bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 482: Comparison of the actin-binding proteins actinin-1 and actinin-4: Their role in cancer
Authors: Foley Kate S. , Young Paul 
Published: August 2012

Abstract
Actinins are cytoskeleton proteins that crosslink actin filaments. Evolution of the actinin family resulted in the formation of calcium-insensitive muscle isoforms (actinin-2 and- 3) and calcium-sensitive non-muscle isoforms (actinin-1 and -4) with regard to their actin-binding function. Although the non-muscle actinin isoforms show 87% amino acid identity, they are currently viewed as distinct entities. Each isoform is reported to exert distinct effects on cell migration, adhesion and proliferation depending on the cell type studied. Actinin-4 is the predominant isoform reported to be associated with the cancer phenotype. Actinin-4 protein levels are elevated in a number of cancers including breast, ovarian, colorectal, bladder, pancreatic, ovarian and glioblastomas. Actinin-4 enhances the motility and metastatic potential of various carcinoma cell lines. This suggests that actinin-4 may have some unique characteristic that facilitates its role in cancer. We aimed to compare the actin-binding affinities, actin-bundling capacities and calcium sensitivities of the non-muscle actinins. We found that the non-muscle actinins have similar actin-binding affinities and calcium sensitivities with regard to their actin-binding and actin-bundling functions. Actinin structure consists of two anti-parallel monomers that form a homodimer. Heterodimer formation is reported to occur between the muscle actinin isoforms however this has not been systematically examined for the non-muscle isoforms. Through yeast two-hybrid analysis and in vitro binding assays we have shown that non-muscle actinin homodimers and heterodimers form with equal affinity. Using native gel electrophoresis we have shown that non-muscle actinin heterodimer formation occurs in a number of cancer cell lines studied. Comparison of non-muscle actinin protein levels indicates that the heterodimer represents the most abundant form of actinin present in the majority of cell lines studied. siRNA- mediated knockdown of actinin-4 resulted in a decrease in heterodimer levels and an increase in actinin-1 homodimer levels. Taken together this data suggests that actinin-1 and actinin-4 cannot be viewed as distinct entities from each other but rather as proteins that can exist in both homodimeric and heterodimeric forms. The ability to behave in this manner may have functional implications. This may be of importance considering that these proteins are central to such processes as cell migration and adhesion.
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 482. doi:1538-7445.AM2012-482
Abstract 4822: Identifiying the anti-Tr antigen in paraneoplastic cerebellar degeneration
Authors: Smitt Peter A.E. Sillevis , de Graaff Esther , Maat Peter , Hulsenboom Esther , van den Berg Robert , van den Bent Martin , Demmers Jeroen , Hoogenraad Casper 
Published: August 2012

Abstract
Introduction: Paraneoplastic cerebellar degeneration (PCD) is characterized by subacute cerebellar ataxia which coincides with the presence of specific tumour types and antineuronal antibodies. One particular form of PCD is associated with Hodgkin Lymphoma (HL) and the presence of antibodies against cerebellar Purkinje cells in several of these patients’ sera. These later called anti-Tr antibodies recognize a specific punctuate immunoreactivity in the large dendritic tree as well as the soma of the Purkinje cells, but not in the axons. Although this characteristic immunoreactive pattern is considered to be a good hallmark for the presence of anti-Tr antibodies, further diagnosis is elaborate. In order to aid this diagnosis, and to understand the pathogenic nature of the PCD we aimed to identify the antigen recognized by anti-Tr antibodies. Objective: We aimed to identify the long sought antigen recognized by anti-Tr antibodies. Methods: To identify the antigen we performed immunoprecipitation using four anti-Tr positive sera on total rat brain extract followed by mass spectrometry. By Western blotting and cell-based assays we subsequently determined the region of the epitope recognized by the anti-Tr antibodies. Deletion and mutant constructs were generated to further map the antigenic region. Results: We identified Delta/Notch-like epidermal growth factor (EGF)-related Receptor (DNER) as the Tr antigen. In a cell-based screening assay 191 control samples were negative, whereas all of the 12 anti-Tr positive sera stained HA-tagged-DNER expressing cells. Using deletion constructs we pinpointed the main epitope to the extracellular domain. Glycosylation inhibitor tunicamycin and N-glycosylation mutations in DNER abolished the anti-Tr staining, indicating that DNER must be glycosylated to be recognized by anti-Tr antibodies. Conclusion: Anti-Tr positive sera recognize DNER. Using the cell based assay, presence of anti-Tr antibodies in patients with PCD and HL can now be screened both quickly and reliably.
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 4822. doi:1538-7445.AM2012-4822
Abstract 4826: A therapeutic sphingosine 1-phosphate antibody improves intratumoral oxygenation and sensitizes to chemotherapy in prostate cancer animal model
Authors: Ader Isabelle , Bouquerel Pierre , Golzio Muriel , Malavaud Bernard , Zalvidea Santiago , Richard Sylvain , Sabbadini Roger A. , Cuvillier Olivier 
Published: August 2012

