bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1577: Contributions of KIT and ABL to the therapeutic responses of GIST and CML cells to imatinib mesylate
Authors: Brown Matthew F. , Duensing Stefan M. , Duensing Anette U. 
Published: February 2011

Abstract
Most GISTs are caused by activating mutations of the KIT receptor tyrosine kinase and can effectively be treated with the small molecule kinase inhibitor imatinib mesylate (IM). IM is a potent inhibitor of KIT as well as ABL, a kinase that is constitutively activated through a chromosomal translocation (BCR-ABL) in chronic myeloid leukemia (CML). Since both KIT and ABL are expressed in GIST as well as CML cells, the present study was designed to determine the individual contributions of KIT and ABL inhibition, respectively, to the therapeutic responses in both malignancies. As expected, siRNA-mediated knock-down of KIT in the human GIST cell line GIST882 led to a significant increase of apoptosis and reduced cellular proliferation as measured by TUNEL and luminescence-based assays. Depletion of ABL1 in human K562 CML cells led to similar results. Immunoblotting for PARP cleavage as well as p27(Kip1) and cyclin A corroborated these findings. Reduction of ABL1 protein levels in GIST cells, however, was only associated with a minimal increase of apoptosis. Nevertheless, it resulted in a significantly reduced cellular proliferation when compared to controls and had approximately 50% of the anti-proliferative effect detected after knock-down of KIT in GIST cells. Combined knock-down of ABL1 and KIT in GIST did not show an additive effect. In contrast, siRNA-mediated knock-down of KIT in K562 cells did not have any significant effects on either cell survival or proliferative activity. Combined depletion of ABL1 and KIT in CML cells had a similar effect as knock-down of ABL1 alone. Immunoblotting analysis confirmed respective siRNA knockdowns, inhibition of downstream pathways and cellular proliferation as well as induction of apoptosis. In conclusion, ABL inhibition is unlikely to contribute to the induction of apoptosis after IM-treatment of GIST cells, however, it may cooperate with KIT inhibition to inhibit GIST cell proliferation. In contrast, inhibition of KIT does not seem to play a role in the therapeutic effect of IM in CML cells. Our results have implications for future strategies to improve the therapeutic effectiveness of targeted therapies in GISTs.
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 1577.
Abstract 1581: IL-13 mediates signal transduction through IL-13 receptor α2 in pancreatic ductal adenocarcinoma: role of IL-13 pseudomonas exotoxin in pancreatic cancer therapy
Authors: Shimamura Takeshi , Fujisawa Toshio , Husain Syed R. , Joshi Bharat H. , Watanabe Seitaro , Kato Shingo , Kobayashi Noritoshi , Kubota Kensuke , Nakajima Atsushi , Puri Raj K. 
Published: February 2011

Abstract
Purpose: Interleukin-13 receptor alpha 2 (IL-13Rα2) is a tumor antigen, which is overexpressed in certain human tumors. However, its expression and significance in pancreatic cancer and whether IL-13 can signal through IL-13Rα2 in cancer is not known. In addition, it is not known whether IL-13-PE can target pancreatic cancer for therapy.
Experimental Design: The expression of IL-13Rα2 was assessed in pancreatic cancer samples by IHC; and in cell lines by flow cytometry and RT-PCR. The role of IL-13Rα2 was examined by IL-13 induced signaling in pancreatic cancer cell lines. IL-13Rα2 positive tumors were targeted by IL-13PE cytotoxin in vitro and in vivo in orthotopic murine model of human pancreatic cancer.
Results: Seventy one percent pancreatic tumor samples overexpressed moderate- to high-density IL-13Rα2 compared to normal pancreatic samples. IL-13 induced TGF-β1 promoter activity in IL-13Rα2 positive tumor cells and in cells engineered to express IL-13Rα2 but not in IL-13Rα2-negative or RNAi knockdown cells. c-Jun and c-Fos of AP-1 family nuclear factors were activated by IL-13 only in IL-13Rα2-positive cells. In orthotopic mouse model, IL13-PE significantly decreased tumor growth when assessed by whole body imaging. In addition, IL13-PE prolonged the mean survival time of treated animals. Similar results were observed in mice xenografted orthotopically with a surgically resected human pancreatic tumor sample.
Conclusions: These results indicate that IL-13Rα2 is a functional receptor as IL-13 mediates signaling in human pancreatic cancer cell lines. IL-13 causes TGF-β activation via AP-1 pathway, which may cause tumor induced immunosuppression in the host. In addition, IL13-PE cytotoxin may be an effective therapeutic agent for the treatment of pancreatic cancer.
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 1581.
Abstract 1587: Targeted deletion of Fra-1 blocks oncogenic K-ras induced lung tumor development and progression in mice
Authors: Vaz Michelle , Reddy Narsa M. , Wagner Erwin F. , Reddy Sekhar P. 
Published: February 2011

