bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2894: Environmentally responsive nanoparticles for the intracellular delivery of RNAi therapeutics into tumor-associated macrophages
Authors: Yu Shann S. , Lau Cheryl M. , Barham Whitney J. , Onishko Halina M. , Nelson Christopher E. , Yull Fiona E. , Duvall Craig L. , Giorgio Todd D. 
Published: August 2012

Abstract
Tumor-associated macrophages (TAMs) represent a potentially promising therapeutic target in cancer because they have been shown to facilitate tumor growth, invasiveness, and metastasis. However, methods to specifically target therapies to TAMs are lacking. To address this problem, we designed and synthesized mannosylated micellar nanoparticles (ManNPs), composed of tri-block co-polymers. The three polymer blocks include (1) an azido-displaying block for functionalization with biomolecules via azide-alkyne ‘click’ chemistry, (2) a cationic block for the condensation of polyanions such as siRNA, and (3) a pH-responsive terpolymer block that facilitates endosomal disruption. This terpolymer is hydrophobic at pH 7.4, allowing these polymers to self-assemble into 25 nm micellar nanoparticles under physiologic conditions. However, they become protonated at lower pH ranges representative of endosomal compartments (5.8 - 6.2), leading to disassembly of the nanoparticles, and increased ability to disrupt endosomal membranes and enable cytoplasmic delivery. This pH-dependent behavior has been validated using a red blood cell hemolysis assay. This environmentally-responsive behavior facilitates improved cytoplasmic delivery of siRNA, access to the intracellular silencing machinery, and consequently, knockdown of target gene expression. Further, we demonstrate that mannosylation of these nanoparticles via ‘click’ chemistry significantly enhances their ability to deliver siRNA into murine bone marrow-derived primary macrophages (BMDMs), relative to control, untargeted nanoparticles. Targeted nanoparticle uptake is mediated specifically through the macrophage mannose receptor (CD206), as validated through competition experiments with free mannose, or by pre-incubating BMDMs with lipopolysaccharide to downregulate CD206 expression. This is particularly important for cancer applications because CD206 is upregulated in tumor-suppressed and non-activated macrophages, enabling more specific targeting of TAMs versus healthy macrophages in other tissues. The ManNPs described here present new opportunities to target TAMs in various cancers, providing an enabling technology for the modification of the immunosuppressive tumor environment by targeting TAM activity. Studies are pending to demonstrate this behavior in an in vivo murine model of metastatic breast 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 2894. doi:1538-7445.AM2012-2894
Abstract 3017: Oct4B mediates hypoxia induced epithelial mesenchymal trans-differentiation of lung cancer
Authors: Chou Yu-Ting , Chung Chi-Hsiu , Chung Chih-Hung , Wu Cheng-Wen 
Published: August 2012

Abstract
Hypoxia, a reduction of normal oxygen levels in cells or tissues, creates a variety of changes in cell metabolism, eliciting a set of genes involved in tissue development and cancer progression. Though Oct4, a homebox transcription factor, is essential for self-renewal of embryonic stem cells, little is known about the functional role of Oct4 in tumorigenesis. In this study, we discovered that hypoxia induces a short isoform of Oct4, termed as Oct4B, in lung cancer through a HIF-2α dependent pathway. Oct4B induced cell proliferation, anchorage-independent growth, and xenograft tumor formation of lung cancer cells, indicating the oncogenic potential of Oct4B. Moreover, ectopic expression of Oct4B in lung cancer cells induced epithelial mesenchymal tans-differentiation (EMT), promoting cell migration and invasion. We observed that Oct4B bound to Slug promoter upon hypoxia stimulation, promoting EMT as well as invasion of lung cancer cells. Thus, our findings provide a novel mechanism of how Oct4B mediates hypoxia signaling to encourage malignancy of 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 3017. doi:1538-7445.AM2012-3017
Abstract 3019: TGFβ3 is a less potent inducer of TGFβ signaling than TGFβ1 in non-small cell lung cancer cells
Authors: McLean Sarah Elizabeth Anne , Guglielmo Gianni M. Di 
Published: August 2012