Abstract
Hypoxia promotes neovascularization, metastasis, and resistance to treatments. The activation of the transcription factor HIF-1α has been identified as the master mechanism of adaptation to hypoxia. We recently identified the sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) pathway as a new modulator of HIF-1α activity under hypoxia in multiple cancer cell models including prostate cancer (Ader et al, Cancer Res, 2008). S1P elicits proliferation, survival, or angiogenesis, and is believed to exert most of its actions as a ligand for a family of specific GPCRs to elicit paracrine or autocrine signaling. We have suggested that inhibiting SphK1/S1P signaling, which is upregulated under hypoxia, may normalize the microenvironment and increase sensitivity to chemotherapy, in the broader concept of “normalization of tumor vessels” as tumor oxygenation is known to enhance response to chemotherapy (Ader et al., Cancer Res, 2009). Methods: Quantification of intratumoral hypoxia and angiogenesis, and treatment efficacy (primary tumor, metatasis dissemination) using an orthotopic (o.t) xenograft model of fluorescent hormone refractory prostate cancer cells. Results: We first provide in vitro evidence that inhibition of the S1P exogenous signaling, through pharmacological inhibition of its receptors or by taking advantage of a monoclonal antibody neutralizing S1P, blocks HIF-1α accumulation and its activity in prostate cancer cells under to hypoxia. Second, using an o.t model of prostate cancer, we show that an anti-S1P antibody inhibits intratumoral hypoxia and modifies vessel architecture and improves tumor perfusion within 5 days of treatment. Third, we show for the first time that an anti-S1P strategy sensitizes to docetaxel, the ‘gold standard’ treatment for hormone-refractory prostate cancer. A 5-day anti-S1P antibody pretreatment markedly sensitizes to docetaxel in an o.t. PC-3/GFP model established in nude mice. The combination anti-S1P antibody together with docetaxel was not only accompanied by a smaller primary tumor volume compared to docetaxel treatment, but also significantly reduced the occurrence and number of metastases. Conclusion: These preclinical data establish the proof-of-concept that blocking the exogenous action of S1P induces vascular normalization, improves intratumoral oxygenation and sensitizes to chemotherapy in prostate cancer animal model.
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 4826. doi:1538-7445.AM2012-4826
Abstract 483: Serine phosphorylation of vasodilator-stimulated phosphoprotein defines the malignant cell phenotype in colon cancer
Authors: Ali Mehboob , Pitari Giovanni M. 
Published: August 2012

Abstract
Metastasis is the principal pathological process underlying mortality for colorectal cancer, the third deadly cancer worldwide. During tumor invasion, cancer cells assume a mesenchymal morphology that confers migratory and proliferative advantages. One of the mechanisms regulating malignant cell shape is the activity of the vasodilator-stimulated phosphoprotein (VASP) on the actin cytoskeleton. Here, human colon carcinoma cells were treated with cell permeant analogs of cAMP or cGMP, to preferentially induce VASP Ser157 (pVASP-Ser157) or Ser239 (pVASP-Ser239) phosphorylation, and examined by confocal microscopy, western blotting and colony formation. Confirming previous results, cancer dynamic membrane regions formed by the actin cytoskeleton were differentially modulated by VASP Ser phosphorylation. However, treatments with cAMP, which promoted a mesenchymal cell phenotype, reduced E-cadherin at tumor cell-cell junctions and enhanced vimentin and vinculin levels. In contrast cGMP induced an opposite cell morphology with increased E-cadherin-rich cell-cell contacts and decreased cellular vimentin and vinculin. Moreover, the cAMP-dependent phenotype increased the cancer cell ability to form tumor colonies, while cGMP compromised that metastatic potential. Importantly, cyclic nucleotide effects were mediated by selective VASP Ser phosphorylation, because VASP phosphomutants at Ser157 and Ser239 blocked cAMP or cGMP actions, respectively. Together, these findings suggest that in colon cancer cells pVASP-Ser157 and pVASP-Ser239 are critical determinants of the malignant phenotype, which define the function of actin cytoskeletal regulators, invasive cell morphology and tumorigenic potential.
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 483. doi:1538-7445.AM2012-483
Abstract 4831: Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain
Authors: Zhuang Xiaoying , Zhang Huang-Ge 
Published: August 2012

