bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5101: Acute inhibition of myostatin-family proteins preserves muscle in cancer cachexia
Authors: Klimek Margaret E. Benny , Aydogdu Tufan , Link Majik , Pons Marianne , Koniaris Leonidas G. , Zimmers Teresa A. 
Published: February 2011

Abstract
Cachexia, progressive loss of fat and muscle mass despite adequate nutrition, is a devastating complication of cancer associated with poor quality of life and increased mortality. Myostatin is a potent tonic muscle growth inhibitor. We tested how myostatin inhibition might influence cancer cachexia using genetic and pharmacological approaches in mice. First, myostatin null mice were challenged with Lewis lung carcinoma or B16F10 melanoma. Although hypermuscular at baseline, myostatin null mice were more sensitive to tumor-induced cachexia, losing more absolute mass and proportionately more muscle mass than wild-type mice. Because myostatin null mice lack expression from development, however, we also sought to manipulate myostatin acutely. The histone deacetylase inhibitor Trichostatin A has been shown to increase muscle mass in normal and dystrophic mice by inducing the myostatin inhibitor, Follistatin. Although Trichostatin A administration induced muscle growth in normal mice, it failed to preserve muscle in colon-26 cancer cachexia. Finally we sought to inhibit myostatin and related ligands by administration of the Activin receptor extracellular domain/Fc fusion protein, ACVR2B-Fc, which inhibits myostatin activity and induces dramatic muscle growth in normal mice. Systemic administration of ACVR2B-Fc potently inhibited muscle wasting and protected adipose stores in both colon-26 and Lewis lung carcinoma cachexia, without affecting tumor growth. Enhanced cachexia in myostatin knockouts indicates that host-derived myostatin is not the sole mediator of muscle wasting in cancer. More importantly, skeletal muscle preservation with ACVR2B-Fc establishes that targeting myostatin family ligands using ACVR2B-Fc or related molecules is an important and potent therapeutic avenue in cancer cachexia.
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 5101.
Abstract 5102: In vitro hedgehog signaling pathway alterations after acquired-platinum resistance in small cell lung cancer
Authors: Ranade Aarati , Weiss Glen J. 
Published: February 2011

Abstract
Background: The Hedgehog (HH) signaling pathway regulates cell growth and differentiation during embryonic tissue development and may play a role of ‘stem cell’ maintenance in adults. Studies have shown that SCLC platinum resistance and cell death is associated with HH signaling pathway maintenance, potentiating SCLC re-growth after chemotherapy. We hypothesized that acquired-platinum resistance would alter HH pathway signaling.
Methods: SCLC cell lines, H69 and H146 along with their acquired cisplatin (H69Cis1) and carboplatin resistant (H69Car1, H146Car1, and H146Car2) versions were used. mRNA expression of genes in HH pathway were measured. Fold changes in mRNA expression in resistant cells (RCs) compared to parent cells were calculated. A two-sided t-test was used to compute the p-values for the fold changes. Proteins from these cells were probed for SHH, SUFU, and GLI1 by immunoblot.
Results: The mRNA expression of genes in HH pathway was altered in platinum RCs compared to their parental cells (Table 1). As with mRNA expression, SHH protein is decreased in both H69 cisplatin and carboplatin RCs (by 93% in H69Cis1 and by 76% in H69Car1) and by 62% in H146 carboplatin RCs. SUFU mRNA and protein expression are not significantly different in the platinum RCs compared to their parental cells. GLI1 protein was not expressed in vitro in these cell lines, but there was a significant increase in GLI1 mRNA expression in platinum RCs.
Conclusions: Our results indicate that the genes in the HH pathway such as GLI1, GLI2, PTCH1, PTCH2, SHH, and SMO are altered in vitro in cisplatin and carboplatin H69 and H146 acquired RCs compared to respective parent cell lines. Detailed studies with other SCLC cells lines with variable sensitivity to platinum and the impact of HH pathway inhibitors on the platinum resistant cell lines in vivo are worth further exploration.Table 1:Relative Fold Changes in mRNA Expression of HH Pathway Genes in Acquired-Platinum Resistant SCLC Cell Lines GLI1GLI2HHIPPTCH1PTCH2SHHSMOSuFuH6911111111H69Car13.17 (0.29)3.46 (0.51)1.21 (0.14)1.52 (0.048*)1.05 (0.93)88.54 (0.17)2.13 (0.037*)0.9 (0.80)H69Cis113.49 (0.028*)3.71 (&lt;0.001*)2.8 (0.018*)1.37 (0.07)1.34 (0.20)55.26 (0.009*)26.01 (&lt;0.001*)1.16 (0.57)H14611111111H146Car16.62 (0.02*)8.49 (&lt;0.001*)0.71 (0.43)0.24 (0.05)0.17 (0.043*)8.49 (&lt;0.001*)0.11 (0.011*)0.71 (0.15)H146Car23.45 (0.05)11.71 (&lt;0.001*)1.13 (0.62)0.17 (0.045*)0.45 (0.15)11.71 (&lt;0.001*)0.13 (0.001*)1.10 (0.49)The values in the table indicate mean (p-value)*Significant p&lt;0.05Fold changes in mRNA expression in resistant cells (RCs) compared to parent cells were calculated.(Supported by the TGen Foundation and SHC Foundation)
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 5102.
Abstract 5104: Cell-surface receptor expression in osteosarcoma
Authors: Geller David S. , Hassan Sheref E. , Gorlick Richard 
Published: February 2011