Abstract
Transforming growth factor beta (TGFβ) is an essential cytokine for tissue homeostasis. Its signalling pathway is under intense study as it is commonly dysregulated in many cancers, including pancreatic cancer, non-small cell lung cancer, and colorectal cancer. The TGFβ signalling cascade is propagated by the binding of ligand to cell-surface serine-threonine kinase receptors, which leads to the phosphorylation of receptor regulated Smad (R-Smad) proteins. There are three main ligands capable of activating the classical TGFβ pathway: TGFβ1, TGFβ2 and TGFβ3. These ligands show distinct spatial and temporal expression patterns and have non-overlapping functions in vivo. Extensive studies have been conducted on the role of TGFβ1 in the tumour microenvironment, and the role of TGFβ3 has largely been thought to be the same as TGFβ1 though there are few studies to support this claim. Interestingly in the wound microenvironment, TGFβ1 and TGFβ3 have vastly different signalling outcomes: TGFβ1 promotes the formation of a scar while TGFβ3 induces scar-free wound resolution. The objective of the present study was to evaluate the signalling capacity of TGFβ1 and TGFβ3 in non-small cell lung cancer cells. Our studies show that TGFβ3 is less potent at initiating Smad2 phosphorylation than TGFβ1, resulting in reduced transcriptional activity, as assessed by microarray analysis. We also observed that TGFβ3 is less effective than TGFβ1 at altering cell-cell adhesions. In order to assess the differences in signalling potential, we investigated TGFβ receptor engagement at the cell surface using radiolabelled TGFβ ligands. We observed that the ratio of activated receptors in signalling complexes is altered in the presence of TGFβ3, which may lead to a decreased signalling capacity. Future studies will evaluate the capacity of TGFβ3 to induce cancer cell migration and invasion.
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 3019. doi:1538-7445.AM2012-3019
Abstract 3024: Elucidation of WNT signaling pathway players “sFRP-1” and “TCF7L2” as novel potential biomarkers of triple negative breast cancer
Authors: Huelsewig Carolin , Goette Martin , Bernemann Christof , Ruckert Christian , von Wahlde Marie-Kristin , Buchweitz Olaf , Kiesel Ludwig , Pusztai Lajos , Liedtke Cornelia 
Published: August 2012

Abstract
Background: Triple negative breast cancer (TNBC) is characterized by an unfavorable prognosis. While patients do not benefit from endocrine or Her2 targeted therapies except chemotherapy, there is an increased propability of response to taxane-/anthracycline-containing therapy compared to other breast cancers. However, molecular determinants of chemotherapy sensitivity for patients with TNBC specifically remain largely unknown. The WNT signaling cascade has been shown to play an important role in breast cancer pathogenesis. Material and Methods: Differentially expressed genes in triple negative (TN) vs. non-TN breast cancers of patients treated with neoadjuvant taxane-/anthracycline-containing chemotherapy were identified and validated in an independent AffymetrixU133A gene chip dataset. Genes were tested for correlation with relapse-free survival, response to neoadjuvant chemotherapy and Ki67 expression. The effects of siRNA mediated knockdown in the TNBC and non-TNBC cell lines on proliferation, chemo sensitivity invasion competency and gene expression of target genes via quantitative real-time PCR were analyzed. Results: sFRP-1 (secreted frizzled related protein 1) and TCF7L2 (transcription factor-7 like 2) were identified as significantly over expressed genes in TNBC vs. non-TNBC and validated in an independent dataset. While sFRP-1 expression was not associated with relapse-free survival in TNBC, it was significantly correlated with a pCR. Importantly, no correlation to Ki67 expression could be demonstrated. While mRNA knockdown of sFRP-1 in MDA-MB 468 was associated with an increased resistance to paclitaxel, doxorubicin and cisplatin, target gene expression analysis suggest sFRP-1 as a biphasic modulator in breast tissue. TCF7L2 knockdown analysis in the TN cell line MDA MB 231 as well as the non-TN lines MCF7 and SKBR-3 shows an increased cell invasiveness of up to 200 %. Conclusion: We suggest sFRP-1 as predictive biomarker and potential mediator of sensitivity to taxane-, anthracycline and platinum-containing chemotherapy in TNBC in vitro referring to its biphasic WNT modulation. Furthermore TCF7L2 is suggested as a prognostic biomarker in vitro breast cancer cell lines including TN and non-TN cell lines. Our results provide proof of principle that high-throughput gene expression analysis may be exploited as a means to derive at a biological / translational hypothesis that may be supported by basic science.
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 3024. doi:1538-7445.AM2012-3024
Abstract 3027: Dishevelled proteins are highly upregulated in chronic lymphocytic leukemia
Authors: Khan Abdul Salam , Österborg Anders , Moshfegh Ali , Mellstedt Håkan 
Published: August 2012