Abstract
In this study, exosomes used to encapsulate curcumin (Exo-cur) or a Stat3 inhibitor, i.e., JSI124, (Exo-JSI124) were delivered non-invasively to microglila cells via an intranasal route. The results generated from three inflammation mediated disease models, i.e., a LPS induced brain inflammation model, experimental autoimmune encephalitis and a GL26 brain tumor model, showed that mice treated intranasally with Exo-cur or Exo-JSI124 are protected from LPS induced brain inflammation, the progression of MOG peptide induced EAE, and had significantly delayed brain tumor growth in the GL26 tumor model. Intranasal administration of Exo-cur or Exo-JSI124 led to rapid delivery of exosome encapsulated drug to the brain that was selectively taken up by microglial cells, and subsequently induced apoptosis of microglial cells. Our results demonstrate that this strategy may provide a non-invasive and novel therapeutic approach for treating brain inflammatory related diseases.
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 4831. doi:1538-7445.AM2012-4831
Abstract 484: A role for mDia formins in epithelial ovarian cancer spheroid invasion
Authors: Pettee Krista , Eisenmann Kathryn M. 
Published: August 2012

Abstract
Ovarian Cancers (OvCa) metastasis is highly unusual, relative to other metastatic cancers, and is typically confined to the peritoneal cavity; metastases are derived from exfoliated epithelial ovarian cancer (EOC) cells that adhere to and invade the mesothelial cell layer and extracellular matrix (ECM) underlying the peritoneal cavity and viscera. Exfoliated ovarian tumor cells are detected in the peritoneal ascites as single cells, small aggregates or highly ordered, compacted multi-cellular spheroids Compacted spheroids are poorly understood yet clinically relevant structures that are highly invasive and chemoresistant. Little is known about the molecular underpinnings of EOC spheroid formation or their cellular invasion into the underlying peritoneal mesothelial lining. Spheroid formation and ensuing invasion requires tight regulation of the actin cytoskeleton; a thorough understanding of the contribution of proteins regulating the spheroid actin cytoskeleton during cell-cell adhesions and adhesion to and transmigration through the peritoneal mesothelium is essential for progress in therapy of metastatic EOC. We showed that a panel of human EOC cells representing serous and clear cell adenocarcinomas express robust levels of mDia1 and mDia2 formins, irrespective of the ability to form compacted spheroids. mDia proteins were localized to the leading edge of migrating (spheroid-forming) serous epithelial OvCa 429 cells and disruption of mDia function inhibited this 2D chemotactic migration; conversely, dominant activated mDia2 in OvCa 429 cells enhanced chemotactic migration. Upon culture in 3D gels, both mDia1 and mDia2 are highly expressed and localized along with F-actin to the leading invasive edges of the compacted spheroids. Confocal analysis of single cell migration away from the spheroids revealed that multiple motility programs are employed by EOC cells- including single cell streaming and amoeboid cell motility. These data indicate a potential role for mDia proteins in driving localized invasion of EOC cells from compacted spheroids, and EOC cells exhibit a morphological plasticity while migrating in 3-dimensions.
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 484. doi:1538-7445.AM2012-484
Abstract 4845: Reeducate the tumor microenvironment to improve the anticancer efficacy of adoptive T-cell therapy
Authors: Liang Wei , Walters Ian , Yu Hua , Jove Richard 
Published: August 2012

Abstract
The hostile tumor microenvironment interferes with the function of efficient antitumor immune cells and constitutes a major obstacle for cancer immunotherapies. Here, we provide evidence that the immunosuppressive tumor microenvironment can be reeducated by an antiangiogenic agent to favor the development of adaptive antitumor immunity and to improve the efficacy of adoptive T cell therapy. Our results demonstrate that treatment with Brivanib, a novel small-molecule kinase inhibitor of VEGFRs and FGFRs, significantly enhanced the frequency and effector function of CD8+ cytotoxic T cells in tumor-bearing mice associated with significant reduction of tumor burden. Enhanced intratumoral infiltration of CD8+ T cells induced by Brivanib was associated with increased expression of chemokines (e.g., ccl3, ccl5, ccl11 and cxcl9) that regulates T cell trafficking and cell adhesion molecules (VCAM-1 and ICAM-1) on endothelial cells in the tumor microenvironment. Moreover, Brivanib treatment skewed the polarization of tumor-associated macrophages (TAM) away from the tumor-supporting M2 phenotype and restored the antigen presenting function of macrophages. Finally, Pretreatment of tumor-bearing animals with Brivanib prior to adoptive T cell transfer promotes in vivo proliferation, intratumoral infiltration and effector function of infused CD8+ T cells, resulting in better antitumor activity than either treatment alone. These findings indicate that Brivanib can be used to modulate the immunosuppressive microenvironment and as a potential adjuvant for enhancing the efficacy of cell-based cancer immunotherapy for cancer treatment.
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 4845. doi:1538-7445.AM2012-4845
Abstract 485: Epidermal growth factor-like repeats of Tenascin C promote melanoma cell invasion, possibly by enabling mesenchymal to ameboid migration transition
Authors: Grahovac Jelena , Wells Alan 
Published: August 2012

