bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5261: Transfection of nerve growth factor cDNA into SK-N-BE(2)C neuroblastoma modulates TrkA and p75 receptor expression and activation
Authors: Holub Janette L. , Lautz Timothy B. , Chu Fei , Clark Sandra H. , Madonna Mary Beth 
Published: February 2011

Abstract
The diverse biological role of nerve growth factor (NGF) as a necessary modulator of neuroectodermal cell survival, proliferation and differentiation has been previously well described in both normal and neoplastic cell lines. However, recent studies demonstrate that neuroectodermal tumors, such as neuroblastoma, contain genetic alterations that result in limited secretion of active NGF, as well as expression abnormalities of its receptors TrkA and p75. To better define the differential effects of exogenous and endogenously synthesized NGF, the in vitro response of wild-type and genetically engineered neuroblastoma cells was investigated. Replication-defective NGF-expressing retroviral vectors were prepared using the calcium phosphate co-precipitation method and used to transfect SK-N-BE(2)C cells. Presence of the NGF cDNA was confirmed by RT-PCR, and secretion of NGF into the conditioned media by western immunoblotting. NGF transfection resulted in decreased cell proliferation as determined by nonradioactive cell proliferation assay. Wild type and NGF transfected (BE(2)C-NGF) cells were then incubated with exogenous NGF at 200ng/mL for varying time periods up to 24 hours. The expression of TrkA and p75, as well as proteins of their associated survival and apoptosis cascades were determined by Western immunoblotting of whole cell lysates. p75 expression in the NGF transfected cell line was equivalent to the parental wild type cell, but TrkA expression was significantly lower in BE(2)C-NGF. At baseline, BE(2)C-NGF cells demonstrate significant down-regulation of phospho-cRAF and its downstream effector phospho-p42/44 in comparison to the wild type cell line. Additionally, NGF stimulation further down-regulated phospho-c-RAF expression in the NGF transfected cell line, with maximal down-regulation occurring at 24 hours. BE(2)C-NGF cells also demonstrate significant baseline activation of phospho-p38 in comparison to the wild type cell line, with expression further up-regulated with NGF stimulation at 5 minutes and 1 hour. In conclusion, nerve growth factor cDNA gene transfer into wild type SK-N-BE(2)C neuroblastoma results in decreased activation of the p-42/44 survival pathway and concomitant up-regulation of the p-38 apoptotic pathway, leading to a overall decreased rate of proliferation. This effect is likely the result of a decreased TrkA to p75 receptor ratio, and further understanding of these pathways may facilitate the discovery of novel therapeutic targets for neuroblastoma treatment.
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 5261.
Abstract 5268: Stimulated metastasis after treatment with epigenetic drugs through up-regulation of Ezrin
Authors: Yu Yanlin 
Published: February 2011

Abstract
Stimulated metastasis after treatment with epigenetic drugs through up-regulation of Ezrin
Yanlin Yu, Pingyao Zeng, Jingbo Xiang, Shelley L. Berger and Glenn Merlino
Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
The metastases at distant sites are still the main cause of death in cancer patients. New prognostic markers are urgently needed to assess the risk for developing metastasis, and novel therapeutic strategies are needed to treat this deadly disease. Epigenetic drugs such as histone deacetylase inhibitors (HDACis) and inhibitors of DNA methylation are emerging as a new class of anticancer agents and are in several ongoing patient treatment regimens. However, those drugs are thought to be “dirty drugs”, affecting many pathways. Previously, we identified Ezrin as a critical regulator of metastasis in a mouse model of the pediatric cancer rhabdomyosarcoma (RMS) (Yu, et al. Nature Medicine, 2004; Yu, et al. Cacner Res, 2006). In the current study, we examined the status of histone modification at the Ezrin gene chromatin locus and of methylation at the Ezrin promoter in highly and poorly metastatic RMS cell lines. Our results showed that RMS cells with high-level Ezrin and high metastatic potential have elevated acetylation of histone H3 lysine 9 (H3K9) and less methylation at the Ezrin promoter. In contrast, RMS cells with low-level Ezrin and poor metastatic potential have reduced acetylation of H3K9 and elevated methylation at the Ezrin promoter. Our data demonstrate that epigenetic covalent modifications to histones within nucleosomes of the Ezrin gene promoter are linked to Ezrin expression, and suggest that epigenetic regulation may affect the expression of Ezrin, thereby regulating metastasis. We further found that treatment with HDACi TSA or DNA demethylating agent 5-aza can restore expression of Ezrin and stimulate the metastatic potential of poorly metastatic cells with low Ezrin levels. Notably, the combination of Ezrin shRNA and HDACi can significantly inhibit this metastasis. This finding provides new mechanistic and therapeutic insights of epigenetic drugs in cancer treatment.
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 5268.
Abstract 527: Pyrrole-Imidazole polyamide inhibits MMP-9 transcription and induces suppression of tumor metastasis
Authors: Wang Xiaofei , Nagase Hiroki 
Published: February 2011

