bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3104: PAX3-FOXO1 increases fibroblast reprogramming efficiency and drives self-renewal in alveolar rhabdomyosarcoma
Authors: Schafer Beat W. , Casanova Elisa , Satheesha Sampoorna , Müller Melanie , Cinelli Paolo , Cinelli Paolo 
Published: May 2015

Abstract
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Most alveolar (ARMS) cases bear the chimeric transcription factor PAX3/7-FOXO1 and have a worse prognosis compared to the embryonal subtype (ERMS). Previous studies identified a CSC subpopulation in ERMS but no study looked at the translocation positive RMS so far. This knowledge would be important to guide future treatment strategies. Here, we show that no CSC subpopulation can be detected in ARMS by a range of common methods. Furthermore, in vivo limiting dilution experiments confirmed that even 100 ARMS cells are sufficient to generate tumors in NOD/SCID mice. Thus, we hypothesized that ARMS follows a clonal evolution model. In line with this hypothesis, the stem cell factors Nanog, Oct4, and Sox2 were homogeneously expressed in ARMS cell lines and genetic loss- or gain-of-function experiments did not change cellular physiology unlike silencing of PAX3-FOXO1 which caused cell cycle arrest and apoptosis. Based on these observations we then investigated whether PAX3-FOXO1 itself can act as stem cell gene. For this we reprogrammed human fibroblast with the known factors Oct4, Sox2, Klf4, and c-Myc in presence or absence of PAX3-FOXO1. Interestingly, the presence of the fusion protein significantly increased the reprogramming efficiency leading to the generation of almost double the number of colonies of induced pluripotent stem cells (iPSC) than the control cells. PAX3-FOXO1 iPSC expressed the core stem cell genes as well as the PAX3-FOXO1 target gene AP2beta. Strikingly, PAX3-FOXO1 iPSC showed reduced ability to differentiate in vitro into all three germ layers. Ongoing experiments aim at confirming these results also in vivo by generation of teratomas. In conclusion and in contrary to ERMS, fusion protein positive ARMS seem to follow the clonal evolution model in which each clone has tumorigenic potential. Moreover, PAX3-FOXO1 is the critical factor for ARMS self-renewal and a general inhibitor of differentiation.
Citation Format: Beat W. Schafer, Elisa Casanova, Sampoorna Satheesha, Melanie Müller, Paolo Cinelli, Paolo Cinelli. PAX3-FOXO1 increases fibroblast reprogramming efficiency and drives self-renewal in alveolar rhabdomyosarcoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3104. doi:10.1158/1538-7445.AM2014-3104
Abstract 3106: The HoxD locus: Its contribution to the osteogenic phenotype and malignancy of Ewing sarcoma
Authors: Heyking Kristina von , Roth Laura , Ertl Miriam , Burdach Stefan , Richter Günther H. 
Published: May 2015

Abstract
Ewing sarcoma (ES), an osteogenic malignancy that mainly affects children and young adults, is characterized by early metastasis to lung and bone. Microarray analysis revealed genes of the posterior HoxD locus to be clearly over-expressed in primary ES. Especially, genes such as HOXD10, HOXD11 and HOXD13 normally involved in bone formation and ossification pattern of bones are significantly over-expressed in ES. The expression of HOXD10, HOXD11 or HOXD13 seems not to be influenced via ES pathognomonic ews/ets translocations, since RNA interference of EWS-FLI1 or its over-expression in mesenchymal stem cells did not influence posterior HOXD expression. However, RNA knock down of the dickkopf 2 homolog DKK2, a canonical WNT/beta-catenin agonist and critical mediator of osteolytic tumor growth in ES (Hauer et al., 2013) resulted in a significant suppression of HOXD11 and HOXD13 expression. Subsequently, RNA interference of individual HoxD genes demonstrated posterior HOXD genes to suppress neuronal differentiation potential of ES. Furthermore, HOXD10, HOXD11 and HOXD13 were found to be critical for chondrogenic, however not for osteogenic differentiation, but promote the expression of bone-associated genes such as RUNX2. HOXD11 and HOXD13 further promote in vitro proliferation and contact independent growth of ES. Similarly, in vitro invasiveness of ES lines was dependent on HOXD10, HOXD11 as well as HOXD13 and seemed mediated via Matrix Metalloproteinase 1 (MMP1), since down-regulation of individual HoxD genes likewise resulted in a suppression of MMP1 expression. In line with these observations, knock down of HOXD11 or HOXD13 significantly suppressed metastasis in a xeno-transplant model in immune deficient Rag2-/-gammaC-/- mice. These data overall provide evidence that posterior HOXD genes are critical mediators of the differentiation phenotype of ES concurrently promoting their metastasis potential.
Reference:
Hauer K, Julia Calzada-Wack J, Steiger K, Grunewald TG, Baumhoer D, Plehm S, Buch T, Prazeres da Costa O, Esposito I, Burdach S, Richter GHS (2013). DKK2 mediates osteolysis, invasiveness and metastatic spread in Ewing sarcoma. Cancer Res. 73(2): 967-77.
Citation Format: Kristina von Heyking, Laura Roth, Miriam Ertl, Stefan Burdach, Günther H. Richter. The HoxD locus: Its contribution to the osteogenic phenotype and malignancy of Ewing sarcoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3106. doi:10.1158/1538-7445.AM2014-3106
Abstract 3108: Copy number variation analysis in neuroblastoma through next generation sequencing data and SNP-microarray
Authors: Fransson Susanne , Östenssson Malin , Djos Anna , Javanmardi Niloufar , Kogner Per , Martinsson Tommy 
Published: May 2015