Abstract
Chronic Lymphocytic Leukemia (CLL) is the most common adult leukemia and is characterized by the progressive accumulation of CD5+ B cells. An important signaling pathway in CLL cells might be Wnt signaling pathways. Wnt signaling pathways include the Wnt/ β-catenin pathway and the non-canonical Wnt pathways. Dishevelled proteins (DVL1, DVL2, and DVL3) are important mediators in Wnt signaling and have been shown in to be expressed many cancer types but their precise role is not clear. The aim of the study was to characterize the expression of DVL1, DVL2 and DVL3 proteins in indolent and progressive CLL and compare to normal white blood cells (PBMC) as well as to assess the expression of other important proteins of the canonical pathway as β-catenin and the non-canonical pathways as GSK-3β, PKC, ERK and AKT respectively. Leukemic cells from indolent (n=9) and progressive (n=9) CLL patients were isolated by Ficoll gradient centrifugation as well as PBMC from healthy donors (n=9). Six cell lines including four CLL cell lines EHEH, CII, I83, 232 B4, and the Jurkat and Lucas cell lines were also used. DVL 1, DVL 2, DVL 3 were analyzed by Western blot and densitometric calculations as well as PKC, GSK-3β, AKT and ERK using antibodies against the total protein and the phosphorylated protein respectively. Overexpression of DVL1, DVL 2, and DVL3 was seen in all indolent and progressive CLL patients and the six cell lines. There was a significantly higher expression of DVL 1 and DVL 3 in indolent compared to progressive CLL patients (p&lt;0.01 and p&lt;0.01 respectively). In contrast to DVL 1 and DVL 3, DVL 2 was highly expressed in indolent as compared to progressive CLL patients. ≤ -catenin followed the same expression pattern as DVL2 being highly expressed in indolent CLL as compared to progressive CLL patients (p&lt;0.001). There was no significant difference in the degree phosphorylation of PKC and GSK-3β between indolent CLL, progressive CLL and healthy donors.The degree of AKT and ERK phosphorylation was significantly higher in indolent than in progressive CLL patients (p&lt;0.001 and p&lt;0.01 respectively). In summary DVL1, DVL2 and DVL3 are highly expressed in CLL patients and CLL cell lines but their expression in normal PBMC is almost negligible but expression of other canonical and non-canonical pathways proteins are seen both in CLL and healthy donors. DVL1, DVL2 and DVL3 may have a key role in the transduction of Wnt mediated signals in CLL.
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 3027. doi:1538-7445.AM2012-3027
Abstract 3029: Biochemical evidence towards the existence of an oncogenic Hsp90 complex
Authors: Rodina Anna , Moulick Kamalika , Ahn James , Zong Hongliang , Cerchietti Leandro , DaGama Erica Gomes , Caldas-Lopes Eloisi , Beebe Kristin , Perna Fabiana , Hatzi Katerina , Vu Ly , Zhao Xinyang , Zatorska Danuta , Taldone Tony , Smith-Jones Peter , Alpaugh Mary , Gross Steven , Pillarsetty Nagavarakishore , Ku Thomas , Lewis Jason , Larson Steven , Levine Ross , Erdjument-Bromage Hediye , Guzman Monica , Nimer Stephen , Melnick Ari , Neckers Len , Chiosis Gabriela 
Published: August 2012