Abstract
Pyrrole-Imidazole (PI) polyamide that targets the AP-1-binding site of the MMP-9 promoter was designed and synthesized as a gene-silencing agent for tumor metastases. MMP-9, the 92-kDa type IV collagenase, contributes to tumor invasion and metastases, and strategies to down-regulate its expression could ultimately be of clinical utility. The synthesized MMP-9 PI polyamide showed selective DNA binding ability and significantly inhibited MMP-9 mRNA and protein expression and enzymatic activity in both MDA-MB-231 and Hela cells. Furthermore, the MMP-9 PI polyamide inhibited migration and invasion by in vitro wound-healing and matrigel-invasion assay. The FITC-labeled PI polyamide was localized in nuclei in 45 minutes of incubation with an MDA-MB-231 cell and remained in the nuclei up to 96 hours after incubation in vitro. It was also quickly localized in the mouse cellular nuclei of many tissues, including liver, kidney and spleen, after intravenous injection without using any drug-delivery system. Moreover, the polyamide treatment significantly decreased metastasis of xenografted tumor cells and host angiogenesis in tumors in a mouse model of liver metastasis. Our results suggest that this PI polyamide that targets the MMP-9 gene promoter can be a novel MMP-9 down-regulating molecule for anti-metastasis.
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 527.
Abstract 5270: Activation of B-raf by TCDD effects on chemotherapeutic resistance and potent inhibition of TCDD mediated tumor invasion of papillary thyroid cancer cells by PD98059
Authors: Ahn Kwang-Sung , Chae Yang Seok , Won Nam Hee , Kim Hyun Gi 
Published: February 2011

Abstract
The BRAF mutation (V599E) is the most common oncogenic genetic alteration in PTC and, through aberrant activation of the MAPK pathway, can initiate the development and promote the progression of PTC. Constitutive activation of the MAPK pathway through genetic alterations, including RAS and B-type RAF (BRAF) mutations, is common in human cancers and is associated with cell malignant transformation and aggressiveness, implicating that targeted inhibition of the MAPK pathway may potentially be an effective therapy for human cancers. AhR receptor ligands such as TCDD are known to activate mitogen activated protein (MAP) kinases and stress-activated protein kinase/c-Jun NH2-terminal kinase. Here we report that PD98059 successfully inhibits cisplatin-induced apoptosis. And induction of phospho-JNK and phospho-ERK-1/2 were noted when SNU-790 cells were treated with 1 nM TCDD. In in vitro tumor invasion assay, TCDD-induced tumor invasion was reduced by either PD98059 or JNK II inhibitor. PD98059 effectively inhibited TCDD-induced tumor invasion when compared to control. The transcription luciferase reporter system demonstrated that PD98059 effectively reduced AP-1 activity when compared to control. The levels of MMP-2 and MMP-9 mRNA expression were reduced slightly by treatment with PD98059. We conclude a significant association of tumor progression in BRAF mutant PTC with the exposure of TCDD. Our findings suggest that MEK inhibitor (PD98059) may function as a small molecule inhibitor of tumor invasion and may provide novel mechanistic insights into the potential therapy for human ATC.
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 5270.
Abstract 5275: Alternate mechanisms of PI3K pathway activation among subtypes of ductal carcinoma in situ suggest distinct pathways for progression to invasive disease
Authors: Sakr Rita , Chandarlapaty Sarat , Barbashina Violetta , Andrade Victor , Heguy Adriana , Morrogh Mary , Olvera Narciso , Paik Wooyul , Arroyo Crispinita , Morrow Monica , Rosen Neal , King Tari 
Published: February 2011

