bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role for Amplification and Expression of Glypican-5 in Rhabdomyosarcoma
Authors: Williamson Daniel , Selfe Joanna , Gordon Tony , Lu Yong-Jie , Pritchard-Jones Kathy , Murai Kasumi , Jones Phil , Workman Paul , Shipley Janet 
Published: January 2007

Abstract
Overexpression of genes, through genomic amplification and other mechanisms, can critically affect the behavior of tumor cells. Genomic amplification of the 13q31-32 region is reported in many tumors, including rhabdomyosarcomas that are primarily pediatric sarcomas resembling developing skeletal muscle. The minimum overlapping region of amplification at 13q31-32 in rhabdomyosarcomas was defined as containing two genes: Glypican-5 (GPC5) encoding a cell surface proteoglycan and C13orf25 encompassing the miR-17-92 micro-RNA cluster. Genomic copy number and gene expression analyses of rhabdomyosarcomas indicated that GPC5 was the only gene consistently expressed and up-regulated in all cases with amplification. Constitutive overexpression and knockdown of GPC5 expression in rhabdomyosarcoma cell lines increased and decreased cell proliferation, respectively. A correlation between expression levels of nascent pre-rRNA and GPC5 (P = 0.001), but not a C13orf25 transcript containing miR-17-92, in primary samples supports an association of GPC5 with proliferative capacity in vivo. We show that GPC5 increases proliferation through potentiating the action of the growth factors fibroblast growth factor 2 (FGF2), hepatocyte growth factor (HGF), and Wnt1A. GPC5 enhanced the intracellular signaling of FGF2 and HGF and altered the cellular distribution of FGF2. The mesoderm-inducing effect of FGF2 and FGF4 in Xenopus blastocysts was also enhanced. Our data are consistent with a role of GPC5, in the context of sarcomagenesis, in enhancing FGF signaling that leads to mesodermal cell proliferation without induction of myogenic differentiation. Furthermore, the properties of GPC5 make it an attractive target for therapeutic intervention in rhabdomyosarcomas and other tumors that amplify and/or overexpress the gene. [Cancer Res 2007;67(1):57–65]
Down-regulation of Type I Insulin-like Growth Factor Receptor Increases Sensitivity of Breast Cancer Cells to Insulin
Authors: Zhang Hua , Pelzer Alissa M. , Kiang David T. , Yee Douglas 
Published: January 2007

Abstract
The type I insulin-like growth factor receptor (IGF1R) and insulin receptor (IR) are structurally and functionally related heterotetrameric receptors. Activation of IGF1R has been shown to regulate breast cancer cell biology, and it has become an attractive therapeutic target. Most strategies have focused on targeting IGF1R alone without affecting IR levels given the known physiologic functions of IR. Human breast cancer cell lines and tissues revealed mRNA expression of both IGF1R and IR. Because αβ chains of IGF1R and IR form hybrid receptors, we hypothesized that agents solely targeting IGF1R may affect tumor biology mediated by IGF1R/IR hybrids and IR. We used small interfering RNA (siRNA) technology to specifically down-regulate IGF1R by 60% to 80% in the MDA-435/LCC6 cell line, which was sufficient to diminish activation of IGF1R by IGF-I. IGF1R down-regulation by siRNA did not affect IR levels but, interestingly, sensitized cells to insulin activation of downstream signaling pathways in several breast cancer cell lines. IGF1R siRNA treatment diminished hybrid receptor formation, suggesting that specific down-regulation of IGF1R resulted in enhanced holo-IR formation. In addition, IGF1R down-regulation increased insulin binding consistent with the formation of an increased number of holo-IR on the cell surface. Accordingly, insulin-stimulated glucose uptake was enhanced on IGF1R down-regulation. In conclusion, our data suggest that specific siRNA targeting of IGF1R alone in breast cancer increases insulin sensitivity. Because IR also activates signaling pathways similar to IGF1R in breast cancer cells, agents targeting both receptors may be necessary to disrupt the malignant phenotype regulated by this growth factor system. [Cancer Res 2007;67(1):391–7]
Adamantyl-Substituted Retinoid-Related Molecules Bind Small Heterodimer Partner and Modulate the Sin3A Repressor
Authors: Farhana Lulu , Dawson Marcia I. , Leid Mark , Wang Li , Moore David D. , Liu Gang , Xia Zeben , Fontana Joseph A. 
Published: January 2007

