bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-482: MiRNA replacement therapy in vivo: antitumor effects of nanoparticle-formulated miR-145 and miR-33a, and targeting of Pim-1
Authors: Weirauch Ulrike , Ibrahim Ahmed Fawzy , Thomas Maren , Lange-Grünweller Kerstin , Grünweller Arnold , Hartmann Roland K. , Aigner Achim M. 
Published: August 2012

Abstract
Various miRNAs are aberrantly expressed in cancer. In colon carcinoma, decreased levels of the pro-apoptotic and anti-proliferative miRNA-145 are observed, while the role of miR-33a has not been analysed yet. In this study, we demonstrate the tumor-inhibitory role of miR-33a and newly identify the proto-oncogenic kinase Pim-1 as its direct target. Comparably to siRNA-mediated knockdown of Pim-1, miR-33a reduces Pim-1 expression and thus inhibits proliferation in leukemia and in colon carcinoma cells by decelerating cell cycle progression. Most recent in vitro and in vivo data from our group further establish the so far unknown functional relevance of Pim-1 in colon carcinoma and identify Pim-1 as attractive target gene. Among others, RNAi-mediated Pim-1 knockdown reduces tumor growth, induces apoptosis and leads to major changes in oncogenic signal transduction, including the inhibition of STAT3. The therapeutic application of miRNAs strongly relies on the development of suitable delivery tools, and we introduce polyethylenimine (PEI)-based nanoparticles for systemic or local miRNA administration in vivo. PEIs mediate miRNA protection, delivery to target organs, cellular uptake and intracellular release. MiRNA replacement therapy through systemic or local injection of PEI/miR-145 complexes results in efficient miRNA delivery and in antitumor effects in s.c. colon carcinoma xenograft mouse models. Likewise, tumor growth inhibition is observed upon treatment with PEI-complexed miR-33a. This is due to the miR-33a-mediated downregulation of Pim-1 expression, comparable with the Pim-1 knockdown through PEI/siRNA complexes. Conclusions: (i) The PEI-complexation of miRNAs represents a novel strategy in miRNA replacement therapy, (ii) miR-145 / miR-33a may be promising candidate miRNAs, and (iii) Pim-1 is a newly identified, attractive target gene in colon carcinoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-482. doi:1538-7445.AM2012-LB-482
Abstract LB-496: Low-dose aspirin targets tumor-associated inflammation and delays neuroblastoma tumor growth in vivo
Authors: Carlson Lena-Maria , Rasmuson Agnes , Segerstrom Lova , Sveinbjornsson Baldur , Kogner Per 
Published: August 2012

Abstract
ABSTRACT Tumor-associated inflammation is a driving force in several adult cancers, and low doses of non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin have proven to reduce cancer incidence. Little is known about tumor-associated inflammation in pediatric neoplasms and no in vivo data exists on the effectiveness of low-dose aspirin on established tumors. Our study evaluates inflammatory patterns paralleling neuroblastoma (NB) tumor growth in vivo and low-dose aspirin as a therapeutic option for high-risk NB. Using the TH-MYCN mouse model of NB, this study demonstrates the presence and progression of tumor-associated inflammation during NB tumor growth. Ex vivo analysis of tumors revealed a transition from an adaptive immune response predominated by CD8+ T-cells in neoplastic lesions from 5 week old homozygous mice, towards an enrichment in immature cells of the innate immune system, including myeloid-derived suppressor cells (MDSCs), immature dendritic cells (DCs) and M2 tumor-associated macrophages (TAMs) during tumor progression. An ongoing M1 to M2 transition of TAMs was demonstrated, which was paralleled by a gradual deterioration of DC status. Ten days of consecutive anti-inflammatory treatment with low-dose aspirin significantly reduced tumor burden (p&lt;0.01) and the presence of tumor-associated cells of the innate immune system (p&lt;0.01) in homozygous mice. In conclusion, our study depicts how inflammatory pathways assist tumor progression through sculpturing of the tumor microenvironment, and for the first time demonstrates an in vivo effect of low-dose aspirin on established MYCN amplified NB tumors in a transgenic mouse model, suggesting a potential new treatment option for high-risk NB patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-496. doi:1538-7445.AM2012-LB-496
Abstract LB-502: Development of three dimensional cancer cell-CAF co-culture system
Authors: Arai Kazuya , Sakamoto Ruriko , Itoh M , Miura Haifeng 
Published: August 2012