Abstract
INTRODUCTION: Activation of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway via kinase mutations or loss of PTEN is frequently reported in invasive breast cancer and laboratory models suggest that these “second hits” promote invasiveness in HER2 amplified disease. The role of PI3K pathway activation in the transition from in situ to invasive disease remains uncertain. The aim of this study was to assess the frequency of activating lesions in the PI3K pathway in pure high grade DCIS and DCIS associated with HER2 amplified invasive cancer.
METHODS: 89 cases of pure high grade DCIS and 73 cases of DCIS associated with HER2 amplified (HER2+) invasive cancer were identified. Sections from FFPE blocks were used for IHC, FISH and DNA extraction. Pure DCIS, DCIS adjacent to invasive and matched invasive cancers were microdissected for multiplex array (Sequenom®) genotyping of PIK3CA and AKT. IHC was performed for HER2 and PTEN. HER2+ was confirmed by FISH. PTEN was scored relative to adjacent normal cells (scale 0-2).
RESULTS: Among 89 cases of pure high grade DCIS, 51 (57%) were HER2+. PIK3CA mutations were identified in 13/73 (18%) HER2+ invasive lesions and in 11/13 cases the mutation was also present in the adjacent DCIS (11/73 (15%)). PIK3CA mutations were less common in pure HER2+ DCIS (2/51 (4%)) and pure HER2 neg DCIS (2/38 (5%)). Mutations in AKT1 were not identified HER2+ invasive lesions or the adjacent DCIS, yet were found in 3 cases of pure DCIS (2 HER2 neg, 1 HER2 +). PTEN loss was rare in HER2+ invasive lesions (4%), adjacent HER2+ DCIS (5%) and pure HER2+ DCIS (4%) but was seen in 7/38 (18%) cases of pure HER2 neg DCIS. Concomitant loss of PTEN and PIK3CA mutation was seen in 1 case of pure HER2 neg DCIS.
CONCLUSIONS: PIK3CA mutations were observed with similar frequency in HER2+ invasive cancers and in the adjacent DCIS and were uncommon in pure DCIS, suggesting that mutational activation of PI3K may cooperate with HER2 in disease progression. PTEN loss was more common in HER2 neg DCIS and may not be mutually exclusive with PIK3CA mutations, suggesting that these mechanisms may interact in the progression of HER2 neg disease. AKT1 mutations were rare in pure DCIS and not identified in matched HER2+ DCIS and invasive cancer. These data support a role for activation of the PI3K pathway in the transition from in situ to invasive disease and suggest that the mechanism of activation may vary by HER2 status. Further work in HER2 neg DCIS and matched HER2 neg invasive cancer is underway.
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 5275.
Abstract 5283: A role for mitochondrial derived reactive oxygen species in regulating pro-migratory signaling pathways via p130cas
Authors: Hempel Nadine , Melendez J. Andres 
Published: February 2011

Abstract
A cell's migratory and invasive potential depends on a multitude of signaling pathways, which present novel targets for anti-cancer therapies. We and others have shown that reactive oxygen species (ROS), such as hydrogen peroxide (H2O2), are modulators of tumorigenicity and contribute to the migratory phenotype of cancer cells (Connor et al. 2008, Cancer Research). Intrinsic levels of ROS are elevated in numerous metastatic cancer types, which suggests that these cells have evolved to utilize sublethal increases in ROS levels as novel second messengers in regulating pro-metastatic signaling events. Here we present evidence to support this hypothesis and describe how ROS may act as second messengers in the Focal Adhesion Kinase (FAK) pathway. Cells displaying intrinsic picomolar changes in H2O2 levels, either endogenously (metastatic 253J-BV bladder cancer cell line, compared to its non-metastatic parental 253J-P line), or as a consequence of enforced mitochondrial manganese superoxide dismutase (Sod2) expression, display an enhanced migratory phenotype. This is accompanied by a loss of mature vinculin positive focal adhesions. Mechanistically, we show that the protein tyrosine phosphatases PTP-PEST and PTEN are oxidized and inactivated in cells displaying enhanced H2O2 levels and that this can be reversed by effective removal of H2O2 following expression of the H2O2 detoxifying enzyme catalase (CAT). A consequence of PTP-PEST oxidation and inactivation is a concomitant increase in phosphorylation of its primary substrate p130cas, an adaptor protein of the FAK signaling cascade. Further, increases in intracellular H2O2 levels shift the localization of p130cas to the cell surface, as assessed by membrane/cytoskeletal fractionation and immunofluorescent staining, indicative of localized activation of FAK pathway signaling at the leading edge. Again co-expression of CAT negates these effects, indicating that these mechanisms are H2O2 dependent. The data described support the hypothesis that elevated mitochondrial ROS levels can regulate the spatial activation of pro-migratory signaling pathways, enhancing the metastatic potential of 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 5283.
Abstract 5294: IIp45 inhibits cell migration through inhibition of HDAC6
Authors: Zhang Wei , Song Sonya W. , Sun Jiyuan , Bruner Janet , Fuller Gregory 
Published: February 2011