Abstract
Purpose: Although numerous cell-signaling receptors have been described in the setting of osteosarcoma, the comprehensive characterization of receptors on the cell-surface has not been described. The goal of the current study was to characterize and quantify the expression of cell-surface receptors across multiple standard osteosarcoma cell lines and patient samples placed in culture.
Methods: Both standard (n=4) and patient derived (n=10) osteosarcoma cell lines were cultured and labelled with a panel of commercially available flurophore-bound antibodies including antibodies to EGFR, HER-2, HER-3, HER-4, IGF-1R, IGF-2R, IR, VEGFR-1, VEGFR-2, VEGFR-3, CMET, FGFR-2, FGFR-3, PDGF alpha, and PDGF beta. Standard cell lines utilized were 143b, HOS, Saos, and U205. Patient samples included samples 229, 231, 232, 238, 252, 293, 308, 311, 242, and 290. Background fluorescence was accounted for using either a known negative control cell line if available or the antibody-specific IgG isotype. Unlabelled cells were also evaluated for inherent fluorescence. Cell analysis was performed using flow cytometry (FACS) and data was analyzed using FloJo software. The geometric fluorescent means were calculated and compared against positive controls.
Results: Although a degree of variability in cell-surface receptor expression existed between the different cell lines, preliminary results show high expression of PDGFR-beta in all 14 cell lines, with an average geometric mean of 1376 (range 93.8 - 4496). A higher expression of IGF-1R was also noted across all cell lines, with an average geometric mean of 881 (range 122 - 3191). In depth analysis of receptor expression and the interrelationship of these various receptors is ongoing.
Conclusion: Preliminary results demonstrate PDGFR-Beta and to a lesser extent IGF-1R to be consistently expressed on the cell-surface in all tested osteosarcomas cell lines. Data analysis of receptor expression and interrelationships between receptor expression is ongoing.
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 5104.
Abstract 5122: Regulation of integrin trafficking by Rab proteins
Authors: Hasan Nazarul , Hu Chuan 
Published: February 2011

Abstract
Integrins, the major receptors for cell adhesion to the extracellular matrix, are synthesized in the endoplasmic reticulum, transported in vesicles, and delivered to the plasma membrane or the cell surface by exocytosis. Like other receptors, integrins at the plasma membrane are constantly endocytosed, transported into endosomal compartments and then recycled back to the surface. Therefore, the density of integrins at the cell surface is ultimately determined by the balance between two vesicle trafficking events: endocytosis and exocytosis. Rab proteins are small (20-29 kDa) monomeric Ras-like GTPases that regulate vesicle budding, transport and tethering to the target membranes. Rab4, Rab11 and Rab25 function in the endocytic and recycling pathway. In this study, we examined roles of the Rab proteins in integrin trafficking. Silencing of Rab11 in HeLa cells had neither obvious effects on cell surface or total cellular expression of α3, α5 and β1 integrins nor on cell migration. Silencing of Rab25 reduced the surface expression of all three integrins and inhibited chemotactic migration. Surprisingly, Rab4 silencing dramatically increased both cell surface and total cellular expression of the integrins, and inhibited cell migration as well. These data suggest that Rab25 is required in integrin trafficking to the cell surface, and that Rab4 negatively regulates the expression and trafficking of integrins. These data support the notion that reduced or excessive integrins at the cell surface diminish cell motility.
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 5122.
Abstract 5127: Prosaposin down-modulation decreases metastatic prostate cancer cell adhesion, migration, and invasion
Authors: Hu SiYi , Delorme Nathalie , Liu Zhenzhen , Liu Tao , Velasco-Gonzalez Cruz , Garai Jone , Pullikuth Ashok , Koochekpour Shahriar 
Published: February 2011