Abstract
Purpose A large number of cell lines have been established and used for cancer research. Monolayer culture of cancer cells alone is a simplified and effective method, however, it does not always reflect the physiological conditions. In this study, we tried to establish a simple co-culture method of cancer cells and CAF (cancer associated fibroblast), to develop three dimensional model of stroma rich tumor with cells such as pancreatic cancer and scirrhous cancer. Method Human tumor tissue samples were obtained from patients who had undergone surgery at the National Cancer Center Hospital East, Japan. Written informed consents were obtained from all patients. BxPC-3 (pancreatic cancer cell line) and A549 (lung cancer cell line) were stained with red-fluorescent dye, PKH-26. Pancreatic cancer derived- and lung cancer derived-CAF were stained with green-fluorescent dye, PKH-67. Cancer cells and CAF are seeded into the microtiter plates for 3D cell culture (NanoCulture® Plate) at a same cell number, and spheroid formation was measured by a fluorescent time lapse microscopy for 3-days. Result BxPC-3 (red) and Pancreatic CAF (green) merged well and formed mosaic spheroids. BxPC-3 (red) and lung CAF (green) did not merge and separately formed spheroids of each cell types. A549 and lung CAF merged, but A549 and Pancreatic CAF did not merge clearly. It is suggested that a specific recognition mechanisms exist by organ types or tumor types, with the adhesion between cancer cell and CAF. A) BxPC-3 and Pancreatic CAF B) BxPC-3 and lung CAF Conclusion In this study, mosaic spheroid were formed by co-culturing of same organ derived cancer cells and CAF. This co-culture system is expected as an effective tool for cancer microenvironment study and/or drug screening targeting with stroma rich tumor.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-502. doi:1538-7445.AM2012-LB-502
Abstract LB-509: Early detection of pancreatic cancer in transgenic mice with ultrasonic molecular imaging and VEGFR2-targeted microbubbles
Authors: Pysz Marybeth A. , Seeley Elliot S. , Foygel Kira , Gambhir Sanjiv S. , Tian Lu , Brentnall Teresa A. , Willmann Juergen K. 
Published: August 2012

Abstract
Pancreatic cancer is a lethal disease largely due to presence of advanced and inoperable disease at the time of diagnosis. Evidence from current screening programs for high-risk individuals suggests that aggressive detection at operable stages could dramatically improve prognosis; however, current radiological imaging screen methods are not standardized and rely on solid mass recognition from anatomical/morphological imaging strategies. Incorporation of a molecular imaging strategy can provide a highly reliable and cancer-specific diagnosis, as well as, improved delineation of tumor boundaries for therapeutic and surgical guidance. Molecular ultrasound imaging is accomplished by conjugating targeting molecules (peptides/antibodies) to the surface of gas-filled microbubble contrast agents (1-4 μm diameter), and these contrast agents bind to markers overexpressed on disease-associated endothelium. In this study, we investigated the ability to detect small pancreatic cancers with contrast microbubbles targeted to vascular endothelial growth factor receptor type 2 (VEGFR2) and small animal transabdominal ultrasound (US) imaging in a transgenic mouse model of pancreatic cancer (Pdx1-Cre; KRasV12G; Ink4a-/-; PC mice). Small tumors ranging from 0.8 mm to 3.0 mm in diameter (mean: 1.7 ± 0.6 mm) could be detected with high-resolution B-mode US imaging, and showed 7.8-fold higher (P &lt; 0.001) VEGFR2-targeted molecular US signal (mean signal intensity: 6.5 ± 8.4 arbitrary units; n=32 tumors) in PC mice compared with normal pancreas in wildtype mice (mean signal intensity: 0.8 ± 0.6 arbitrary units; n=14 mice). Small pancreatic tumors showed 3-fold higher VEGFR2-targeted US signal (mean signal intensity: 10.5 ± 9.4 arbitrary units) compared with US signal measured with non-targeted microbubbles (mean signal intensity: 3.6 ± 1.8 arbitrary units), indicating high specificity for VEGFR2. Ex vivo histological (H&E) analysis and immunostaining of VEGFR2 confirmed millimeter-sized tumors in the pancreas and VEGFR2 expression in PC mice (VEGFR2-positive tumors); in contrast, pancreas tissue from normal, wildtype mice was VEGFR2-negative. Taken together, these studies indicate that VEGFR2-targeted US imaging can detect small pancreatic cancers that are not normally recognized with conventional anatomical imaging, and may be highly useful for establishing a standardized pancreatic cancer screening/monitoring method for high-risk patients. Supported by the Canary Foundation, and NIH/NCI grants R21 CA139279 and Fellowship R25 CA11868.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-509. doi:1538-7445.AM2012-LB-509
Abstract LB-513: Abelson Interactor 1 is a novel substrate of protein kinase D2: potential implications in tumor cell migration
Authors: Nimmagadda Subbaiah Chary , Eiseler Tim , Lint Johan Van , Storz Peter , Seufferlein Thomas 
Published: August 2012

