bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B85: High malignant prostate cancer cells developed enhanced tumor-initiating/metastatasis-initiating activity and altered the lung microenvironment
Authors: Tzeng Sheue-Fen , Tsai Chin-Hsien , Lee Ming-Shyue , Hsiao Pei-Wen 
Published: May 2015

Abstract
Hormone-refractory and metastatic prostate cancer (PCa) both result in therapeutic failure. Developing PCa animal model is critical to understand the cancer progression and to access therapeutic effects. Here, we established the orthotopic xenograft of androgen-independent PCa cell line, 22Rv1, in nude mouse model and cultured the metastatic cancer cells. The same procedure was repeated to evolve highly metastatic cells, 22Rv1-LN3. In experimental metastasis, 22Rv1-LN3 can colonize and grow in the LN, lung and brain through tail vein injection but 22Rv1 cell failed to colonize in these organs. Besides, intracardiac injection of 22Rv1-LN3 also caused bone metastasis. In the model, we found 22Rv1-LN3 cell have higher protease activity (e.g. matriptase and MMP9) along with lower level of protease inhibitors, (e.g. HAI-2, a matriptase inhibitor and TIMP2/TIMP3). Transcriptional level of these genes determined the in vitro invasion activity and in vivo tumorigenicity. Given the differential capacity to seed different tissues, we further analyze the stem cell property by tumorsphere assay and in vivo transplantation with a reduced cell number. Sphere-formation rate in 22Rv1-LN3 cells was 8% compared to only 0.1% in 22Rv1 cells. Tumorigenicity of 22Rv1-LN3 cells in orthotopic transplantation was 100% (8/8) compared to 20% (2/10) in 22Rv1 cells. Moreover, primary tumor of 22Rv1-LN3 cells developed spontaneous metastases in lymph nodes and lung at 8-week, whereas 22Rv1 cells hardly metastasized even at 14-week. As analyzed by qRT-PCR, primary 22Rv1-LN3 tumor vs. 22Rv1-Luc2 induced higher levels of Arginase and iNOS expression in lung tissue, which indicates the proclivity for metastatic niche formation. In conclusion, this PCa progression model not only elevated the malignant properties of cancer cells but also influenced the tumor microenvironment.
Citation Format: Sheue-Fen Tzeng, Chin-Hsien Tsai, Ming-Shyue Lee, Pei-Wen Hsiao. High malignant prostate cancer cells developed enhanced tumor-initiating/metastatasis-initiating activity and altered the lung microenvironment. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B85. doi:10.1158/1538-7445.CHTME14-B85
Abstract IA21: Of niche construction and loss of homeostasis: New insights into the cancer diaspora
Authors: Pienta Kenneth J. 
Published: May 2015

Abstract
Merging the social science concept of diaspora with ecological and population sciences concepts can inform the cancer field to understand the biology of tumorigenesis and metastasis and inspire new ideas for therapy. Together, cancer cells and host cells, interacting within their habitat, create an ecosystem. This ecosystem, in turn, exists within a larger environment (the host patient as biosphere). Cancer cells escape their confinement of their original habitat in the primary tumor, likely forced out by ecological changes in their home niche.
A diaspora is the scattering of people away from an established homeland. To date, “diaspora” has been a uniquely human term utilized by social scientists, however, the application of the diaspora concept to metastasis may yield new biological insights as well as therapeutic paradigms. The diaspora paradigm takes into account and models several variables: the quality of the primary tumor microenvironment, the fitness of individual cancer cell migrants as well as migrant populations, the rate of bidirectional migration of cancer and host cells between cancer sites, and the quality of the target microenvironments to establish metastatic sites.
Once seeded to a new site, diaspora populations do not assimilate into the new environment, they try “recapitulate” their homeland. Niche construction is the process in which an organism alters its own (and consequently, other species) environment, usually in a manner that increases its chances of survival. This creates a feedback relationship between natural selection and niche-construction: when organisms affect their environment, that change can then cause a shift in what traits are being naturally selected for. The effect of niche construction is especially pronounced in situations where environmental alterations persist for several generations, introducing the evolutionary role of ecological inheritance.
