bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4264: NFκB activation in mesenchymal stromal cells induced by leukemia-stroma interaction plays a central role in stroma-mediated chemo-resistance of leukemic cells
Authors: Jacamo Rodrigo O. , Chen Ye , Wang Zhiqiang , Ma Wencai , Zhang Min , Venkata Batulla L. , Schober Wendy D. , Davis Richard E. , Konopleva Marina , Andreeff Michael 
Published: August 2012

Abstract
Within the bone marrow (BM) microenvironment, BM mesenchymal stromal cells (BM-MSC) produce cytokines and chemokines and initiate cellular adhesion-mediated signals that tightly regulate normal and malignant hematopoietic cell development. This rich environment serves as a sanctuary for malignant hematopoietic cells, offering protection from chemotherapeutic agents and promoting residual disease with greater potential for developing acquired drug resistance. In this study we utilized gene expression profiling (GEP) as a genome-wide exploratory approach to characterize changes caused by the interaction between leukemic cells and BM-MSC, and how these changes can contribute to the observed microenvironment-mediated chemoresistance. Co-culture of REH, a pre-B-ALL cell line, with normal-donor BM-MSCs for 48 hours upregulated a variety of genes encoding cytokines and chemokines in BM-MSCs such as CXCR6, CCL5, CCL2, IL32, IL34, IL8, IL6, CXCL12, and the VLA4 ligand VCAM-1. These microarray-based GEP findings were confirmed by qRT-PCR. Gene Set Enrichment Analysis (GSEA) implicated activation of NFκB in BM-MSCs as a potential cause of these changes. Similar upregulation of NFκB target genes was found in MSC co-cultured with the AML cell line OCI-AML3, suggesting that NFκB activation is a common consequence of leukemia-stroma interation. Given known paracrine functions of NFκB-regulated target genes such as IL-8, we hypothesized that stromal NFκB activation contributes to stroma-mediated chemo-resistance of leukemic cells. Stable transduction of BM-MSC to overexpress a super-repressor form of IαBβ (IαBβ-SR), to block canonical-pathway NFκB activation in the stromal compartment, significantly reduced the stroma-mediated chemo-resistance to Vincristine (VCR) of REH cells. NFκB inhibition using a specific IKKα inhibitor (MLN120B), affecting both BM-MSC and tumor cells, highly increased the apoptotic effects in leukemia-stroma co-cultures of VCR in REH cells and NALM6, another pre-B-ALL cell line. Similar results were obtained with CDDO-Me, another NFκB inhibitor. Altogether these results indicate that the interaction of leukemic cells with BM stromal cells activates NFκB in the stromal compartment, with subsequent transcriptional upregulation of a number of cytokines and chemokines ultimately favoring the survival of leukemic cells. We propose that targeting NFκB may ameliorate stroma-mediated chemo-resistance and help in eliminating bone-marrow resident leukemic cells.
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 4264. doi:1538-7445.AM2012-4264
Abstract 4280: Genome-wide expression and methylation analysis in CD31+ cells from African American and Caucasian American benign and malignant prostate tissue
Authors: Luo Wei , Deeb Kristin K. , Liu Song , Ma Yingyu , Morrison Carl D. , Trump Donald L. , Johnson Candace S. 
Published: August 2012

