensolide significantly inhibits NF-κB transcription factor and decreased the cell growth of HT-29 colon cancer cells in a dose-dependent manner. In the present study, we investigated the effects of goyazensolide in a hollow fiber assay using in vivo setting. We also examined the involvement of ROS-signaling components (ROS levels, NF-κB transcription factor, mitochondrial membrane potential) and demonstrated that the antiproliferative effect of cancer cells is partially mediated by induction of oxidative stress. It is our aim to further investigate the molecular mechanism through which goyazensolide exerts its cytotoxic effect in vitro and its antitumor effect in vivo. Our data therefore supports goyazensolide as an active anti-proliferative agent with great potential for further development.
Acknowledgment
This research was supported by Program Project Grant P01-CA125066 funded by the National Cancer Institute, NIH.We also wish to acknowledge the plant taxonomists who collected the plant material used in this investigation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4040. doi:10.1158/1538-7445.AM2011-4040
Abstract 424: Interference with alphaVbeta3 integrins via cyclic RGD peptides affects breast cancer cell behavior
Authors: Martel Alexandra , Poettler Marina , Kalinowska Waclawa , Valent Peter , Zielinski Christoph , Prager Gerald W. 
Published: June 2012

Abstract
Integrin alphavbeta3 is mainly expressed in stimulated endothelial cells, thus it has recently become the focus of intense research mainly to interfere with tumorangiogenesis. However, alphavbeta3 integrins are also expressed in a variety of tumor cells, such as melanoma, prostate cancer, breast cancer, cervix carcinoma or pancreatic cancer.
While inhibition of integrin alphavbeta3 activity in endothelial cells has been studied extensively, any direct effects on integrin alphavbeta3 expressing tumor cells is hitherto unknown.
In this study we examined alphavbeta3 integrin expression in breast cancer cell lines, where by MDA MB 231 revealed high integrin alphavbeta3 as well as VEGFR-2 and VEGF expression.
While adhesion of MDA MB231 cells to an alphavbeta3 specific matrix such as fibrinogen was blocked by the addition of cyclic RGD peptides, sequentially addition of cyclic RGD peptides to already adherent MDA MB231 cells led to a diminished spreading in a time and dose dependent manner, starting at 20nM.
Furthermore, tumor cell migration as well as transmigration through an EC monolayer upon VEGF stimulation was blocked whenever alphavbeta3 integrins were targeted by RGD mimetic peptide.
Our data give first functional insights into the previously described effects of alphavbeta3 targeting small molecules, which led to a reduced breast cancer metastasis in vivo.
Thus interfering with alphavbeta3 integrins on tumor cells might represent a promising therapeutic lead in certain malignancies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 424. doi:10.1158/1538-7445.AM2011-424
Abstract 4332: Conditional transgenic mice for the carboxyl-terminus of MUC16
Authors: Tian Huasong , Spriggs David R. 
Published: June 2012

Abstract
The cancer antigen 125 (CA125) is encoded by the MUC16 gene, which is present in sera of women with ovarian cancer. Currently, CA125 is widely used to diagnose the epithelial ovarian cancer and monitor the effects of treatment. Despite the widespread use of CA125, the biochemical and molecular functions of this antigen is poorly understood. There is no phenotype for MUC16 knockout mice (Cheon et al., PLoS ONE, 2009). Our previous data have demonstrated that the carboxyl-terminus of MUC16 has at least the partial functions of MUC16 since CA125 protein is too big (up to 2.5 MDa). To better understanding of the biological functions and characterizations of MUC16, we made a construct to create a conditional transgenic mouse model for the carboxyl-terminus of MUC16 using the Cre-loxP system. This mouse model encodes for the specific portion of MUC16, we named as MUC16ΔC354 mouse, which includes 354 amino acids of carboxyl-terminus of MUC16 with a HA tag. The CMV early enhancer plus chicken β actin (CAG) promoter is used to drive hGFP between two loxPs and the carboxyl-terminus of MUC16 after removing hGFP. After mating with EIIa-Cre transgenic mice, we found two founders which highly express MUC16ΔC354 in many organs, for example, brain, colon, heart, kidney, liver, lung, ovary and spleen. Lung and heart have higher expression level of MUC16ΔC354, and ovary has a middle level. MUC16ΔC354 heterozygous animals appear to be viable, fertile, and develop normally through the first four months of life. However, MUC16ΔC354 transgenic mice regulate PI3K/AKT and MAPK/ERK signaling pathways in some organs. Additional MUC16ΔC354 mice are being bred and selected for phenotypes. Cross breeding with N-Myc transgenic mice, or Rb-1 and p53 knockout mice is planned based on the preliminary results of The Cancer Genome Atlas (TCGA).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4332. doi:10.1158/1538-7445.AM2011-4332
Abstract 4340: Sorafenib induces growth arrest and apoptosis in neuroblastoma cells via inhibition of JAK2/STAT3 and MEK1/2/MAPK (p44/42) signaling pathways
Authors: Yang Fan , Jove Veronica , Buettner Ralf , Xin Hong , Nam Sangkil , Ara Tasnim , DeClerck Yves A. , Seeger Robert C. , Yu Hua , Jove Richard 
Published: June 2012