Abstract
Introduction and Objective: The serine/threonine kinases of the protein kinase D family (PKCmu/PKD1, PKD2, PKCnu/PKD3), a subfamily of the CAMK superfamily, have been implicated in regulation of multiple biological processes including proliferation, survival, apoptosis, angiogenesis and motility. The precise mechanisms by which the three PKDs modulate these processes are incompletely understood and require a better knowledge of their signaling context. Methodology and Results: Using the ProtoArray Human Protein Microarray v4.0 (Invitrogen), we identified Abelson interactor 1 (ABI1) as a novel PKD2 substrate. ABI1 was first identified as the downstream target of Abl tyrosine kinase and is an adaptor protein involved in actin reorganization and lamellipodia formation along with WAVE2. In the present study we illustrate that PKD2 interacts and phosphorylates ABI1 in vitro and in vivo at two potential serine residues. The sites were validated using an antibody that specifically identifies the consensus PKD substrate sequence. Furthermore, PKD2-induced phosphorylation of ABI1 destabilized the interaction between ABI1 and WAVE2 and resulted in relocation of both the proteins from plasma membrane to perinuclear region. Consequences of this destabilization and its potential impact on WAVE2 driven actin polymerization and the associated processes are in the process of investigation. Preliminary results also suggest reduced migration velocity and directedness of a tumor cell. Conclusion: In conclusion, our data demonstrate that ABI1 is a novel substrate of PKD2 that might negatively regulate tumor cell migration via terminating a constitutive interaction between ABI1 and WAVE2. *Impact of ABI1-WAVE2 subcomplex destabilization on WAVE2 induced actin polymerization and lamellipodia extension will be presented at the meeting.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-513. doi:1538-7445.AM2012-LB-513
Abstract LB-518: Amplification and activation of EGFR wild-type mediates invasion of human glioblastoma in vivo
Authors: Talasila Krishna M. , Soentgerath Anke , Euskirchen Philipp , Rosland Gro V. , Wang Jian , Huszthy Peter C. , Prestegarden Lars , Skaftnesmo Kai Ove , Sakariassen Per Øystein , Eskilsson Eskil , Keunen Olivier , Brekka Narve , Moen Ingrid , Nigro Janice , Vintermyr Olav , Lund-Johansen Morten , Mørk Sverrre J. , Enger Per Øyvind , Bjerkvig Rolf , Miletic Hrvoje 
Published: August 2012

Abstract
Glioblastoma (GBM) is the most aggressive form of primary brain tumors with a median survival of 15 months. Although angiogenesis is one of the main features of GBMs, non-angiogenic tumor infiltration into brain parenchyma still is the major challenge for therapy. Tumor cells can migrate very far from the main tumor mass and the invasive pattern of tumor subpopulations has not been characterized properly. Epidermal growth factor receptor (EGFR) gene amplification is one of the major mutations of primary GBMs, where multiple copies of the wild-type EGFR gene are present as double minutes. Although studies have proposed a role for EGFR gene amplification in tumor development, the function of EGFR in vivo is not characterized properly mainly due to inefficient tumor models. Here, we report a key role for EGFR wild-type in tumor invasion. In a human GBM xenograft model, we show that tumor cells with EGFR amplification and expression are highly invasive and non-angiogenic. By blocking EGFR activation using Cetuximab and a dominant-negative approach, we show that maintenance of the non-angiogenic, invasive growth pattern is dependent on EGFR function and that downregulation of its activity leads to angiogenic tumor growth. As EGFR amplification and expression is present in 40-60% of GBMs, our results might implicate that activation of EGFR wild-type is one of the major mechanisms of glioblastoma invasion in vivo.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-518. doi:1538-7445.AM2012-LB-518
Abstract LB-54: The foundation for melanoma research
Authors: Beston Richard 
Published: August 2012