Abstract
6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (CD437/AHPN) and 4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC/MM002) are inducers of apoptosis of malignant cells both in vitro and in vivo. Numerous mechanisms have been proposed for how these compounds exert this effect. This report shows that AHPN/3-Cl-AHPC binds specifically to the orphan nuclear receptor small heterodimer partner (SHP; NR0B2), and this binding promotes interaction of the receptor with a corepressor complex that minimally contains Sin3A, N-CoR, histone deacetylase 4, and HSP90. Formation of the SHP-Sin3A complex is essential for the ability of AHPN and 3-Cl-AHPC to induce apoptosis, as both knockout SHP and knockdown of Sin3A compromise the proapoptotic activity of these compounds but not other apoptosis inducers. These results suggest that AHPN/3-Cl-AHPC and their analogues are SHP ligands and their induction of apoptosis is mediated by their binding to the SHP receptor. [Cancer Res 2007;67(1):318–25]
Extracellular Matrix Metalloproteinase Inducer Up-regulates the Urokinase-Type Plasminogen Activator System Promoting Tumor Cell Invasion
Authors: Quemener Cathy , Gabison Eric E. , Naïmi Benyoussef , Lescaille Géraldine , Bougatef Faten , Podgorniak Marie Pierre , Labarchède Géraldine , Lebbé Celeste , Calvo Fabien , Menashi Suzanne , Mourah Samia 
Published: January 2007

Abstract
Extracellular matrix metalloproteinase inducer (EMMPRIN) is a membrane glycoprotein overexpressed in many cancer tissues and is known for its ability to stimulate MMP expression. In this work, we show that EMMPRIN is also a regulator of the urokinase-type plasminogen activation (uPA) system of serine proteases, thus participating to the increase of the overall proteolytic function of the cancer cells. Enhanced EMMPRIN expression in a tumorigenic breast epithelial cell line NS2T2A increased the levels of uPA, uPA receptor, and the uPA inhibitor plasminogen activator inhibitor-1 (PAI-1), as measured by quantitative reverse transcription-PCR, Western blot, and plasminogen-casein zymography. This response was down-regulated by either EMMPRIN small interfering RNA or a blocking antibody to EMMPRIN. EMMPRIN-containing purified membrane fraction from Chinese hamster ovary cells when added exogenously to NS2T2A cells induced a similar activation of the uPA/PAI-1 system. Additionally, overexpression of EMMPRIN in NS2T2A cells increased uPA levels in cocultured endothelial cells, showing a paracrine regulation loop involving a tumor-stroma interaction. EMMPRIN-expressing cells also exhibited enhanced invasive potential in vitro, and the use of amiloride (uPA inhibitor) and marimastat (MMP inhibitor) showed that the two proteolytic systems reduced alone and in combination the invasive potential mediated through EMMPRIN. These data show a novel regulatory pathway for uPA activity and suggest that EMMPRIN is involved in uPA dysregulation observed in cancer. [Cancer Res 2007;67(1):9–15]
ADAM10 Inhibition of Human CD30 Shedding Increases Specificity of Targeted ImmunotherapyIn vitro
Authors: Eichenauer Dennis A. , Simhadri Vijaya Lakshmi , von Strandmann Elke Pogge , Ludwig Andreas , Matthews Vance , Reiners Katrin S. , von Tresckow Bastian , Saftig Paul , Rose-John Stefan , Engert Andreas , Hansen Hinrich P. 
Published: January 2007

AbstractCD30 is a transmembrane protein selectively overexpressed on many human lymphoma cells and therefore an interesting target for antibody-based immunotherapy. However, binding of therapeutic antibodies stimulates a juxtamembrane cleavage of CD30 leading to a loss of target antigen and an enhanced release of the soluble ectodomain of CD30 (sCD30). Here, we show that sCD30 binds to CD30 ligand (CD153)–expressing non-target cells. Because antibodies bind to sCD30, this results in unwanted antibody binding to these cells via sCD30 bridging. To overcome shedding-dependent damage of normal cells in CD30-specific immunotherapy, we analyzed the mechanism involved in the release. Shedding of CD30 can be enhanced by protein kinase C (PKC) activation, implicating the disintegrin metalloproteinase ADAM17 but not free cytoplasmic calcium. However, antibody-induced CD30 shedding is calcium dependent and PKC independent. This shedding involved the related metalloproteinase ADAM10 as shown by the use of the preferential ADAM10 inhibitor GI254023X and by an ADAM10-deficient cell line generated from embryonically lethal ADAM10−/− mouse. In coculture experiments, the antibody-induced transfer of sCD30 from the human Hodgkin's lymphoma cell line L540 to the CD30-negative but CD153-expressing human mast cell line HMC-1 was inhibited by GI254023X. These findings suggest that selective metalloproteinase inhibitors blocking antibody-induced shedding of target antigens could be of therapeutic value to increase the specificity and reduce side effects of immunotherapy with monoclonal antibodies. [Cancer Res 2007;67(1):332–8]
Imaging Tumors with an Albumin-Binding Fab, a Novel Tumor-Targeting Agent
Authors: Dennis Mark S. , Jin Hongkui , Dugger Debra , Yang Renhui , McFarland Leanne , Ogasawara Annie , Williams Simon , Cole Mary J. , Ross Sarajane , Schwall Ralph 
Published: January 2007