Abstract
IIp45 (aka MIIP) is a newly discovered gene whose protein product inhibits cell migration. HDAC6 is a class IIb deacetylase that specifically deacetylates α-tubulin, modulates microtubule dynamics and promotes cell migration. A yeast two-hybrid assay using IIp45 as the bait identified HDAC6 protein as a binding partner of IIp45. This physical interaction of the two functionally antagonizing proteins was confirmed by Glutathione S-transferase (GST) pull-down assay and co-immunoprecipitation (Co-IP) assay in human cells. Serial deletion constructs of HDAC6 were used to characterize the interaction of HDAC6 and IIp45, and this analysis found that the two catalytic domains of HDAC6 protein were required for IIp45 binding. We examined the protein expression patterns of IIp45 and HDAC6 in glioma tissues. Elevated protein levels of HDAC6 were found in high grade glioma samples in contrast to the decreased protein expression of IIp45. The potential negative regulation of HDAC6 expression by IIp45 was confirmed in cell lines with altered IIp45 expression by constitutive overexpression or small interfering RNA knockdown. Protein turnover study revealed that overexprsssion of IIp45 significantly reduced intracellular protein stability of endogenous HDAC6, indicating a possible mechanism for the negative regulation of HDAC6 by IIp45. Results from the HDAC activity assay demonstrated that overexpressed IIp45 effectively decreased HDAC6 activity, increased acetylated α-tubulin, and reduced cell migration. The increased cell migration by siIIp45 knockdown was significantly reversed by co-transfection of siHDAC6. Thus, we report here for the first time a novel mechanism by which IIp45 inhibits cell motility through inhibition of HDAC6
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 5294.
Abstract 5295: S100A4 regulates tumor growth, motility, and invasion in pancreatic cancer
Authors: Sekine Hitoshi , Tabata Takahiro , Tsukamoto Nobukazu , Yamamura Akihiro , Abe Keiko , Yoshino Yuki , Sato Keisuke , Chen Na , Umetsu Yukiko , Sato Daisuke , Gu Zhaodi , Fukushige Shinichi , Shima Kentaro , Motoi Fuyuhiko , Egawa Shinichi , Sunamura Makoto , Horii Akira 
Published: February 2011

Abstract
S100A4 protein belongs to the S100 subfamily, which has grown to be one of the large subfamilies of the EF-hand Ca2+-binding proteins, and overexpression of S100A4 is suggested to associate with cell proliferation, invasion, and metastasis. We observed frequent overexpression of S100A4 in pancreatic cancer cell lines by quantitative real-time RT-PCR and Western blotting. Tissue microarray analysis validated S100A4 overexpression in primary pancreatic cancer tissues, and overexpression of S100A4 associated with perineural invasion. We further analyzed RNAi-mediated knockdown to address the possibility of its use as a therapeutic target for pancreatic cancer. The specific knockdown of S100A4 strongly suppressed cell growth, induced G2 arrest and eventual apoptosis, and decreased cell migration. Furthermore, microarray analyses revealed that knockdown of S100A4 induced expression of the tumor suppressor genes PRDM2 and VASH1. We further established stably S100A4-expressing cell lines using two pancreatic cancer cell lines with low level of S100A4 expression; remarkable accelerated cell growth and motility was observed after induction of S100A4, whereas no change was observed in the control cells. Comparison of the expressional profiles after siRNA-mediated knockdown and expression vector-mediated induction is underway, and the results will also be demonstrated and discussed.
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 5295.
Abstract 5300: Dopamine prevents malignant tumor induced thymic involution in mice
Authors: Sarkar Chandrani , Chakroborty Debanjan , Yu Hongmei , Dasgupta Partha Sarathi , Basu Sujit 
Published: February 2011

Abstract
T cell functions are significantly impaired during tumorigenesis and the thymus being the major site of T cell maturation is severely affected by tumor development. Also, a high incidence of premature thymic involution is seen especially in childhood cancer, which often rebounds after curative treatment. Most importantly, this thymic involution may be one of the important causes for T cell defects in cancer. Recently, it has been reported that high concentration of vascular endothelial growth factor-A (VEGF-A) produced during cancer may induce thymic involution. We here show for the first time that dopamine treatment prevents thymic involution in mice bearing murine T cell lymphoma and dopamine in turn acts by inhibiting the actions of VEGF-A on bone marrow derived T progenitor cells. This finding is important as it suggests a new adjuvant therapy for the treatment of childhood cancer in which high incidence of thymic involution has been reported.
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 5300.