Abstract
In malignant melanoma, the most dangerous skin cancer, Tenascin-C (TNC) is overexpressed, especially at the invasive fronts of invasive melanomas. We found that the migration and invasiveness of a set of melanoma cell lines correlates with levels of TNC expression suggesting, surprisingly, that the melanoma cells themselves provide much of this matrix component. Adding TNC to matrices enhanced individual cell migration in cells that did not express much TNC, whereas it did not enhance the rapid motility of the cells expressing high levels. As TNC is a multidomain protein, the signaling pathways that promote this motogenic invasiveness are not obvious. Herein, we examined the potential role of the EGF-like repeats of TNC that have been shown to preferentially activate motogenic-signaling cascades. To analyze the effects of EGFL signaling on melanoma migration and invasion, we overexpressed TNC fragment containing the assembly and EGFL domains of TNC (TNCEGFL). Interestingly, this led to impaired cell migration in in vitro wound healing assays and live cell tracking experiments. This was likely due to a shift in the adhesion-contractility balance during cell migration. TNCEGFL expressing cells presented a spindle-shaped morphology and formed cords in culture. Expression of TNCEGFL delayed melanoma cell attachment and spreading, as determined in cell adhesion and inverted centrifugation assays. This anti-adhesive phenotype was concomitant with increased MLC2 phosphorylation. Inhibition of ROCK activity, which drives transcellular contractility, restored adhesion of TNCEGFL expressing cells and improved migration in 2D. In distinction to the findings in 2D, TNCEGFL expressing cells had higher invasion potential in Matrigel invasion assays, with cells expressing high TNC having rounded “ameboid” morphology, underlying the importance of morphological shifts, and possibly ROCK signaling, in 3D movement through barrier matrices during invasion and dissemination. These results imply that TNCEGFL repeats are involved in melanoma invasion both by directly influencing cell migration and indirectly changing the tumor microenvironment composition, possibly allowing transition from mesenchymal to ameboid migrational mode.
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 485. doi:1538-7445.AM2012-485
Abstract 4911: Systems level network analysis of NCI60 cell lines by alignment of protein pathway activation modules with multiple -omic data fields and therapeutic response signatures
Authors: Federici Giulia , Maria Ruggero De , Liotta Lance A. , Wulfkuhle Julia D. , Petricoin Emanuel F. 
Published: August 2012

Abstract
BACKGROUND: The NCI-60 cell line set is the most extensively profiled set of human tumor cell lines worldwide and have been characterized through chromosome karyotyping, SNP, mutation analysis, miRNA profiling, transcriptional profiling, metabolomic analysis, protein expression measurements, and functional enzymatic analysis. These types of “-omic” data have been mined for correlations with the tremendous drug response data that populates the dataset and provide a great opportunity for a systems level connectivity analysis between drug response and in-depth molecular characterization. However, a missing component of previous attempts to connect datasets together has been the lack of comprehensive functional protein signaling activation analysis. METHODS: Using Reverse-phase Protein MicroArray (RPMA) analysis, we were able to measure the activation state of nearly 200 key signaling proteins representative of the main pathways involved in cell proliferation, survival, migration and adhesion in all 60 cell lines. We used the nature of the comprehensive pathway activation analysis we performed to focus our analysis on modules of interconnected kinase-substrate protein architecture for the following 7 key signaling pathways known to be involved in cancer tumorigenesis and metastasis: AKT signaling, mTOR signaling, EGFR signaling, IGF1R signaling, integrin signaling, autophagy signaling, and apoptosis signaling. These modules were then used to define a systems level view of functional interactions through the correlation of protein phosphorylation/activation states within each module and the mutational, metabolomic, miRNA, transcriptional and drug sensitivity data available.RESULTS AND DISCUSSION: The integration of individual protein pathway activation measurements into biochemically interconnected modules provided a new means to align the functional protein architecture with multiple -omic data sets and therapeutic response correlations. This approach may provide a deeper understanding of how cellular biochemistry through genetic, genomic, transcriptomic, proteomic and metabolomic signatures predicts and defines therapeutic response. Such -omic portraits could inform rational anticancer agent screenings and drive personalized therapeutic approaches.
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 4911. doi:1538-7445.AM2012-4911