Abstract
Background: Fra-1 (Fosl1) is a dimeric partner of AP-1 transcription factor and regulates gene expression in a context-dependent (cell-type and stimulus-specific) manner through the TPA response element (AP-1 site). We have previously shown that Fra-1 is strongly activated in lung epithelial cells by cigarette smoke, a major determinant of lung cancer, as well as tumor promoting mitogenic and pro-inflammatory stimuli. Ectopic expression of Fra-1 promotes human lung cancer cell progression in vitro, and tumor development in nude mice. We hypothesized that Fra-1, an effector of ERK signaling, is required for oncogenic K-ras promoted lung tumor development in vivo. Methods: To test our hypothesis and to better understand the role of Fra-1 in lung tumor development and progression in vivo, we have generated transgenic mice bearing floxed allele Fra-1 (Fra-1FF) and LSL K-rasG12D by cross-breeding Fra1F/F and LSL K-rasG12D mice (NCI), which carry a latent point-mutant allele of K-ras (K-rasG12D). Fra1wt/wt +LSL-K-rasG12D mice (abbreviated as Kras+/−) and Fra1F/F+ LSL-K-rasG12D mice (Fra1FF- K-rasG12D) were instilled intratracheally with adenovirus Cre (2.5 ×107 pfu) and then were allowed to recover for an additional 13 weeks. Mice were sacrificed, lungs were fixed, and lung tumor induction was analyzed by histopathology. Results: As anticipated, activation of K-ras oncogene by Ade-Cre instillation induced lung tumor development in Kras+/− mice bearing Fra-1 wild type alleles. Hyperplastic lesions with papillary structures and adenomas were clearly visible in these mice. Strikingly, the lung tumor formation in Fra-1 floxed mice bearing LSL-K-rasG12D allele (Fra1F/F+ LSL-K-rasG12D mice) infected with Adeno-cre virus was markedly reduced. In all animals, with exception of few hyperplastic lesions, no adenomas were detected in mice lacking Fra-1. Conclusions: The present data suggest that Fra-1 is critical for oncogenic K-ras promoted lung tumor development in vivo.
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 1587.
Abstract 1589: Low shear stress induces the novel tumor endothelial marker CLEC14A that mediates cell migration and vascular development
Authors: Mura Manuela , Zhuang Xiadong , Vorschmitt Henrik , Swain Rajeeb K. , Durant Sarah , Herbert John M. , Sheldon Helen , Andre Maud , Sanderson Sharon , Reynolds Gary , Glen Katie , Luu Nguyet-Thin , McGettrick Helen , Antczak Phillip , Falciani Francesco , Nash Gerard , Nagy Zsuzsanna , Bicknell Roy 
Published: February 2011