Abstract
The childhood cancer neuroblastoma show high degree of clinical heterogeneity ranging from aggressive tumors with fatal outcome to cases of spontaneous regression. Analysis of recurrent chromosomal aberrations such as losses of 1p, 11q, gain of 1q, 17q and/or MYCN amplification are currently used for patient stratification and definition of therapeutic strategy. Different analysis techniques for detection of segmental abnormalities include FISH, CGH-microarrays or multiplex ligation-dependent probe amplification (MLPA). However, as next-generation sequencing (NGS) becomes available for clinical use, this could also be used for assessment of copy number alterations simultaneously with mutational analysis. In this study we compare genomic profiles generated through the bioinformatical tool Control-FREEC on Exome sequencing data with profiles generated from Affymetrix 250K or 50K SNP-microarrays on 20 NB tumors of different stages. Exome sequencing was performed by paired-end sequencing on Illumina instrumentation after DNA enrichment with Agilent SureSelect All Exome. The sequencing were performed at three separate occasions with a median raw coverage of 91X, 127X and 340X respectively. Neuroblastoma tumors were normalized with either corresponding constitutional DNA or normal control DNA for NGS data while microarrays were normalized against healthy control DNA. Gross genomic changes were extracted through visual and/or ratio inspection from 20 neuroblastoma tumors. A total of 128 larger segmental aberrations and 63 numerical aneuploidies were detected trough SNP-microarrays. Discrepancies between the two methods were detected in three cases; one segmental loss detected through microarray could not be confirmed by NGS-profiling, one smaller deletion were only detected through NGS-profiling and in one instance both methods indicated 2p-gain but at different positions. Otherwise the results were concordant. Furthermore, through exome sequencing data were we also able to detect ALK mutations in four patients, ATRX-deletions in two patients and chromothripsis of chromosome 5 in one patient. In conclusion, exome sequencing could be used as a new diagnostic tool for neuroblastoma tumors combining mutational screening with detection of common chromosomal and segmental aneuploidies such as 2p-gain, 17q-gain, 11q-deletion as well as MYCN-amplification and alterations of ALK or ATRX.
Citation Format: Susanne Fransson, Malin Östenssson, Anna Djos, Niloufar Javanmardi, Per Kogner, Tommy Martinsson. Copy number variation analysis in neuroblastoma through next generation sequencing data and SNP-microarray. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3108. doi:10.1158/1538-7445.AM2014-3108
Abstract 311: Autophagic pathways and activity in breast and pancreatic cancer
Authors: Egilsson Mar , Thoroddsen Ulfur , Jonasson Jon Gunnlaugur , Ogmundsdottir Margret Helga , Ögmundsdottir Helga M. 
Published: May 2015