Abstract
Prostate cancer exhibits striking racial disparity; African American (AA) men have a markedly higher risk of being diagnosed and of dying of prostate cancer compared to Caucasian American (CA) men. This disparity may be due to biologic differences associated with race or to sociologic factors, such as economic disparities or differences in access to care or interactions of all these factors. Differences in tumor gene expression and methylation might be associated with the poorer prognosis seen among AA men and may contribute to better understanding of these disparities and the delineation of new therapeutic targets. In order to study the effect of the tumor microenvironment on endothelial cells found in tissue from AA and CA patients with prostate cancer, we first established a method for the isolation of the endothelial cells from malignant and benign prostate tissue obtained at prostatectomy. We then conducted a pilot study of transcriptome and methylome analysis in 5 pairs of CD31+ endothelial cells isolated from paired samples of benign and malignant tissue from AA and CA patients with prostate cancer. We have identified 2,096 and 920 differentially expressed transcripts for the tumor versus normal in AA and CA group, respectively. However, only 140 transcripts are shared. Furthermore, a total of 2,248 transcripts show different level of expression change for tumor versus normal in samples with AA origin compared to samples with CA origin. Genome-wide DNA methylation profiling in the same endothelial samples have identified 18,093 differentially methylated loci in AA group, and 12,372 differentially methylated loci in CA group. Only a total of 1,324 loci are shared. Remarkably, there are a total of 20,164 loci with different level of methylation change for tumor versus normal in AA group compared to CA group. Integrative analysis of transcriptome and methylatome data showed that a large percentage of differentially expressed genes have loci whose methylation change is inversely correlated with gene expression change, and vice versa. Taken together, our pilot data, while preliminary, suggest the possibility that there is a potential racial difference in terms of differential expression and methylation between CA and AA endothelial cell populations. Future large studies are warranted to confirm our findings and further explore the role of race disparity in the delineation of novel therapeutic targets to be utilized clinically for prostate 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 4280. doi:1538-7445.AM2012-4280
Abstract 4283: Cross-species hybridization of microarrays for studying tumor transcriptome of brain metastasis
Authors: Park Eun Sung , Kim Sun-Jin , Kim Seung Wook , Yoon Se-Lyun , Leem Sun-Hee , Kim Sang-Bae , Kim Soo Mi , Park Yun-Yong , Cheong Jae-Ho , Woo Hyun Goo , Mills Gordon B. , Fidler Isaiah J. , Lee Ju-Seog 
Published: August 2012

Abstract
Although the importance of the cellular microenvironment (soil) during invasion and metastasis of cancer cells (seed) has been well-recognized, technical challenges have limited the ability to assess the influence of the microenvironment on cancer cells at the molecular level. Here, we show that an experimental strategy, competitive cross-species hybridization of microarray experiments, can characterize the influence of different microenvironments on cancer cells by independently extracting gene expression data of cancer and host cells when human cancer cells were xenografted into different organ sites of immunocompromised mice. Surprisingly, the analysis of gene expression data showed that the brain microenvironment induces complete reprogramming of metastasized cancer cells, resulting in a gain of neuronal cell characteristics and mimicking neurogenesis during development. We also show that epigenetic changes coincide with transcriptional reprogramming in cancer cells. These observations provide proof of principle for competitive cross-species hybridization of microarray experiments to characterize the effect of the microenvironment on tumor cell behavior
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 4283. doi:1538-7445.AM2012-4283
Abstract 4285: Visualizing cancer vaccine clearance in vivo using magnetic resonance imaging
Authors: Brewer Kim , Lake Kerry , Pelot Nicole , DeBay Drew , Penwell Andrea , Weir Genevieve , Bowen Chris , Karkada Mohan , Mansour Marc 
Published: August 2012