Abstract
Association with albumin as a means to improve biodistribution and tumor deposition of a Fab was investigated using AB.Fab4D5, a bifunctional molecule derived from trastuzumab (HERCEPTIN) capable of binding albumin and tumor antigen HER2 (erbB2) simultaneously. AB.Fab4D5 was compared with trastuzumab and a trastuzumab-derived Fab (Fab4D5) for the ability to target tumors overexpressing HER2 in mouse mammary tumor virus/HER2 allograft models. Biodistribution was monitored using intravital microscopy, histology, and integrated single-photon emission computed tomography/computed tomography analysis. Fab4D5 tumor deposition was characterized by rapid but transient appearance in tumor at 2 h with little retention, followed by rapid accumulation in kidney by 6 h. Trastuzumab was slow to accumulate in tumors and slow to clear from normal tissues, although significant tumor deposition was achieved by 24 h. In contrast, AB.Fab4D5 was observed at 2 h in tumor and its presence was sustained beyond 24 h similar to trastuzumab. Intravital microscopy revealed that at peak tumor accumulation, tumor cell staining by AB.Fab4D5 was more uniform than for Fab4D5 or trastuzumab. Similar tumor deposition was achieved for both AB.Fab4D5 and trastuzumab at 48 h (35.9 ± 1.8% and 38.2 ± 3.1% injected dose/g); however, AB.Fab4D5 targeted tumors more rapidly and quickly cleared from blood, leading to a lower overall normal tissue exposure. Importantly, unlike Fab4D5, AB.Fab4D5 did not accumulate in kidney, suggesting that association with albumin leads to an altered route of clearance and metabolism. Rapid targeting, excellent tumor deposition and retention, coupled with high tumor to blood ratios may make AB.Fab an exceptional molecule for imaging and cancer therapy. [Cancer Res 2007;67(1):254–61]
Transcriptional Cooperation between the Transforming Growth Factor-β and Wnt Pathways in Mammary and Intestinal Tumorigenesis
Authors: Labbé Etienne , Lock Lisa , Letamendia Ainhoa , Gorska Agnieszka E. , Gryfe Robert , Gallinger Steven , Moses Harold L. , Attisano Liliana 
Published: January 2007

Abstract
Transforming growth factor-β (TGF-β) and Wnt ligands function in numerous developmental processes, and alterations of both signaling pathways are associated with common pathologic conditions, including cancer. To obtain insight into the extent of interdependence of the two signaling cascades in regulating biological responses, we used an oligonucleotide microarray approach to identify Wnt and TGF-β target genes using normal murine mammary gland epithelial cells as a model. Combination treatment of TGF-β and Wnt revealed a novel transcriptional program that could not have been predicted from single ligand treatments and included a cohort of genes that were cooperatively induced by both pathways. These included both novel and known components or modulators of TGF-β and Wnt pathways, suggesting that mutual feedback is a feature of the coordinated activities of the ligands. The majority of the cooperative targets display increased expression in tumors derived from either Min (many intestinal neoplasia) or mouse mammary tumor virus (MMTV)–Wnt1 mice, two models of Wnt-induced tumors, with nine of these genes (Ankrd1, Ccnd1, Ctgf, Gpc1, Hs6st2, IL11, Inhba, Mmp14, and Robo1) showing increases in both. Reduction of TGF-β signaling by expression of a dominant-negative TGF-β type II receptor in bigenic MMTV-Wnt1/DNIIR mice increased mammary tumor latency and was correlated with a decrease in expression of Gpc1, Inhba, and Robo1, three of the TGF-β/Wnt cooperative targets. Our results indicate that the TGF-β and Wnt/β-catenin pathways are firmly intertwined and generate a unique gene expression pattern that can contribute to tumor progression. [Cancer Res 2007;67(1):75–84]
Gene Expression Profile of Metastatic Human Pancreatic Cancer Cells Depends on the Organ Microenvironment
Authors: Nakamura Toru , Fidler Isaiah J. , Coombes Kevin R. 
Published: January 2007