Abstract
Autophagy is induced as a homeostatic process by energy shortage and cellular stress but can also be influenced by drugs. Poor autophagic function contributes to carcinogenesis but autophagy also promotes survival of tumours. We performed immunohistochemistry for LC3, pAMP kinase, p62, p53 on 15 samples from breast cancer and 14 from pancreatic cancer. P53 mutations were detected using CDGE. Autophagy was active (LC3 puncta in ≥ 30% of cells) in 5/15 breast carcinomas and 7/14 pancreatic carcinomas. This was associated with energy shortage (strong pAMP kinase expression) in 4/5 in breast samples and 5/7 in those from pancreas, often clearly colocalized when expression was variable. In contrast, activation of AMP kinase was not associated with autophagy in 4/8 breast and 2/7 pancreatic cancers. In 2/5 breast samples and 2/7 from pancreas impaired autophagic flux was suggested by absent cytoplasmic LC3 staining and strong expression of p62. Nuclear expression of p53 was seen in 10/15 breast cancer samples and of those 3 were mutated, 11/14 pancreas samples showed nuclear staining for p53, none mutated. Three out of 7 non-mutated p53-protein-positive breast cancers had low autophagy. Autophagy was thus often associated with energy shortage, can clearly also be induced by other pathways, but p53 appears not to be involved. Lack of autophagy in the presence of energy shortage suggests defects in induction. There is, therefore, considerable variability in autophagic pathways and activity in cancer and this will have to be taken into account when considering therapeutic intervention in the autophagic process.
Citation Format: Mar Egilsson, Ulfur Thoroddsen, Jon Gunnlaugur Jonasson, Margret Helga Ogmundsdottir, Helga M. Ögmundsdottir. Autophagic pathways and activity in breast and pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 311. doi:10.1158/1538-7445.AM2014-311
Abstract 3111: Identification of genes that frequently exhibit copy number alterations in pediatric ependymomas
Authors: Hamm Christopher A. , Costa Fabricio F. , Bischof Jared M. , Vanin Elio F. , Bonaldo Maria de Fatima , Iannaccone Steve , Rajaram Veena , George David , Tomita Tadanori , Goldman Stewart , Jennings Lawrence J. , Gilbertson Richard J. , Soares Marcelo B. 
Published: May 2015

Abstract
Ependymoma is a common pediatric central nervous system (CNS) tumor that is believed to originate from ependymal cells located in the lining of ventricular surfaces in the brain. Ependymoma presents great challenges in treatment despite the advances in neurosurgical techniques and adjuvant therapy. To uncover protein interaction networks that are consistently compromised in pediatric ependymomas, we conducted a computational analysis of the array CGH data derived from 203 primary ependymomas from the St. Jude Children's Research Hospital cohort, published by Johnson and colleagues [Nature, 466(7306):632-6, 2010]. The analysis (Bischof and Soares, manuscript in preparation) revealed 15 regions of copy number variation (CNVs) that occurred in at least 50% of the tumors. Peak genes from these CNVs were selected for a confirmatory study using DNA digital PCR assays with an independent ependymoma cohort from the Ann & Robert H Lurie Children's Hospital of Chicago. In this study, all ependymomas displayed copy number alterations in at least one of the 10 genes tested by digital PCR. The digital PCR data sheds light into the biology of ependymomas as the 10 candidate genes have a wide range of cellular functions; from neural stem cell development, to tumor suppression, to the pathogenesis of glioblastoma. In conclusion, we have confirmed that the occurrence of DNA copy number variation in these 10 genes prevail in ependymomas. Indeed, all tumors exhibited at least one of these CNVs. These alterations provide insights into the protein interaction networks underlying development of ependymomas while uncovering targets that may be exploited for therapeutic intervention.
Citation Format: Christopher A. Hamm, Fabricio F. Costa, Jared M. Bischof, Elio F. Vanin, Maria de Fatima Bonaldo, Steve Iannaccone, Veena Rajaram, David George, Tadanori Tomita, Stewart Goldman, Lawrence J. Jennings, Richard J. Gilbertson, Marcelo B. Soares. Identification of genes that frequently exhibit copy number alterations in pediatric ependymomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3111. doi:10.1158/1538-7445.AM2014-3111
Abstract 3115: Calcitriol effects on breast cancer tumorgrafts
Authors: Katayama Maria Lucia Hirata , Fonseca-Filho Victor Celso N. , Lyra Eduardo Carneiro , Maria Durvanei Augusto , Basso Ricardo Alves , Nonogaki Suely , Guerra Juliana Mariotti , Maistro Simone , Goes João Carlos Sampaio , Folgueira Maria Aparecida A. Koike 
Published: May 2015