Abstract
Factors responsible for invasive and metastatic progression of prostate cancer (PCa) remain largely unknown. Previously, we reported cloning of prosaposin (PSAP) and its genomic amplification and/or overexpression in several androgen-independent metastatic PCa cell lines and lymph node metastases. PSAP is the lysosomal precursor of saposins, which serve as activators for lysosomal hydrolases involved in the degradation of ceramide (Cer) and other sphingolipids. Our current data show that, in metastatic PCa cells, stable down-modulation of PSAP by RNA-interference via a lysosomal proteolysis-dependent pathway decreased β1A-integrin expression, its cell-surface clustering, and adhesion to basement membrane proteins; led to disassembly of focal adhesion complex; and decreased phosphorylative activity of focal adhesion kinase and its downstream adaptor molecule, paxillin. Cathepsin D (CathD) expression and proteolytic activity, migration, and invasion were also significantly decreased in PSAP knock-down cells. Transient-transfection studies with β1A integrin- or CathD-siRNA oligos confirmed the cause and effect relationship between PSAP and CathD or PSAP and Cer-β1A integrin, regulating PCa cell migration and invasion. Our findings suggest that by a coordinated regulation of Cer levels, CathD and β1A-integrin expression, and attenuation of “inside-out” integrin-signaling pathway, PSAP is involved in PCa invasion and therefore might be used as a molecular target for PCa therapy.
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 5127.
Abstract 513: Inhibition of histone deacetylase activity down-regulates urokinase plasminogen activator and matrix metalloproteinase-9 expression in gastric cancer cell lines
Authors: Lee Kyung Hee , Kim Min Kyung , Kim Jae Ryong , Kim Sang Woon , Song Sun Kyo 
Published: February 2011

Abstract
Histone acetylation plays an important role in chromatin remodeling and gene expression. An imbalance of this reaction leads to aberrant behavior of cells in the cell cycle, i.e., carcinogenesis. Histone deacetylase (HDAC) inhibitors have been shown to have anti-tumor effects in clinical trials. However, the exact mechanisms by which HDAC inhibitors exert anti-tumor effects and modulate gene expression are not completely understood, and thus remain a subject of intense investigation. In the current study, we determined whether HDACs regulate urokinase plasminogen activator (uPA), matrix metalloproteinase (MMP)-9, and tumor invasion. Using cDNA microarray analysis, we showed that hepatocyte growth factor (HGF) induced HDAC-5 expression in both gastric cancer cell lines. TSA, a HDAC inhibitor, decreased HGF-induced HADC-5 expression and also repressed uPA and MMP-9 expression. We confirmed these results using HDAC-5 gene overexpressing cell lines. The number of viable cells in the cultures with or without TSA treatment was determined by the MTT assay. TSA inhibited cell proliferation in both cell lines. We characterized the effects of TSA on MMP-9-mediated proteolysis as assessed by zymography. In vitro Matrigel invasion assays showed that the HDAC inhibitor resulted in a significant decrease in cancer cell invasion. Furthermore, Gö6976, a PKC inhibitor, significantly inhibited HGF-induced HDAC-5 expression and invasion. These results demonstrated that HDACs regulate HGF-induced uPA and MMP-9 expression of gastric cancer cells, and the PKC pathway may play an important role in HGF-mediated cell invasion in gastric cancer cells, suggesting that such activities serve as anti-tumor mechanisms of the HDAC inhibitor.
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 513.
Abstract 5139: Trop2 modulates beta1 integrin-mediated adhesion and migration of prostate cancer cells
Authors: Trerotola Marco , Alberti Saverio , Languino Lucia R. 
Published: February 2011