Abstract
Neuroblastoma is the most common extracranial solid tumor in the pediatric population. It accounts for 6-10% of all childhood cancers. Currently, there is a critical need to find new drugs that are less toxic and target cell signaling pathways implicated as key mediators in the formation of neuroblastoma. Sorafenib (Nexavar), a multikinase inhibitor, blocks cell proliferation and induces apoptosis in certain types of cancers. Here, we tested antitumor effects of sorafenib (≤ 10 µM) on three human neuroblastoma cell lines, CHLA255, CHLA171 and SK-N-AS. Sorafenib inhibited cell proliferation and induced apoptosis in these neuroblastoma tumor cells in a time- and dose-dependent manner. Sorafenib inhibited phosphorylation of Signal Transducer and Activator of Transcription 3 (STAT3) proteins at Tyr705 in these cells as early as 15 min after treatment, associated with inhibition of phosphorylated JAK2, an upstream kinase that mediates STAT3 phosphorylation. Expression of a constitutively-activated STAT3 mutant (pSTAT3-C) partially blocked the antitumor effects of sorafenib on neuroblastoma cells. Sorafenib also inhibited the phosphorylation of STAT3 induced by IL-6 in these tumor cells. Moreover, sorafenib downregulated phosphorylation of MAPK (p44/42) in these neuroblastoma cells after 5 min treatment, consistent with inhibition of their upstream regulators MEK1/2. Finally, sorafenib inhibited expression of cyclin E, cyclin D1, cyclin D2 and cyclin D3, key regulators for cell cycle, and the antiapoptotic protein Mcl-1, which was accompanied by induction of growth arrest and apoptosis in neuroblastoma cells. Taken together, these findings suggest the potential use of sorafenib for the treatment of pediatric neuroblastomas.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4340. doi:10.1158/1538-7445.AM2011-4340
Abstract 4345: AZD8055, a combined TORC1/TORC2 inhibitor regulates Mycn protein expression and prevents neuroblastoma growth in vitro and in vivo
Authors: Vaughan Lynsey S. , Barker Karen , Webber Hannah , Jamin Yann , Robinson Simon , Guichard Sylvie , Chesler Louis 
Published: June 2012

Abstract
Neuroblastoma is the most common and deadly solid tumour of childhood (Brodeur, 2003). Amplification of the MYCN oncogene occurs in 25% of NBs correlating with poor clinical outcome. High risk neuroblastoma responds to current therapies but rapidly acquires chemoresistance; therefore alternative treatment strategies are required. Because of the importance of MYCN amplification in high risk neuroblastoma and specific expression of Mycn protein in tumour tissue, we have examined indirect methods of destabilising Mycn by targeting key components of upstream signalling pathways, responsible for maintenance of Mycn protein levels. Mycn protein stability is maintained by the RAS (RAF/MEK/ERK) and PI3K (PI3K/AKT/mTOR) pathways. The mammalian target of rapamycin (mTOR) plays an important role in cell proliferation, metabolism and tumourigenesis, and is frequently altered in cancer. Rapamycin and its analogues target the TORC1 complex and are effective against tumour xenografts but are limited by consequent up regulation of PI3K activity. Inhibition of TORC1 alleviates a TORC1 dependent negative feedback loop, with resulting activation of PI3K and AKT-dependent survival pathways.
AZD8055 is an mTOR kinase inhibitor that inhibits both TORC complexes with IC50 values in the nanomolar (nM) range. Treatment of N-myc wild-type or phosphomutant expressing neuroblastoma cell lines with AZD8055 inhibited mTOR-dependent phosphorylation of key pathway components, coincident with selective inhibition of wild-type but not phospho-mutated N-myc protein. Cell proliferation was reduced and sensitive cells accumulated in G1 as shown by flow cytometric analysis. Cells expressing N-myc phosphomutant proteins showed less sensitivity to AZD8055, with GI50 values above mechanistic range for targeted effects of this drug.
The ability of AZD8055 to inhibit neuroblastoma tumour progression was tested in a transgenic model of neuroblastoma (TH-MYCN) that over expresses Mycn protein and is predisposed to spontaneous tumour formation (Weiss, 97). We present data showing that AZD8055 inhibits tumour progression, reduces tumour cell proliferation and targets the mTOR complex in vivo.
In conclusion, inhibition of mTOR signalling is highly effective against MYCN-driven cell lines and tumours, and therefore could be a promising therapeutic strategy for targeted treatment of MYCN-amplified neuroblastoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4345. doi:10.1158/1538-7445.AM2011-4345