Abstract
Antiproliferative effects of calcitriol were mainly detected in breast carcinoma lineages exposed in vitro to high hormone concentrations, which is associated with hypercalcemia in human beings. To test the hypothesis that intra-tumoral administration of calcitriol would allow higher tissue concentration of the hormone and activation of the genomic pathway, a tumorgraft model, that more closely reproduces the molecular characteristics of the primary tumor, was established. Freshly collected breast cancer samples from 14 patients were ortothopically grafted in nude mice. On the sixth week after xenografting, no palpable nodules were detected in mice implanted with 6 samples. Intra-tumoral weekly injections of calcitriol 0.06 μg (dose that allow peak serum calcitriol levels in the predicted therapeutic range) or vehicle were initiated and maintained for six weeks in mice xenografted with another 8 samples. Tumorgraft proliferation, apoptosis and target genes expression were evaluated through immnunohistochemistry reactions or RT-PCR. At the end of the experiment, tumorgrafts originated from three samples were available for analysis. VDR expression was detected in these samples as well as a trend towards higher expression of CYP24A1 mRNA (10-18 fold) in calcitriol treated samples, indicating that the genomic pathway was induced. A high proliferative index, evaluated by Ki67 expression, was observed, however, neither differences in the expression of proliferation markers (BrdU incorporation, Ki67 and CDKN1B expression) nor in apoptosis markers (cleaved caspase 3 and BCL2 expression) between vehicle and calcitriol treated tumorgrafts was detected. Additionally, no difference between groups was noticed for the expression of CDKN1A mRNA. In summary, in this small study, calcitriol antitumoral effects were not observed in tumorgrafts, established from highly proliferative breast cancer samples. This preclinical model in conjunction with pharmacokinetic calcitriol determinations might contribute to clarify the hormone effects in breast cancer.
Citation Format: Maria Lucia Hirata Katayama, Victor Celso N. Fonseca-Filho, Eduardo Carneiro Lyra, Durvanei Augusto Maria, Ricardo Alves Basso, Suely Nonogaki, Juliana Mariotti Guerra, Simone Maistro, João Carlos Sampaio Goes, Maria Aparecida A. Koike Folgueira. Calcitriol effects on breast cancer tumorgrafts. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3115. doi:10.1158/1538-7445.AM2014-3115
Abstract 312: Autophagy mediates HIF2α degradation and suppresses renal tumorigenesis
Authors: Liu Xian-De , Yao Jun , Tripathi Durga N. , Ding Zhiyong , Xu Yi , Sun Mianen , Zhang Jiangwei , Bai Shanshan , German Peter , Hoang Anh , Zhou Lijun , Zhang Xuesong , Conti Claudio J. , Efstathiou Eleni , Eissa Tony N. , Mills Gordon B. , Walker Cheryl L. , Jonasch Eric 
Published: May 2015

Abstract
Autophagy is a conserved process involved in lysosomal degradation of protein aggregates and damaged organelles. The role of autophagy in cancer is a topic of intense debate, and the underlying mechanism is still not clear. Here we reported that the hypoxia inducible factor 2α (HIF2α), an oncogenic transcription factor implicated in renal tumorigenesis, was in part constitutively degraded by autophagy. HIF2α interacts with autophagy protein LC3, autophagy receptor p62, and lysosome protein LAMP1. Inhibition of autophagy results in HIF2α accumulation, while induction of autophagy promotes HIF2α degradation. The E3 ubiquitin ligase activity of the von Hippel-Lindau (VHL) is required for autophagic degradation of HIF2α. There is a complementary interaction between the proteasome and autophagy in HIF2α degradation. Autophagy inactivation in ATG5 knockout cells redirects HIF2α to proteasomal degradation, while proteasome inhibition induced autophagy and favored the HIF2α-p62 interaction. Importantly, we reported that clear cell renal cell carcinoma (ccRCC) was frequently associated with mono-allelic loss and/or mutation of autophagy related gene ATG7, and low expression level of autophagy genes correlated with ccRCC progression. This study sheds light on the anticancer role for autophagy in ccRCC tumorigenesis, and reveals constitutive autophagic degradation of HIF2α as a novel tumor suppression mechanism.
Citation Format: Xian-De Liu, Jun Yao, Durga N. Tripathi, Zhiyong Ding, Yi Xu, Mianen Sun, Jiangwei Zhang, Shanshan Bai, Peter German, Anh Hoang, Lijun Zhou, Xuesong Zhang, Claudio J. Conti, Eleni Efstathiou, Tony N. Eissa, Gordon B. Mills, Cheryl L. Walker, Eric Jonasch. Autophagy mediates HIF2α degradation and suppresses renal tumorigenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 312. doi:10.1158/1538-7445.AM2014-312
Abstract 3122: Combination effect of metformin with gemcitabine for gemcitabine-resistant pancreatic adenocarcinoma
Authors: Suzuki Keiichi , Takeuchi Osamu , Osaku Masayoshi , Yamada Yoshinori 
Published: May 2015