Abstract
To maintain homeostasis, cells employ intricate molecular machineries comprised of thousands of proteins programmed to execute well-defined functions. Dysregulation of these pathways, through protein mis-expression or mutation, provides biological advantages that confer the malignant phenotype. At the molecular level, this requires cells to invest energy in maintaining the stability and function of these proteins, and for this reason cancer cells co-opt molecular chaperones, including Hsp90. Hsp90 is recognized to play important roles in maintaining the transformed phenotype - the chaperone and its associated co-chaperones assist in the correct folding of cellular proteins, collectively referred to as “client proteins,” many of which are effectors of signal transduction pathways controlling cell growth, differentiation, the DNA damage response, and cell survival. Tumor cell addiction to these proteins (i.e. through mutations, aberrant expression, improper cellular translocation, etc) thus makes them critically reliant on Hsp90. While Hsp90 is expressed in all cells and tissues, it was shown that tumors preferentially contain Hsp90 that is in a higher order multi-chaperone complex with high affinity for certain Hsp90 inhibitors, while normal tissues harbor a latent, uncomplexed Hsp90 that has low affinity for these inhibitors. We here extend this model and propose that Hsp90 forms biochemically distinct complexes in cancer cells. In this view, a major fraction of cancer cell Hsp90 retains “house keeping” chaperone functions similar to normal cells, whereas a functionally distinct Hsp90 pool enriched or expanded in cancer cells specifically interacts with oncogenic proteins required to maintain tumor cell survival. Perhaps this Hsp90 fraction represents a cell stress specific form of chaperone complex that is expanded and constitutively maintained in the tumor cell context. Our data suggest that it may execute functions necessary to maintain the malignant phenotype. One such role is to regulate the folding of mutated (i.e. mB-Raf) or chimeric proteins (i.e. Bcr-Abl). We here also present experimental evidence for an additional role; that is, to facilitate scaffolding and complex formation of molecules involved in aberrantly activated signaling complexes.
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 3029. doi:1538-7445.AM2012-3029
Abstract 3032: Role of ruffles and filopodia in adhesion gradient sensing
Authors: Heckman Carol A. , Amarachintha Surya P. 
Published: August 2012

Abstract
Filopodia play a sensory role in directing motility during embryonic development and axon pathfinding. They also show a low prevalence in cancer cells. Here, we determine whether cells from a rat tracheal epithelial line in vitro use filopodia to sense adhesive gradients. Cells exhibit haptotaxis (movement toward a more adhesive surface) when placed on a metal-glass gradient. Tantalum (Ta) and platinum (Pt) gradients were created on glass slides and high (H), middle (M), and low (L) positions defined along the gradient. Cell counts in randomly selected fields confirmed that the cells recognized the gradient. To determine whether the prevalence of protrusions differed at the H, M, and L locations, we measured the values of latent factors 4 (filopodia), 5, and 7. Factor 4 values were high at H and significantly lower at M and L (p&lt;0.05). Cells’ ability to form large protrusions, represented by factors 5 (lamellar distribution) and 7 (nascent neurites), was uniform across the Ta gradient. To detect the cells’ ability to interpret directional cues, we distinguished the cell's top (T) side, i.e. the side oriented toward H location, from the bottom (B) side. Factor 4 values at H-T exceed those at M-B and L-T (Table 1). Trend analysis confirmed a decrease in factor 4 over the gradient with significance of p&lt;0.001 (Ta) and p&lt;0.023 (Pt). On Pt only, factor 5 increased (p=0.000) as the metal content of the substrate declined. Ruffling activity is generally inverse to filopodia but positively related to factor 5 (Heckman et al., doi:10.1016/j.cellsig.2011.08.023). On haptotactic substrates, the former relationship was observed by correlation analysis but was restricted to the L location on the gradient. This suggests that poor adhesion may help to convert mechanisms of filopodia formation to ruffle formation. The above results suggest that sensing depends on net filopodia stabilization at the more adhesive H location. We conclude that filopodia respond to the gradient and that regulation of the sensing and signaling mechanisms can now be evaluated.