Abstract
Experimental evidence using animal models has proven the efficacy of targeting a tumor endothelial marker (TEM) in eradicating large solid tumours. It follows that a well characterised tumor endothelial marker would offer much promise as an anti-cancer target. Despite many efforts by numerous groups, a well defined tumor endothelial marker in man has remained elusive. CLEC14A is a novel endothelial specific C-type lectin that is a member of the endosialin/TEM1 and thrombomodulin family of lectins. Protein sequence alignment of CLEC14A shows conservation from fish to man and endothelial specificity of expression is seen in the embryonic zebrafish. Detailed analysis of CLEC14A expression using human tissue arrays showed that CLEC14A is absent in human adult tissue but highly expressed in endothelium across a wide range of tumour tissues. CLEC14A is a superior tumor endothelial marker to Robo4 in terms of specificity and level of expression on the cell surface. CLEC14A is only expressed by endothelium in the absence of shear stress and this could explain its tumor specific expression due to poor blood flow in ill-formed tumor vessels. Functional studies have shown that CLEC14A is present on filopodia and mediates endothelial cell migration and tube formation. Anti-sera to CLEC14A similarly inhibited these processes suggesting that anti-CLEC14A monoclonal antibodies would have anti-angiogenic activity. The expression profile of CLEC14A, its cell surface localisation and inhibition of pro-angiogenic activities by anti-sera make CLEC14A a uniquely interesting target.
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 1589.
Abstract 1594: Targeting UBP43 for repression destabilizes PML/RARα and inhibits acute promyelocytic leukemia growth
Authors: Guo Yongli , Dolinko Andrey , Chinyengetere Fadzai , Bomberger Jennifer , Gallagher Robert , Ma Tian , Galimberti Fabrizio , Liu Xi , Sekula David , Busch Alexander , Freemantle Sarah , Dmitrovsky Ethan 
Published: February 2011

Abstract
All-trans-retinoic acid (RA) successfully treats acute promyelocytic leukemia (APL) at least partly through triggering degradation of the PML/RARα translocation product. Prior work revealed that the E1-like ubiquitin-activating enzyme (UBE1L) associates with the interferon-stimulated gene 15 (ISG15) to repress PML/RARα protein expression. The ubiquitin protease 43 (UBP43) removes ISG15 from conjugated proteins. We derived two different anti-human UBP43 antisera to examine UBP43 protein expression. This study explored whether RA regulates UBP43 expression and if UBP43 affects PML/RARα protein stability as well as growth or apoptosis of APL cells. Retinoid regulation of the UBE1L-ISG15-UBP43 pathway was studied in cultured NB4 APL cells, transgenic APL mice and leukemic cells harvested from APL patients. Whether the deconjugase UBP43 was a therapeutic target was determined through gain and loss of UBP43 expression experiments. This study extends prior work by reporting that RA-treatment induced UBP43 expression in RA-sensitive, but not in RA-resistant NB4 APL cells. This followed an induction of UBE1L and ISG15 expression in RA-sensitive APL cells. UBP43 functions as a negative feedback loop by reversing ISG15 conjugation of PML/RARα protein. Deregulating this loop by UBP43 knock-down repressed APL cell growth by further destabilizing the PML domain of PML/RARα protein. Notably, this triggered apoptosis in APL cells. In contrast, UBP43 over-expression stabilized PML/RARα protein and promoted APL cell growth by inhibiting apoptosis. RA-treatment of a murine transgenic APL model and of de novo cultures of APL cells from patients increased UBE1L, ISG15 and UBP43 expression. Thus, this study found that the deconjugase UBP43 was retinoid regulated in NB4 APL cells as well as in leukemic cells isolated directly from APL patients and in a mouse model for APL. Oncogenic effects of PML/RARα were reversed by UBP43 knock-down, which destabilized PML/RARα protein and triggered apoptosis in APL cells. Taken together, these findings establish UBP43 as a novel molecular pharmacologic target for APL.
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 1594.
Abstract 1598: Vasculogenic properties of triple negative breast carcinoma cells: possible implication for new molecular target
Authors: Tagliabue Elda , Plantamura Ilaria , Dugnani Erica , Ghirelli Cristina , Tortoreto Monica , Barajon Isabella , Arnaboldi Francesca , Agresti Roberto , Carcangiu Maria Luisa , Balsari Andrea , Iorio Marilena V. 
Published: February 2011