Abstract
Metformin (MET) is the first-line treatment for type-2 diabetes mellitus. Several epidemiological studies have revealed the anti-cancer effects of metformin, including against pancreatic ductal carcinoma (PDC). Gemcitabine (GEM) has become the standard chemotherapy for PDC but tolerance to GEM is an important issue.
We evaluated the anti-tumor effects of MET for GEM-resistant PDC in a xenograft mouse model. For this in vivo study, wild-type BxPC-3 was implanted into both flanks of 7-week-old female BALB/c nude mice. Mice were divided into four groups: (i) control (without any treatment); (ii) GEM-treated group; (iii) MET-treated group; and (iv) combined treatment group (GEM+MET). Mice were fed for 4 weeks. Estimated tumor volumes and body weights were measured each week. Treatments were initiated 2 weeks after implantation. MET (600 mg/kg) was administrated orally every day. GEM (100 mg/kg) was given by intraperitoneal injection every week.
The final tumor volumes (in g) were: control, 0.59±0.05; GEM, 0.32±0.07; MET, 0.42±0.08; GEM+MET, 0.23±0.06. The two groups treated with GEM had significantly reduced tumors compared with control, but there were no differences between control and MET groups. The anti-tumor effect of MET for BxG30 (the cell line for GEM-resistant PDC) was evaluated using the method described above. The final tumor volumes were: control, 0.26±0.05; GEM, 0.21±0.05; MET, 0.15±0.06; GEM+MET, 0.11±0.03. Tumor volumes were decreased significantly in GEM+MET groups compared with control. The treated control ratio (T/C%) was calculated: GEM, 80.2%; MET, 54.0%; GEM+MET, 47.2%. The anti-tumor effect of GEM for BxG30 was limited. The MET group showed satisfactory anti-tumor effects, but T/C% was &lt;50% only in the GEM+MET group. This result revealed that combination therapy had excellent anti-tumor effects even for GEM-resistant PDC. The IC50 was 20.25 mM for GEM and 0.004 µg/mL for MET upon single-drug use.
Our results showed that MET has a partial anti-tumor effect for PDC. Combination therapy has an excellent effect not only for wild-type PDC but also for GEM-resistant PDC. These data suggest that MET could be used to treat PDC.
Citation Format: Keiichi Suzuki, Osamu Takeuchi, Masayoshi Osaku, Yoshinori Yamada. Combination effect of metformin with gemcitabine for gemcitabine-resistant pancreatic adenocarcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3122. doi:10.1158/1538-7445.AM2014-3122
Abstract 3124: Xenograft models for development of new drugs targeting fibroblast growth factor receptor (FGFR)
Authors: Zhang Lan , Zhang Juan , Shi Qian 
Published: May 2015

Abstract
The fibroblast growth factor receptors (FGFR) are tyrosine kinases that are present in many types of endothelial and tumor cells. There are 4 different fibroblast growth factor receptors (FGFR) in the cell: FGFR1, FGFR2, FGFR3, and FGFR4. The activation of FGFR pathway plays an important role in tumor angiogenesis, tumor growth, survival, as well as migration. Mutation or amplification/overexpresion of FGFR has been found in several types of tumors, including breast cancer, bladder cancer, gastric cancer, prostate cancer, colon cancer, multiple myeloma, and non-small cell lung carcinoma. Therefore, targeting FGFRs represents an attractive strategy for development of new cancer therapeutics. However, the lack of suitable models hinders the progress of research on FGFR inhibitors. Here we successfully validated subcutaneous models in several cancer types, in which FGFR is mutant or amplified/overexpressed, such as breast cancer MDA-MB-134 (FGFR1 amplification), gastric cancer SNU-16 (FGFR2 amplification), endometrial cancer AN3CA (FGFR2 N549K/K310R mutation), bladder cancer RT-4 (FGFR3 overexpression) and RT-112 (FGFR3 overexpression), lung cancer NCI-H1581 (FGFR1 amplification), as well as human derived gastric cancer GA114 (FGFR2 amplification). In conclusion, the validated cell line derived (CDX) and patient derived xenograft models (PDX) in several cancer types provide valuable platforms for the development of new compounds targeting FGFRs.
Citation Format: Lan Zhang, Juan Zhang, Qian Shi. Xenograft models for development of new drugs targeting fibroblast growth factor receptor (FGFR). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3124. doi:10.1158/1538-7445.AM2014-3124