Abstract
Magnetic Resonance Imaging (MRI) is a powerful tool in the evaluation of immunotherapies, since it permits non-invasive longitudinal assessment of tumor growth, and as our group has previously demonstrated, it allows monitoring of immune response via volumetric changes in lymph nodes (LNs) adjacent to (inguinal LNs) or distant from (popliteal LNs) the site of vaccination. MRI also offers potential for visualizing the uptake behavior of vaccines such as DepoVaxTM, a novel liposome-in-oil-based vaccine platform developed by Immunovaccine Inc. In the context of cancer immunotherapy, this platform uses tumor-associated antigens (TAA), adjuvant and stimulator of T helper cells encapsulated in liposomes and suspended in oil. The oil substrate of the DepoVaxTM immunotherapy vaccine platform acts as an adjuvant that greatly increases the potency of the vaccines, eliciting a strong cytotoxic T-cell response, and also permits longitudinal visualization of the vaccine site with MRI. However, this does not reveal any information about the clearance time of the individual vaccine components, particularly the TAAs. By attaching superparamagnetic iron oxide (SPIO) to the TAA and then encapsulating it in liposomes, it is possible to visualize the biodistribution of the TAA over time using MRI and evaluate whether there is truly a slow clearance of the antigen from the depot site, facilitating a prolonged immune response. In this study, tumor-bearing mice challenged with C3 cells (HPV16 tumor model) were evaluated for the longitudinal clearance of the DepoVaxTM vaccine components using SPIO conjugated to the TAA or associated with the lipid component of the vaccine. The SPIO-conjugated antigen was also tested in a Montanide® oil emulsion vaccine as a control. Over the course of this study, we observed the vaccine being distributed to the surrounding tissue from the injection site, and the antigen was actively transported from the vaccine depot site. The iron-labeled antigen cleared slowly but consistently, decreasing by approximately 40% over 35 days. This study provides direct in vivo evidence that DepoVaxTM resides at the vaccine injection site for a prolonged period of time, increasing exposure to antigen in a controlled fashion, which is likely a key factor in the enhanced immune response elicited by this novel depot vaccine.
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 4285. doi:1538-7445.AM2012-4285
Abstract 4291: Near-infrared optical imaging visualizes tumor cell death induced by adoptive transferred T cells
Authors: Sato Noriko , Aras Omer , Choyke Peter 
Published: August 2012

Abstract
Cytotoxic functions of CD8 T cells change as the cells differentiate and are under the control of various positive and negative regulators. The number of cytotoxic T cells found in the tumor site does not necessarily correlate with the growth or reduction of the tumor. Monitoring the functionality of T cells is desired. In order to visualize tumor killing effects of adoptive transferred cytotoxic T cells, near-infrared optical imaging was employed using a probe against phosphatidylserine exposed on the tumor cells attacked by the T cells. CD8 T cells specific for ovalbumin (OVA) were isolated from OT-1 T cell receptor transgenic mice and were stimulated with an OVA peptide (257-264, SIINFEKL) followed by an antigen free culture. T cells were transferred to the recipient mice bearing intramuscular OVA-positive thymoma (EG.7) and the parental OVA-negative thymoma (EL4) in the thigh. One day later, a near-infrared optical probe with a phosphatidylserine binding motif, PSVue 794 (Em 810 nm, 3 mg/kg), was intravenously injected and optical images were acquired up to 5 days after the injection. Some mice also received an injection of fluorescein (FITC)- or Alexa 488-labeled annexin V 12hr after the PSVue 794 injection. Flow cytometry analysis showed a double staining of apoptotic tumor cells with PSVue 794 and annexin V, confirming the binding ability of PSVue 794 to the cells undergoing apoptosis. Whole-body optical images demonstrated an accumulation of PSVue 794 in the OVA expressing EG.7 tumor, the target of OT-1 CD8 T cells, at 24hr and later, but not in the control EL4 tumor. Analysis of tumor sections revealed co-localization of PSVue 794 and annexin V, with a migration of OT-1 T cells to the site. Collectively, a near-infrared optical probe targeting phosphatidylserine enabled visualization of tumor cell death induced by adoptively transferred cytotoxic T cells in an immunotherapy model. Monitoring functionality and therapeutic effects of T cells or natural killer cells transferred in therapies would provide crucial information for the improvements of therapeutic strategies.
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 4291. doi:1538-7445.AM2012-4291
Abstract 4293: In vivo imaging and tracking of a PARP inhibitor at single-cell resolution
Authors: Yang Katherine , Thurber Greg , Reiner Thomas , Kohler Rainer , Weissleder Ralph 
Published: August 2012