Abstract
Trop1 and Trop2 are highly related transmembrane glycoproteins, which are overexpressed in many human carcinomas and have been suggested to contribute to cancer progression. Recently, Trop2 has been discovered as an important marker for identification of candidate tumor-initiating cells in a mouse model of prostate cancer (PrCa), suggesting that this protein is a novel regulator of PrCa progression.
In this study, we show that Trop2 was expressed at high levels in aggressive human PrCa cells, and was co-localized with beta1 integrins, which are known to modulate cell adhesion and invasion and to be deregulated in PrCa. We demonstrate that Trop2 inhibited adhesion of PC3 PrCa cells on fibronectin (the major ligand for beta1), but strongly enhanced their ability to migrate on fibronectin as compared to controls. This effect was specific for cells seeded on fibronectin, since no effect was observed on vitronectin.
Confocal microscopy studies using PC3 cells seeded on fibronectin showed strong co-localization of Trop2 with beta1 in leading edges. On the other hand, Trop2 did not co-localize with beta5, an integrin that did not affect migration of PC3 cells on fibronectin. We did not observe any change of beta1 expression in Trop2-overexpressing PC3 cells compared to controls, suggesting that affinity for fibronectin or clustering in focal complexes might be modulated by Trop2. Our studies on Trop2-overexpressing PC3 cells seeded on fibronectin demonstrated that beta1 was in fact displaced from focal adhesions to relocate to Trop2-containing leading edges.
Our findings demonstrate a novel cross-talk between Trop2 and beta1 integrins in PrCa cells. We hypothesize that this interplay can result in destabilization of firm adhesion to fibronectin and accelerated re-organization of dynamic structures responsible for migration/invasion of PrCa cells.
MT is recipient of a fellowship from the Italian Foundation for Cancer Research (FIRC).
Grant Support: NIH R01 CA109874 (LRL).
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 5139.
Abstract 5149: Nucleostemin is a key factor in maintenance of human glioblastoma-derived cancer stem cells
Authors: Izquierdo Marta L. , Gil Jon 
Published: February 2011

Abstract
Glioblastomas (GBM) may contain a variable proportion of active cancer stem cells (CSCs) capable of self-renewal, of aggregating into CD133+ neurospheres, of retaining their multi-lineage potential over time, and to develop intracranial tumors that phenocopy the original ones. We hypothesized that nucleostemin may contribute to cancer stem cell biology as these cells share characteristics with normal stem cells. We will report that nucleostemin is expressed in GBM-CSCs isolated from patient samples. The significance of its expression was addressed by targeting the corresponding mRNA using lentivirally transduced short hairpin RNA (shRNA). Knockdown of nucleostemin in GBM-CSC abolishes proliferation and induces apoptosis. Furthermore, GBM-CSCs with decreased nucleostemin levels failed to form neurospheres in vitro or tumors when xenotransplanted into the brains of immunocompromised rats. These findings suggest a central role of nucleostemin in regulating proliferation, self-renewal and survival of GBM-CSC, and targeting its expression may offer a new therapeutic approach for this incurable type of brain tumors.
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 5149.
Abstract 5154: Human umbilical cord matrix stem cells transfected with the interferon-β gene markedly attenuated the growth of bronchioloalveolar carcinoma xenografts in mice
Authors: Kawabata Atsushi , Doi Chiyo , Matsuzuka Takaya , Rachakatla Raja Shekar , Ohta Naomi , Pyle Marla , Marini Frank , Troyer Deryl , Tamura Masaaki 
Published: February 2011