Ecological scientific principles can be applied to the cancer diaspora to develop new therapeutic strategies (ecotherapy). It is easier to drain the swamp that the cancer cells created than swat a million cancer cell mosquitos. Alternatively, ecological traps, habitats that lead to the extinction of a species, could be developed to attract cancer cells to a place where they can be better exposed to treatments or to cells of the immune system for improved antigen presentation. Targeting the microenvironment in addition to the cancer cells themselves should improve therapeutic outcomes.
Citation Format: Kenneth J. Pienta. Of niche construction and loss of homeostasis: New insights into the cancer diaspora. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr IA21. doi:10.1158/1538-7445.CHTME14-IA21
Abstract PR06: Lymphocyte invasion of basal breast tumors is associated with wild-type p53
Authors: Quigley David A. , Vaske Charlie , Silwa-Pandit Laxmi , Dannenfelser Ruth , Langerød Anita , Vollan Hans Kristian M. , Troyanskaya Olga , Chin Suet-Feung , Caldas Carlos , Balmain Allan , Børresen-Dale Anne-Lise , Kristensen Vessela 
Published: May 2015

Abstract
The tumor suppressor p53 is mutated in approximately 30% of breast adenocarcinomas, but the clinical implications of p53 mutation depend on the subtype of breast tumor. Although p53 mutation is associated with worse outcome for patients with Luminal B and Her2 subtypes, the same is not true in Basal tumors, despite the fact that Basal tumors have the highest frequency of p53 mutation of any subtype. Lymphocytic infiltration is associated with better prognosis in several epithelial malignancies including triple-negative breast tumors. In this study we identify an association in Basal breast cancer between lymphocytic infiltration and the number of copies of wild-type p53 by combining gene expression, p53 sequencing, DNA copy number analysis, and semi-quantitative immune cell histology in 1,281 tumors. We use the Nanodissect algorithm to define signatures for T cell types and show that the infiltration consists primarily of cytotoxic T lymphocytes. Elevated expression of this gene signature is associated with better outcome in Basal tumors, and differential pathway activity analysis identifies significant activation of caveolin 1 signaling to TGF-beta in p53 wild-type Basal tumors. These findings identify a new link between the p53 pathway and beneficial adaptive immune response in breast tumors not responsive to the estrogen receptor, supporting a connection between a lack of p53 function and the failure of tumor immunosurveillance.
This abstract is also presented as Poster A35.
Citation Format: David A. Quigley, Charlie Vaske, Laxmi Silwa-Pandit, Ruth Dannenfelser, Anita Langerød, Hans Kristian M. Vollan, Olga Troyanskaya, Suet-Feung Chin, Carlos Caldas, Allan Balmain, Anne-Lise Børresen-Dale, Vessela Kristensen. Lymphocyte invasion of basal breast tumors is associated with wild-type p53. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr PR06. doi:10.1158/1538-7445.CHTME14-PR06
Abstract PR07: Neutralizing the activity of murine TGF-β receptor 2 promotes a differentiated tumor cell phenotype and inhibits pancreatic cancer metastasis
Authors: Ostapoff Katherine T. , Cenik Bercin Kutluk , Wang Miao , Ye Risheng , Xu Xiaohing , Nugent Desiree , Hagopian Michelle , Topalovski Mary , Rivera Lee B. , Carroll Kyla D. , Brekken Rolf A. 
Published: May 2015

Abstract
Elevated levels of TGF-β are a negative prognostic indicator for patients diagnosed with pancreatic cancer; as a result the TGF-β pathway is an attractive target for therapy. However, clinical application of pharmacologic inhibition of TGF-β remains challenging because TGF-β has tumor suppressor functions in many epithelial malignancies including pancreatic cancer. In fact, direct neutralization of TGF-β promotes tumor progression of genetic murine models of pancreatic cancer. Here we report that neutralizing the activity of murine TGF-β receptor 2 using a monoclonal antibody (2G8) has potent anti-metastatic activity in orthotopic human tumor xenografts, syngenic tumors and a genetic model of pancreatic cancer. 2G8 induced an anti-metastatic stromal phenotype by increasing pro-inflammatory macrophages and NK cells and concomitantly decreasing anti-inflammatory macrophages, MDSCs and activated fibroblasts. These stromal specific changes resulted in tumor cell epithelial differentiation and a potent reduction in metastases. We conclude that TGF-β signaling within stromal cells participates directly in tumor cell phenotype and pancreatic cancer progression. Thus, strategies that inhibit TGF-β dependent effector functions of stromal cells could be efficacious for the therapy of pancreatic tumors.