AbstractTo determine the influence of the microenvironment on changes in gene expression, we did microarray analysis on three variant lines of a human pancreatic cancer (FG, L3.3, and L3.6pl) with different metastatic potentials. The variant lines were grown in tissue culture in the subcutis (ectopic) or pancreas (orthotopic) of nude mice. Compared with tissue culture, the number of genes of which the expression was affected by the microenvironment was up-regulated in tumors growing in the subcutis and pancreas. In addition, highly metastatic L3.6pl cells growing in the pancreas expressed significantly higher levels of 226 genes than did the L3.3 or FG variant cells. Growth of the variant lines in the subcutis did not yield similar results, indicating that the orthotopic microenvironment significantly influences gene expression in pancreatic cancer cells. These data suggest that investigations of the functional consequence of gene expression require accounting for experimental growth conditions. [Cancer Res 2007;67(1):139–48]
Tumor-Induced Oxidative Stress Perturbs Nuclear Factor-κB Activity-Augmenting Tumor Necrosis Factor-α–Mediated T-Cell Death: Protection by Curcumin
Authors: Bhattacharyya Sankar , Mandal Debaprasad , Sen Gouri Sankar , Pal Suman , Banerjee Shuvomoy , Lahiry Lakshmishri , Finke James H. , Tannenbaum Charles S. , Das Tanya , Sa Gaurisankar 
Published: January 2007

AbstractCancer patients often exhibit loss of proper cell-mediated immunity and reduced effector T-cell population in the circulation. Thymus is a major site of T-cell maturation, and tumors induce thymic atrophy to evade cellular immune response. Here, we report severe thymic hypocellularity along with decreased thymic integrity in tumor bearer. In an effort to delineate the mechanisms behind such thymic atrophy, we observed that tumor-induced oxidative stress played a critical role, as it perturbed nuclear factor-κB (NF-κB) activity. Tumor-induced oxidative stress increased cytosolic IκBα retention and inhibited NF-κB nuclear translocation in thymic T cells. These NF-κB–perturbed cells became vulnerable to tumor-secreted tumor necrosis factor (TNF)-α (TNF-α)–mediated apoptosis through the activation of TNF receptor-associated protein death domain–associated Fas-associated protein death domain and caspase-8. Interestingly, TNF-α–depleted tumor supernatants, either by antibody neutralization or by TNF-α-small interfering RNA transfection of tumor cells, were unable to kill T cell effectively. When T cells were overexpressed with NF-κB, the cells became resistant to tumor-induced apoptosis. In contrast, when degradation-defective IκBα (IκBα super-repressor) was introduced into T cells, the cells became more vulnerable, indicating that inhibition of NF-κB is the reason behind such tumor/TNF-α–mediated apoptosis. Curcumin could prevent tumor-induced thymic atrophy by restoring the activity of NF-κB. Further investigations suggest that neutralization of tumor-induced oxidative stress and restoration of NF-κB activity along with the reeducation of the TNF-α signaling pathway can be the mechanism behind curcumin-mediated thymic protection. Thus, our results suggest that unlike many other anticancer agents, curcumin is not only devoid of immunosuppressive effects but also acts as immunorestorer in tumor-bearing host. [Cancer Res 2007;67(1):362–70]
Identification of a Novel Tumor Suppressor Gene p34 on Human Chromosome 6q25.1
Authors: Wang Min , Vikis Haris G. , Wang Yian , Jia Dongmei , Wang Daolong , Bierut Laura J. , Bailey-Wilson Joan E. , Amos Christopher I. , Pinney Susan M. , Petersen Gloria M. , de Andrade Mariza , Yang Ping , Wiest Jonathan S. , Fain Pamela R. , Schwartz Ann G. , Gazdar Adi , Minna John , Gaba Colette , Rothschild Henry , Mandal Diptasri , Kupert Elena , Seminara Daniela , Liu Yan , Viswanathan Avinash , Govindan Ramaswamy , Anderson Marshall W. , You Ming 
Published: January 2007