Abstract
PARP is an enzyme involved in sensing single-stranded DNA breaks and plays a critical role in the organization of DNA damage repair. Several PARP inhibitors have been developed for clinical use, particularly in breast and ovarian cancers with BRCA mutations. Despite the scientific rationale and promising early clinical results with PARP inhibitors, more advanced clinical trials in breast cancer have been disappointing. One of the questions arising from these trials is to better understand why the PARP inhibitors failed. We used a window-chamber system in mice to image the distribution and function of model PARP inhibitors such as AZD2281-Bodipy. Specifically, we measured the kinetics of vascular, cellular, and subcellular uptake and distribution of AZD2281-Bodipy in breast (MDA-MB-231, MDA-MB-436) and ovarian (OVCAR429, A2780) tumors over time. Additionally, using the fluorescently-labeled inhibitor, we were able to examine the heterogeneity of AZD2281 localization in single cancer cells in vivo. Our data provide the first example of single-cell distribution of fluorescent small molecule inhibitors. When coupled with reporter cell lines (e.g. for apoptosis, DNA damage, autophagy, and senescence), this approach will be a powerful tool to understand drug action 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 4293. doi:1538-7445.AM2012-4293
Abstract 4310: TWIST1, a B-RAF effector, promotes invasion and is a novel regulator of MMP-1 in human melanoma cells
Authors: Weiss Michele B. , Abel Ethan V. , Mayberry Melanie M. , Aplin Andrew E. 
Published: August 2012

Abstract
Metastatic melanoma is the deadliest form of skin cancer due to its highly aggressive and chemotherapy-resistant nature. Therefore, determining the factors impacting melanoma advancement toward metastasis is an important and clinically-relevant task. Importantly, RAF/MEK/ERK signaling is hyperactive in the great majority of melanoma cells and is a driver of melanoma growth and invasion. In addition, the TWIST1 protein is up-regulated in melanoma and its expression correlates strongly with poor clinical prognosis. However, the mechanism underlying TWIST1 up-regulation, as well as the role of high TWIST1 expression in traits associated with the progression of melanoma, has yet to be uncovered. In this study, we report that disruption of RAF/MEK/ERK signaling strongly represses TWIST1 at the mRNA and protein level. We further show that TWIST1 protein levels are especially high in B-RAF mutant cells as well as in vertical growth phase melanoma cells, which are those that first begin to invade downward into the deeper dermal layers eventually leading to metastasis. To that effect, depletion of TWIST1 in several invasive melanoma cell lines significantly reduces Matrigel invasion. The inverse phenotype is apparent when TWIST1 is overexpressed in low TWIST1-expressing, non-invasive melanoma cell lines. Additionally, we tested the effect of altered Twist expression in three-dimensional collagen spheroid outgrowth assays, which mimic both tumor architecture and the in vivo collagen-rich dermal layer. We observe significant reduction in spheroid outgrowth when invasive cell lines are depleted for TWIST1 as well as increases in outgrowth when non-invasive cells overexpress TWIST1. Alterations to spheroid outgrowth were not as a result of apoptotic changes or proliferative rate. Importantly, we have found matrix metalloproteinase-1 (MMP-1) to be a downstream effector of TWIST1. Furthermore, TWIST1 acts as a mediator between activated B-RAF signaling and MMP-1 in a dose-dependent and direct manner at the level of transcription. Our findings uncover the novel interplay between B-RAF, TWIST1, and MMP-1 which is likely important in the progression of melanoma towards metastasis.
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 4310. doi:1538-7445.AM2012-4310
Abstract 4314: Dynamin 2 mediates PDGFRα-SHP-2-promoted glioblastoma growth and invasion
Authors: Feng Haizhong , Guo Ping , Liu Kun-wei , Cheng Shi-Yuan , Zhang Peng , Hu Bo , Cheng Tao , McNiven Mark A. , Johnson Gibbes R. 
Published: August 2012