This abstract is also presented as Poster A38.
Citation Format: Katherine T. Ostapoff, Bercin Kutluk Cenik, Miao Wang, Risheng Ye, Xiaohing Xu, Desiree Nugent, Michelle Hagopian, Mary Topalovski, Lee B. Rivera, Kyla D. Carroll, Rolf A. Brekken. Neutralizing the activity of murine TGF-β receptor 2 promotes a differentiated tumor cell phenotype and inhibits pancreatic cancer metastasis. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr PR07. doi:10.1158/1538-7445.CHTME14-PR07
Abstract A32: A specific antibody for Histone H3 Lys27Met mutation for the characterization of pediatric glioblastomas
Authors: Lozsa Anita , Clark Robin T. , Lewis Peter W. , Koletsky Matthew S. , Becher Oren J. , Rosenfeld John , Michael Sturges , Allis David C. , Chuang Trinette , Speckmann Wayne , Solache Alejandra 
Published: May 2015

Abstract
Pediatric gliomas such as glioblastoma multiforme (GBM) and diffuse intrinsic pontine glioma (DIPG) are aggressive brain tumors for which there is no effective therapy. The reason for the poor therapeutic outcome for children diagnosed with glioblastomas might be due to the therapeutic approach, which is not significantly different from the treatment of adult gliomas. Recent studies have shown that the gene expression profile of pediatric gliomas is distinct from histologically similar tumors in adults. These findings strongly suggest that the underlying mechanisms of tumor progression are different in these gliomas. Whole-genome sequencing of these pediatric tumors has revealed mutations in genes of H3F3A and HIST1H3B encoding histone H3.3 or H3.1, respectively. The mutations resulted in a substitution of lysine (K) to methionine (M) at position 27 of the protein (H3K27M). The lysine 27 residue of histone H3 is a posttranslational modification site, methylated by the polycomb repressive complex 2 (PRC2). A mutation like H3K27M might play a significant role in tumorigenesis and tumor progression since histones and their posttranslational modifications are key epigenetic regulators. In collaboration with the laboratory of David Allis, we raised antibodies against the K27M mutation of histone H3. Using this antibody, Lewis et al. corroborated the presence of H3 K27M protein in DIPG samples containing the mutant allele. Furthermore, they provided evidence that this mutation can alter the molecular processes in the nucleus through a gain-of-function mechanism in glioblastoma. Here we show that this Anti-Histone H3, K27M mutant antibody (Cat. No.: ABE419), together with other modified histone antibodies, are useful tools for the characterization and classification of different type of brain tumors and can be used in several applications including immunoblotting and chromatin immunoprecipitation (ChIP).
Citation Format: Anita Lozsa, Robin T. Clark, Peter W. Lewis, Matthew S. Koletsky, Oren J. Becher, John Rosenfeld, Sturges Michael, David C. Allis, Trinette Chuang, Wayne Speckmann, Alejandra Solache. A specific antibody for Histone H3 Lys27Met mutation for the characterization of pediatric glioblastomas. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A32.