Abstract
Triple negative (TN) breast cancers account for about 15-20% of breast cancers and are associated with aggressiveness, poor prognosis and shorter survival.
Because of the lack of specific therapy guidelines for this subgroup there is an urgent need to define specific markers for therapeutic targeting in these tumors.
We observed that TN breast cancer cells lines are able to perform “Vasculogenic Mimicry” (VM) in vitro. In fact, all four TN cell lines evaluated (MDA-MB-231, MDA-MB-157, MDA-MB-468 and HCC1937) were able to form vascular channels when seeded on the murine tumor-derived basement membrane (Matrigel), whereas luminal (MCF7 and ZR-75-1) and HER2-positive (MDA-MB-361 and SKBr3) breast carcinoma cell lines did not exhibit vascular structures. Then, we evaluated the VM in xenograft tumors derived from MDA-MB-231, MCF7 and MDA-MB-361 using transmission electron microscopy (TEM). In MDA-MB-231 xenografts it has been revealed channel-like structures formed by tumor cells encompassing erytrocytes, whereas in MCF7 and MDA-MB-361 xenografts the endothelial lining delimiting blood vessels was clearly visible. Notably, blood vessels surrounded by tumor cells were also identified in human TN specimens processed for TEM, and these structures were significantly more frequent in TN compared to non-TN tumors. 60% reduction in TN vascular channel formation in vitro by an anti-bFGF monoclonal antibody together with no effect using anti-VEGF antibody indicated that TN breast carcinoma cells can generate vascular channels through bFGF-mediated pathway. Silencing different receptors involved in bFGF signal (i.e. FGFR2 and PDFGR) abrogated VM in TN cells.
Treatment of MDA-MB-231 xenografts with a TKI able to block both FGFR and PDGFR induced tumor regression, versus only slight growth inhibition in tumors derived from MCF7 luminal cell line.
In conclusion our findings point to the possibility that TN tumors generate vascular channels independent of tumor angiogenesis and that targeting this VM capability may represent a valid therapeutic tool. (Partially supported by AIRC).
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 1598.
Abstract 160: CpG island methylator phenotype (CIMP) and P53 methylation patterns in Puerto Rican Hispanic colorectal cancer patients
Authors: Castro Cristina I. , Lacourt Mercedes Y. , Bernabe Raul D. , Cruz-Correa Marcia R. 
Published: February 2011

Abstract
Introduction: The CpG island methylator phenotype (CIMP) with extensive promoter methylation seems to be a distinct epigenotype of colorectal cancer (CRC). CIMP hypermethylation blocks transcriptional activation of several genes associated with tumor suppression, cell cycle, DNA repair, differentiation and apoptosis. Moreover, the promoter CpG island hypermethylation is an important epigenetic change associated with gene silencing, poor prognosis and lower response to chemotherapy in CRC patients. However, specific clinical and pathologic features have not been associated with CIMP status in Puerto Rican Hispanic CRC patients. In this pilot study we determined the CIMP status and the methylation pattern of P53 gene in CRC to establish a possible correlation between aberrant methylation and clinicopathological characteristics.
Methods: We employed methylation-specific PCR (MSP) to evaluate DNA methylation in eight CIMP-specific promoters (CACNA1G, IGF2, NEUROG1, RUNX3, SOCS1, hMLH1, p16) and the methylation pattern of the tumor suppressor gene P53 in twenty-five CRC cases. No CIMP status was defined as no methylated locus, CIMP-Low status as one to three methylated loci, and CIMP-High status as four or more methylated loci. In addition, clinicopathological and methylation patterns were correlated to the CIMP status using Wilcoxon rank tests, Chi square and Fisher exact t-tests, as appropriate using STATA 10.0.
Results: Twenty-five CRC cases (mean age at diagnosis 64.2 ± 11.7 years; 11 males) were evaluated. Tumors were mostly located in the distal colon (76.2%), were moderately differentiated (88.8%), and were Dukes Stage B/C (86.7%). Twelve percent (3/25) of CRC cases were CIMP-High, 80% (20/25) were CIMP-Low and 16% (4/25) were No-CIMP. Aberrant methylation was not detected in the tumor suppressor gene P53. There were no significant statistical associations between CIMP status and age at diagnosis, gender, tumor staging, differentiation, tumor location or survival.
Discussion: This pilot study is the first work to evaluate the CIMP status in Puerto Rican Hispanics CRC patients. CIMP is a distinct epigenotype of colorectal cancer, and may be less frequent among Hispanic patients than previously reported in other racial and/or ethnic groups. Understanding epigenetic silencing by methylation of promoter regions of the CpG island will enable understanding of the colorectal tumorigenesis in Hispanic patients that may help tailor screening and therapeutic strategies for Hispanic patients. Current efforts are underway to characterize a large number of Puerto Rican Hispanics CRC patients.
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 160.
Abstract 1600: Molecular Characterization of PAX5 alterations in Adult BCR-ABL1-Positive Acute Lymphoblastic Leukemia (ALL)
Authors: Lonetti Annalisa , Iacobucci Ilaria , Papayannidis Cristina , Ferrari Anna , Guadagnuolo Viviana , Cilloni Daniela , Messa Francesca , Paolini Stefania , Chiaretti Sabina , Soverini Simona , Saglio Giuseppe , Pane Fabrizio , Baccarani Michele , Foà Robin , Martinelli Giovanni 
Published: February 2011