Abstract
Dynamin 2 (Dyn2), a large GTPase, is involved in receptor tyrosine kinase (RTK)-promoted cell migration. However, molecular mechanisms by which Dyn2 regulates RTK-induced cell migration have not been established. Recently we reported that SHP-2 and PI3K mediate PDGFR[[Unsupported Character - Symbol Font &#945;]]-promoted glioma tumor growth and invasion. Here, we show that Dyn2 is an effector downstream of the PDGFR[[Unsupported Character - Symbol Font &#945;]]-PI3K/SHP-2 signaling in glioma cells. Depletion of endogenous Dyn2 by shRNAs inhibited PDGFR[[Unsupported Character - Symbol Font &#945;]]-stimulated phosphorylation of Akt, Erk1/2, Rac1 and Cdc42 activities, glioma cell migration and survival in vitro, tumor growth and invasion in the brains of mice. Dyn2 binds to SHP-2, PI3K and co-localizes with PDGFR[[Unsupported Character - Symbol Font &#945;]] at the invasive fronts in PDGF-A-stimulated glioma cells. Inhibition of SHP-2 by siRNA knockdown abrogated Dyn2 association with activated PDGFR[[Unsupported Character - Symbol Font &#945;]] and PDGFR[[Unsupported Character - Symbol Font &#945;]] activation of Rac1 and Cdc42, glioma cell migration, thereby establishing a link between SHP-2 interaction with Dyn2 and the PDGFR[[Unsupported Character - Symbol Font &#945;]] signaling. Furthermore, a dominant negative SHP-2 C459S mutant inhibited PDGF-A-stimulated glioma cell migration, phosphorylation of Dyn2 and concomitantly blocked PDGFR[[Unsupported Character - Symbol Font &#945;]]-induced Src activation. Inhibition of Src by Src inhibitors attenuated PDGF-A-stimulated phosphorylation of Akt and Dyn2 and glioma cell migration. Additionally, mutations of binding sites to PI3K, SHP-2 or Src of PDGFR[[Unsupported Character - Symbol Font &#945;]] impaired PDGFR[[Unsupported Character - Symbol Font &#945;]]-stimulated phosphorylation of Akt and Dyn2, and Dyn2 association with activated PDGFR[[Unsupported Character - Symbol Font &#945;]]. Taken together, this study identifies Dyn2 as an effector that mediates PDGFR[[Unsupported Character - Symbol Font &#945;]]-SHP-2-induced glioma tumor growth and invasion, suggesting that targeting the PDGFR[[Unsupported Character - Symbol Font &#945;]]-SHP-2-Dyn2 pathway may be beneficial to patients with malignant glioblastomas.
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 4314. doi:1538-7445.AM2012-4314
Abstract 4320: Overexpression of Homeobox A5 decreases the invasive and migration capabilities of lung cancer cells
Authors: Liu Ya-Jung , Yu Sung-Liang , Chen Jeremy J. W. , Wang Chi-Chung 
Published: August 2012

Abstract
Homeobox genes are a family of regulatory genes containing a common homeobox and act as transcription factors. Many cancers exhibit unusual alteration and expression in homeobox genes, including leukemia, colon, skin, prostate, breast, and ovary cancers. Recent studies indicated that homeobox A5 (HOXA5) may behave as a tumor suppressor gene in breast cells. However, the real roles of HOXA5 in lung cancer remains to be further clarified. In this study, we investigated the effect of HOXA5 on the invasive ability of more invasive CL1-5 cells transfected with HOXA5 constitutively expressed system. The results revealed that the excessive expression of HOXA5 can inhibit tumor cell invasion and migration capabilities. In addition, the HOXA5 specific siRNA could restore these effects. The results of metastatic analysis in SCID mice also demonstrated that HOXA5-overexpressed transfectants could decrease in vivo tumor nodule numbers. Furthermore, the HOXA5 mRNA expression was measured by real time RT-PCR in NSCLC surgical specimens and correlated with the patients’ clinical outcome. The HOXA5 downstream genes and HOXA5-regulated pathways were identified by using Affymetrix microarray and CRSD bioinformatics platform built in-house. Our studies herein provide a new insight into how HOXA5 may contribute to tumor metastasis inhibition in lung 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 4320. doi:1538-7445.AM2012-4320