Abstract A41: Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma
Authors: Kiezun Adam , Perry Jennifer , Tonzi Peter , Allen Eliezer Van , Carter Scott L. , Baca Sylvan , Bhatt Ami , Lawrence Michael , Walensky Loren , Wagle Nikhil , Mora Jaume , deTorres Carmen , Lavarino Cinzia , Velasco-Hidalgo Liliana , Cardenas-Cardos Rocio , Aguiar Simone dos Santos , Yunes Jose A. , Mercado Gabriela , Melendez-Zajgla Jorge , Roberts Charles , Garraway Levi , Rodriguez-Galindo Carlos , Golub Todd , Orkin Stuart , Getz Gad , Janeway Katherine 
Published: May 2015

Abstract
Osteosarcoma is the most common primary bone tumor and yet there have been no substantial advances in treatment or survival in over 2 decades. We examined 59 tumor/normal pairs by whole-genome, whole-exome and RNA-Sequencing. Only TP53 was mutated at significant frequency across the 59 samples. The mean non-silent somatic mutation rate was 1.2 mutation per megabase and there were a median of 231 somatic rearrangements per tumor. Complex chains of rearrangements and localized hypermutation were detected in almost all cases. Given the inter-tumor heterogeneity, the extent of genomic instability and the difficulty in acquiring a large sample size in a rare tumor we used several methods to identify genomic events contributing to osteosarcoma proliferation and survival. Pathway analysis, a heuristic analytic algorithm, a comparative oncology approach and a genome-wide, pooled short hairpin RNA (shRNA) screen all point to the PI3K/mTOR pathway as a potential central vulnerability for therapeutic exploitation in osteosarcoma. Osteosarcoma cell lines are responsive to pharmacologic and genetic inhibition of the PI3K/mTOR pathway both in vitro and in vivo.
Citation Format: Adam Kiezun, Jennifer Perry, Peter Tonzi, Eliezer Van Allen, Scott L. Carter, Sylvan Baca, Ami Bhatt, Michael Lawrence, Loren Walensky, Nikhil Wagle, Jaume Mora, Carmen deTorres, Cinzia Lavarino, Liliana Velasco-Hidalgo, Rocio Cardenas-Cardos, Simone dos Santos Aguiar, Jose A. Yunes, Gabriela Mercado, Jorge Melendez-Zajgla, Charles Roberts, Levi Garraway, Carlos Rodriguez-Galindo, Todd Golub, Stuart Orkin, Gad Getz, Katherine Janeway. Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A41.
Abstract A42: miR34a: A valuable indicator of differential outcome of Ewing sarcoma patients with complex functions
Authors: Scotlandi Katia , Marino Maria Teresa , Grilli Andrea , Picci Piero , Carè Alessandra , Tripodo Claudio , Ferrari Stefano 
Published: May 2015

Abstract
The identification of reliable indicators of prognosis, which may allow the stratification of patients according to different risk at diagnosis isan important aspect of translational research in Ewing sarcoma (ES). In this paper, we validated our previous evidence showing how expression of miR34a in ES tumor samples at diagnosis was signficantly associated with tumor progression (Nakatani F. J Pathol 2012). Here we analyzed a different series of speciments derived from very controlled and homogeneously treated non-metastatic ES patients, and we compared evaluation of miR34a by RT-PCR using frozen samples with that obtained by in situ hybridization on paraffin-embedded samples . The median follow-up of the 109 EWS patients was 90 months (range 9 to 241 months). 68 patients (63%) remained continuously free of disease and 41 (38%) relapsed. Expression of miR34a was evaluated by qRT-PCR using TaqMan miRNA assay kit and/or by in situ hybridization ISH optimization kit from Exiqon. High expression of miR34a was significantly related to better EFS and OVS : 5-year EFS was 74% for the 55 patients with high expression of miR34a and was 51% for the 54 patients with low expression (p = 0.004); 5-year OVS was 83% in high-expressors and 58% in low-expressors . By multivariate Cox regression analysis, the value of low miR-34a expression as well as of non-total necrosis and high LDH were all confirmed as independent risk factors associated with poor outcome. miR34a was also evaluated by ISH on TMA. miRNA expression by ISH correlates with that obtained by RT-PCR (r=0.59, p&lt;0.0001, Spearman test). Although not significant, high expression of miR34a evalutated on tissue microarray still shows an association with better outcome (p=0.19). Expression of miR34a inversely correlated with expression of cyclin D1 mRNA, as well as with Ki-67 labelling. In contrast positive association was observed with YY1, a transcription factor that regulates a dazzling list of genes and whose role in malignancy is complex and has just started to emerge. The value of miR34a as predictor was higher than that of these specific targets, indicating a more complex relationship with tumor malignancy.