Abstract
Background: Recently, a genome-wide analysis using single nucleotide polymorphism (SNP) microarrays, identified genetic alterations targeting PAX5 in over 30% of pediatric acute lymphoblastic leukemia cases (Mullighan et al. Nature 2008). However, the occurrence of PAX5 alterations has not been investigated in adult BCR-ABL1-positive ALL.
Aim: To characterize mutations and rearrangements on 9p involving PAX5 in adult BCR-ABL1-positive ALL.
Patients and Methods: Eighty-nine patients with de novo adult BCR-ABL1-positive ALL were enrolled into institutional (n = 15) or Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto Acute Leukemia Working Party (n = 74) clinical trials and after obtaining informed consent their genome was analyzed by SNP arrays (Affymetrix 250K NspI and SNP 6.0), FISH, genomic PCR and resequencing.
Results: SNP array analysis identified a loss of PAX5 in 29 patients (33%). In all cases the deletion was heterozygous. Four patterns of PAX5 deletion were observed: focal deletion involving only the PAX5 gene in one case (3%); deletions involving only a portion of PAX5 and both telomeric and centromeric genes in 11 cases (38%) with a median size of 310 kb (range: 101 kb-16,395 kb); broader deletions involving the entire PAX5 locus and a variable number of flanking genes in 10 patients (34%) with a median size of 1,999 kb (range: 567 kb-1,208 kb); deletion of all chromosome 9 or 9p in 7 patients (24%). These deletions may result in PAX5 haploinsufficiency or altered gene expression. In one patient the deletion of PAX5 involved only a subset of exons (2-6) resulting in an alternative transcript encoding a prematurely truncated protein lacking key PAX5 functional domains.
To investigate the consequences of genomic PAX5 alteration, quantitative PCR (q-PCR) was used: genomic alterations on 9p13.2 lead to a significant down-modulation at the transcript level of Pax5. Normal and deleted PAX5 subgroups were also investigated for point mutations, analyzing each exon by direct sequencing, but we did not found nucleotide substitutions.
Conclusion: PAX5 deletions, but not point mutations, are frequent events in adult BCR-ABL1 positive ALL and are the main mechanism of inactivation of PAX5 in BCR-ABL1 positive ALL.
Supported by: European LeukemiaNet, AIL, AIRC, FIRB 2006, Strategico di Ateneo, GIMEMA Onlus.
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 1600.
Abstract 1606: SON is a novel therapeutic target for pancreatic cancer
Authors: Furukawa Toru , Tanji Etsuko 
Published: February 2011

Abstract
To find novel therapeutic molecular targets for pancreatic cancer, we conducted a systematic knockdown screening of signaling-associated molecules in pancreatic cancer cells. During the course of screening, we found that knockdown of SON, a DNA binding protein of unknown function, by short interference RNA induced a strong inhibitory effect on proliferation of cultured pancreatic cancer cells in vitro. The colony formation assay employing the short hairpin RNA vector targeting SON (shRNA-SON) revealed a strong suppression of survival of cells. Flowcytometry analysis uncovered that the knockdown of SON induced G2/M arrest and apoptosis. Stable transfectants of cancer cells with shRNA-SON showed marked retardation of tumor formation in xenograft model. Knockdown of SON induced less suppressive effect on HPDE, the immortalized normal pancreatic duct epithelial cell, which indicated that the suppressive effect on proliferation was specific for cancer cells. We established 293-cell clones stably expressing EGFP-SON and found that SON was confined in speckles in intercalated nuclei and released in cytoplasm during mitosis. These results indicated that SON was a novel therapeutic target for pancreatic cancer.
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 1606.