Abstract
In this study, we observed loss of heterozygosity (LOH) in human chromosomal fragment 6q25.1 in sporadic lung cancer patients. LOH was observed in 65% of the 26 lung tumors examined and was narrowed down to a 2.2-Mb region. Single-nucleotide polymorphism (SNP) analysis of genes located within this region identified a candidate gene, termed p34. This gene, also designated as ZC3H12D, C6orf95, FLJ46041, or dJ281H8.1, carries an A/G nonsynonymous SNP at codon 106, which alters the amino acid from lysine to arginine. Nearly 73% of heterozygous lung cancer tissues with LOH and the A/G SNP also exhibited loss of the A allele. In vitro clonogenic and in vivo nude mouse studies showed that overexpression of the A allele exerts tumor suppressor function compared with the G allele. p34 is located within a recently mapped human lung cancer susceptibility locus, and association of the p34 A/G SNP was tested among these families. No significant association between the less frequent G allele and lung cancer susceptibility was found. Our results suggest that p34 may be a novel tumor suppressor gene involved in sporadic lung cancer but it seems not to be the candidate familial lung cancer susceptibility gene linked to chromosomal region 6q23-25. [Cancer Res 2007;67(1):93–9]
Anti-HER2 Cationic Immunoemulsion as a Potential Targeted Drug Delivery System for the Treatment of Prostate Cancer
Authors: Goldstein Danny , Gofrit Ofer , Nyska Abraham , Benita Simon 
Published: January 2007

AbstractPresent management of metastatic prostate cancer, which includes hormonal therapy, chemotherapy, and radiotherapy, are frequently palliative. Taxanes, and specifically docetaxel, are being extensively investigated to improve the survival of metastatic prostate cancer patients. Although paclitaxel exhibits a wide spectrum of antitumor activity, its therapeutic application is limited, in part, due to its low water solubility that necessitates the use of Cremophor EL, which is known to induce hypersensitivity reactions. Therefore, the objective of this present study was to assess the efficiency of paclitaxel palmitate–loaded anti-HER2 immunoemulsions, a targeted drug delivery system based on cationic emulsion covalently linked to anti-HER2 monoclonal antibody (Herceptin), in a well-established in vivo pharmacologic model of metastatic prostate cancer that overexpresses the HER2 receptor. It was clearly noted that the cationic emulsion and immunoemulsion did not activate the complement compared with the commercial and paclitaxel palmitate hydroalcoholic formulations. In addition, 10 mg/kg of paclitaxel palmitate–loaded immunoemulsion once weekly over 3 weeks inhibits the tumor growth in severe combined immunodeficient mice much more than the cationic emulsion (P &lt; 0.05) and the paclitaxel palmitate formulation (P &lt; 0.01). The histopathologic analysis suggested a therapeutic improvement trend in favor of the immunoemulsion. However, there was no significant difference in antimetastatic activity between the emulsion and the immunoemulsion despite the affinity of the immunoemulsion towards the HER2 receptor. Although the tumor growth was not fully inhibited, the actual results are encouraging and may lead to an improved therapeutic strategy of metastatic prostate cancer treatment. [Cancer Res 2007;67(1):269–75]
DNA Replication Licensing Factor Minichromosome Maintenance Deficient 5 Rescues p53-Mediated Growth Arrest
Authors: Agarwal Mukesh K. , Amin A.R.M. R. , Agarwal Munna L. 
Published: January 2007

Abstract
Inactivation of p53 signaling by mutation of p53 itself or abrogation of its normal function by other transfactors, such as MDM2, is a key event in the development of most human cancers. To identify novel regulators of p53, we have used a phenotype-based selection in which a total cDNA library in a retroviral vector has been introduced into TR9-7ER cells, which arrest when p53 is expressed from a tetracycline-regulated promoter. We have isolated several clones derived from cells that are not growth-arrested when p53 is overexpressed. In one clone, the levels of p53, p21, and MDM2 are comparable with those in TR9-7ER cells and, therefore, the abrogation of growth arrest by an exogenous cDNA is likely to be distal to p21. Using reverse transcription-PCR, we were able to isolate a cDNA of ∼2.2 kb, which was found to have 99% identity to the nucleotides between about 80 and 2,288 of the open reading frame of a gene encoding DNA replication licensing factor. It encodes complete peptide of 734 residues of this protein also called minichromosome maintenance deficient 5 (MCM5) or cell division cycle 46 (Saccharomyces cerevisiae). Northern and Western blot analyses revealed that the expression of MCM5 and its transcriptional regulator, E2F1, is negatively regulated by p53. When MCM5 cDNA was reintroduced into fresh TR9-7ER cells, numerous colonies that grow in the absence of tetracycline were formed. This novel observation establishes a role for MCM5 in negating the growth arrest function of p53. [Cancer Res 2007;67(1):116–21]