Citation Format: Katia Scotlandi, Maria Teresa Marino, Andrea Grilli, Piero Picci, Alessandra Carè, Claudio Tripodo, Stefano Ferrari. miR34a: A valuable indicator of differential outcome of Ewing sarcoma patients with complex functions. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A42.
Abstract A46: HSP-90 inhibition in pediatric sarcomas
Authors: Arnaldez Fernanda I. , Terwilliger Toby , Yeung Choh , Neckers Len , Helman Lee 
Published: May 2015

Abstract
Hsp90 is a molecular chaperone that regulates post-translational folding, stability, and function of many client proteins, which play critical roles in key signal transduction pathways implicated in cell growth, differentiation, and survival. Several relevant oncogenic proteins are described as clients, such as insulin growth factor receptor 1, AKT/PKB, and src-family kinases. Signaling through these molecules is critical in the biology of rhabdomyosarcoma and Ewing's sarcoma, which are two of the most common pediatric sarcomas. Novel therapies for these tumors are clearly needed since patients with relapsed and metastatic disease continue to have poor outcomes and multimodality therapy, even when successful, is often accompanied by long-term morbidity.
Ganetespib (Synta Pharmaceuticals) is a small molecule Hsp90 inhibitor that binds to the ATP pocket in the N-terminus of Hsp90, leading to down-regulation of Hsp90 client protein levels. We sought to evaluate the preclinical activity of ganetespib in a panel of Ewing's Sarcoma and rhabdomyosarcoma cell lines. We evaluated in vitro activity of ganetespib in Ewing Sarcoma cell lines (TC71, TC32, EW8, RDES) and in rhabdomyosarcoma (RMS) cell lines (RD, RH30) using kinetic proliferation assays and MTS. In all cases, marked inhibition of cell growth was achieved in a dose-dependent manner with drug IC50s in the low nanomolar range (3-6 nM). We found that ganetespib exposure is associated with both induction of apoptosis and alterations in cell cycle progression. In addition to upregulation of Hsp70, which is considered a biomarker of Hsp90 inhibition, ganetespib treatment was associated with loss of expression of IGF1R-beta as well as downregulation of key signaling pathways including mammalian target of rapamycin (mTOR), pAKT, and Src-family kinases, particularly YES1, a kinase we previously identified as critical in rhabdomyosarcoma biology. Moreover, we observed a cooperative effect between Hsp90 inhibition and IGF1R blockade with R1507, a monoclonal antibody targeting this receptor (Hoffman-La Roche). Furthermore, synergy was seen when ganetespib was combined with the SFK inhibitor dasatinib. While in-vivo validation of these results is ongoing, we conclude that Hsp90 inhibition with ganetespib is an attractive strategy to explore for the therapy of pediatric sarcomas, possibly in combination with other targeted therapies.
Citation Format: Fernanda I. Arnaldez, Toby Terwilliger, Choh Yeung, Len Neckers, Lee Helman. HSP-90 inhibition in pediatric sarcomas. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A46.
Abstract A51: The HoxD locus: Its contribution to osteogenic phenotype and malignancy of Ewing sarcoma
Authors: Richter Guenther HS , Heyking Kristina von , Roth Laura , Ertl Miriam , Burdach Stefan 
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 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 HOXD expression. However, RNA knock down of DKK2, a canonical WNT/β-catenin agonist and critical mediator of osteolytic tumor growth in ES resulted in a significant suppression of HOXD11 and HOXD13 expression. Subsequently, RNA interference of individual HoxD genes demonstrated HOXD11 and HOXD13 to be critical for 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 MMP1, since down-regulation of individual HoxD genes similarly resulted in a suppression of MMP1 expression. But, HoxD genes only marginally influenced the expression of osteogenic genes in ES nor did they promote its chondrogenic or osteogenic differentiation. Whether HOXD10, HOXD11 or HOXD13 expression further metastasis or contribute to osteolytic tumor growth is currently investigated in a xenograft model using Rag2-/-gammaC-/- mice and data will be presented.
Citation Format: Guenther HS Richter, Kristina von Heyking, Laura Roth, Miriam Ertl, Stefan Burdach. The HoxD locus: Its contribution to osteogenic phenotype and malignancy of Ewing sarcoma. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A51.