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 3032. doi:1538-7445.AM2012-3032
Abstract 3034: Hsp90-dependent stabilization of active NPM-ALK kinase: Structural insights by mutagenesis of the ALK catalytic domain
Authors: Bonvini Paolo , Mussolin Lara , Cozza Giorgio , Moro Stefano , Rosolen Angelo 
Published: August 2012

Abstract
Background. Among the posttranslational modifications occurring in eukaryotic cells, phosphorylation is the most critical for proteins, as phosphate-mediated conformational switching of catalytic and non-catalytic motifs impacts expression and activity through changes in structure stability. Activation by phosphorylation is the rule for protein kinases, including oncogenic protein tyrosine kinase NPM-ALK (nucleophosmin-anaplastic lymphoma kinase) in Anaplastic Large Cell Lymphomas, though it renders the kinase prone to degradation. For several of them, however, the maintenance of functional stability is provided by the molecular chaperone Hsp90, through the recognition of specific motifs within the catalytic domain. Objectives. Herein, we determined whether NPM-ALK kinase activity facilitates Hsp90 binding, and whether structural motifs within NPM-ALK catalytic domain favor or impair Hsp90 interaction. Design/Methods. To test this hypothesis we prepared a series of N- and C-terminal deletion mutants of wild-type NPM-ALK, as well as inactive point mutants by site-directed mutagenesis of the NPM-ALK ATP-binding site and activation loop. Results. Using NPM-ALK constructs in COS7 and 293T cells, we showed that Hsp90 strongly interacts with wild-type NPM-ALK, but fails to co-adsorb with inactive point mutants and with deletion mutants lacking the entire kinase domain. By comparison, binding to Hsp90 family members Hsc70 and Hsp70 is independent of NPM-ALK activity, suggesting a greater dependence of active NPM-ALK on Hsp90 function. Accordingly, phosphorylated NPM-ALK associated with Hsp90 and co-chaperone cdc37, and pharmacological inhibition of NPM-ALK prevented the interaction of NPM-ALK with both proteins. Of note, mutants unmasking the αC-helix motif in the N-terminal lobe of the catalytic domain maintained the ability to bind Hsp90, whereas mutants lacking αC-helix did not. Conclusions. Our findings, therefore, suggest a model in which, in addition to a role in folding nascent NPM-ALK, Hsp90 provides an “ongoing folding support” to activated NPM-ALK kinase, by protecting self-phosphorylated NPM-ALK from ubiquitination through recognition of specific unstable motifs within its catalytic domain.
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 3034. doi:1538-7445.AM2012-3034
Abstract 3035: Bone morphogenetic proteins signal through Smad2 and Smad3 to regulate cell migration and proliferation
Authors: Holtzhausen Alisha , How Tam , Gersh Bradley C. , Blobe Gerard C. 
Published: August 2012

Abstract
The TGF-β superfamily consists of a large number of growth factors, including transforming growth factor-β (TGF-β) and bone morphogenetic proteins (BMPs) that regulate cellular proliferation, differentiation, invasion, migration and apoptosis. TGF-β activates the transcription factors Smad2/3, as well as Smad1/5/8, while BMP stimulation results in the activation of Smad1/5/8. Unexpectedly, we have demonstrated that BMP family members, including BMP2, 3, 4, 7, 9 and GDF5 can also induce Smad2/3 phosphorylation and downstream gene transcription in ovarian, pancreatic and breast cancer cell lines. BMP2-induced Smad2 phosphorylation can be attenuated by expression of dominant negative TβRII or shRNA-mediated knockdown of TβRII, while BMP2-induced Smad3 phosphorylation can be attenuated by expression of dominant negative BMPRII or shRNA-mediated knockdown of BMPRII, suggesting different mechanisms of BMP-mediated activation of Smad2 and Smad3. BMP2-induced Smad1, Smad2 and Smad3 phosphorylation increase cell invasion, migration and proliferation, respectively. BMP stimulated Smad2/3 phosphorylation suggests that BMP-mediated effects on cancer progression may be regulated, in part, through these novel signaling pathways. Current studies are focused on further elucidating the role of BMP-induced Smad2 and Smad3 phosphorylation on human cancer progression.
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 3035. doi:1538-7445.AM2012-3035