Abstract
Mesenchymal stem cells derived from the human umbilical cord matrix (UCMSC) have great potential for therapeutic use in multiple diseases including cancer. UCMSC can be used as carriers for targeted delivery of genes or therapeutics and for local production of biologic agents. The therapeutic strategy using UCMSC as cellular vehicles for targeted gene delivery can avoid the problem of short life or excessive toxicity of a particular gene product in vivo. Interferon-β (IFN-β) has demonstrated a potent anti-tumor effect on many tumor cell lines in vitro. However, in vivo inhibition of tumor cell growth by IFN-β required blood concentrations much higher than the maximally tolerated dose. Therefore, clinical therapy by systemic administration of IFN-β was not possible. The aim of this study was to determine the anti-cancer effect of IFN-β gene transfected-UCMSC (IFN-UCMSC) on bronchioloalveolar carcinoma (BAC) cell lines in vitro and in vivo. The conditioned medium derived from IFN-UCMSC significantly attenuated cell growth of H358 and SW1573 BAC cell lines in vitro compared to the medium derived from non-transfected UCMSC. The percentage of dead cells, as measured by the trypan blue exclusion test, was significantly higher in the cells treated with the medium derived from IFN-UCMSC than UCMSC alone. The co-culture of IFN-UCMSC with cancer cells inhibited cell growth significantly through stimulation of apoptosis. Finally, systemic administration of IFN-UCMSC (0.3 million cells/injection, 5 day interval for four times) markedly attenuated tumor multiplicity and size of orthotopic H358 BAC xenografts in SCID mouse lungs. Histochemical analysis of the tumors indicated tumor-targeted localization of UCMSC and significant reduction of tumor cell proliferation index as measured by Ki-67 staining. These results clearly indicated that IFN-β production by IFN-UCMSC attenuated growth of BAC cells by inducing programmed cell death both in vitro and in vivo. This research clearly demonstrated that IFN-UCMSC are a powerful anti-cancer therapeutic tool as delivery vehicles for IFN-β. This work was supported by the KSU Terry C. Johnson Center for Basic Cancer Research, KSU Provost's Fund, KSU CVM Dean's Fund, NIH P20 RR017686 and a Joan's Legacy Research Grant.
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 5154.
Abstract 5166: Sex determining region Y-box 2 (SOX2) is a potential cell-lineage gene highly expressed in the pathogenesis of squamous cell carcinomas of the lung
Authors: Yuan Ping , Kadara Humam , Behrens Carmen , Tang Ximing , Woods Denise , Solis Luisa M. , Huang Jiaoti , Spinola Monica , Dong Wenli , Yin Guosheng , Fujimoto Junya , Kim Edward , Xie Yang , Girard Luc , Moran Cesar , Hong Waun Ki , Minna John D. , Wistuba Ignacio Ivan 
Published: February 2011

Abstract
Non-small cell lung cancer (NSCLC) represents the majority (85%) of lung cancers and is comprised mainly of adenocarcinomas and squamous cell carcinomas (SCCs). The sequential pathogenesis of lung adenocarcinomas and SCCs occurs through dissimilar phases as the former tumors typically arise in the lung periphery whereas the latter normally arise near the central airway. We assessed the expression of SOX2, an embryonic stem cell transcriptional factor that also plays important roles in the proliferation of basal tracheal cells and whose expression is restricted to the main and central airways and bronchioles of the developing and adult mouse lung, in NSCLC by various methodologies. Here, we found that SOX2 mRNA levels, from various published datasets, were significantly elevated in lung SCCs compared to adenocarcinomas (all p&lt;0.001). Moreover, a previously characterized OCT4/SOX2/NANOG signature effectively separated lung SCCs from adenocarcinomas following integration with two independent publicly available gene expression microarray datasets and which correlated with increased SOX2 mRNA in SCCs. Immunohistochemical analysis of various histological lung tissue specimens demonstrated marked nuclear SOX2 protein expression in all normal bronchial epithelia, alveolar bronchiolization structures and premalignant lesions in SCC development (hyperplasia, dysplasia and carcinoma in situ) and absence of expression in all normal alveoli and atypical adenomatous hyperplasias. Moreover, SOX2 protein expression was greatly higher in lung SCCs compared to adenocarcinomas following analyses in two independent large tissue microarray (TMA) sets (TMA set I, n=287; TMA set II, n=511 both p&lt;0.001). Furthermore, amplification of SOX2 DNA was detected in 20% of lung SCCs tested (n=40) and in none of the adenocarcinomas (n=17). Our findings highlight a cell-lineage gene expression pattern for the stem cell transcriptional factor SOX2 in the pathogenesis of lung SCCs and raise the intriguing possibility of the growth addiction of lung SCCs specifically to SOX2-dependent pathways. Supported in part by grants from the Department of Defense (W81XWH-04-1-0142 and W81XWH-07-1-03060), and the Specialized Program of Research Excellence in Lung Cancer grant P50CA70907.
Running title: SOX2 abnormalities in NSCLC
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 5166.