Abstract
The Foundation for Melanoma Research was founded in 1999 by Noreen O'Neill, a prominent Philadelphia businessperson. Noreen, who was diagnosed with malignant melanoma in 1995 and lost her battle to the disease in 2000. She looked to volunteer with organizations dedicated to advancing treatments for melanoma patients. Finding none, she decided to build one herself. The organization is dedicated to raising awareness about melanoma and funding research into increased prevention, early detection, and new treatments, with the eventual goal of finding a cure. All funds raised go to melanoma research scientists at The Wistar Institute, a world-reknowned biomedical research organization at the University of Pennsylvania in Philadelphia. Wistar continues to be on the cutting-edge of melanoma discoveries towards a cure. The Noreen O'Neill Foundation for Melanoma Research is dedicated to raising awareness about melanoma and funding research into increased prevention, early detection, and new treatments. Annual intiatives include Running for Cover 5k walk/run, Date With a Plate, the annual Wallace Clark Lectures, and a close tie with Philadelphia professional sports teams.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-54. doi:1538-7445.AM2012-LB-54
Abstract LB-67: COX-2/PGE2: molecular ambassadors of Kaposi's sarcoma associated herpes virus (KSHV) oncoprotein-v-FLIP
Authors: Sharma-Walia Neelam , Patel Kinjan , Chandran Karthic , Marginean Alexandru , Bottero Virginie , Kerur Nagaraj , George-Paul Arun 
Published: August 2012

Abstract
Kaposi's sarcoma herpesvirus latent oncoprotein viral FLICE-like inhibitory protein (v-FLIP) or K13, a potent activator of NF-κB has well established roles in KSHV latency and oncogenesis. KSHV induced COX-2 represents a novel strategy employed by KSHV to promote latency and inflammation/angiogenesis/invasion. Here, we demonstrate that v-FLIP/K13 promotes tumorigenic effects via induction of host protein COX-2 and its inflammatory metabolite PGE2 in an NF-κB dependent manner. In addition to our previous studies demonstrating COX-2/PGE2's role in transcriptional regulation of KSHV latency promoter and latent gene expression, current study adds to the complexity that though LANA-1 (latency associated nuclear antigen) is utilizing COX-2/PGE2 as critical factors for its transcriptional regulation, it is the v-FLIP/K13 gene in the KSHV latency cluster that maintains continuous COX-2/PGE2 levels in infected cells. We demonstrate that COX-2 inhibition, via its chemical inhibitors (NS-398 or celecoxib), reduced v-FLIP/K13 mediated NF-κB induction, and extracellular matrix (ECM) interaction mediated FAK/Src/AKT, Rac-1 activation, mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD) levels, and subsequently down-regulated detachment-induced apoptosis (anoikis) resistance. COX-2 inhibition in v-FLIP/K13-Human microvascular endothelial cells (HMVECs) reduced inflammation and invasion/metastasis related genes along with reduced anchorage independent colony formation via modulating ‘extrinsic’ as well as ‘intrinsic’ cell death pathways. COX-2 blockade in v-FLIP/K13-HMVECs drastically augmented cell death induced by removal of essential growth/survival factors secreted in the microenvironment. Transformed cells obtained from anchorage independent colonies of COX-2 inhibitor treated v-FLIP/K13-HMVEC cells expressed lowered levels of endothelial mesenchymal transition (EndMT) genes such as slug, snail and twist, and higher expression of the tumor suppressor gene E-cadherin. Taken together, our study provides strong evidences that FDA approved COX-2 inhibitors have great implications in blocking tumorigenic events linked to KSHV's oncogenic protein v-FLIP/K13.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-67. doi:1538-7445.AM2012-LB-67
Abstract LB-68: Mouse mammary tumor virus suppress apoptosis through Src signaling in the mammary epithelial cells
Authors: Kim Hyoung H. 
Published: August 2012

Abstract
Many receptors in the hematopoietic immune cells use common signaling pathway that relies on immunoreceptor tyrosine-based activation motif (ITAM). ITAMs are highly conserved sequence. Signal transduction by these motifs is mediated by Src family tyrosine kinases including Lyn, Fyn, Lck. ITAM bearing proteins are found in many oncogenic viruses and associated with transformation and tumorigenesis in epithelial and endothelial cells. These proteins include Epstein Barr Virus LMP2A, Kaposi's sarcoma virus K1, and bovine leukemia virus gp30. MMTV envelope protein is another viral ITAM bearing protein implicated in mammary tumor development. We previously have shown that MMTV envelope protein expression transform mouse mammary epithelial cells and Src kinases are important mediators in this transformation. To study how ITAM signaling affects transformation and progression of mammary tumor we developed mammary cell lines that express MMTV provirus and have a mutated ITAM counterpart. Using PCR based expression profiling we found that MMTV-ITAM turns on the embryonic transcription factors and induce epithelial-mesenchymal transition which is important in malignant tumor progression. Many genes related to cell adhesion and invasion was changed. Anti-apoptotic regulator bcl-2 level was significantly increased. Importantly MMTV expressing cells became resistant to apoptosis induced by serum starvation. Cells transduced with ITAM mutated MMTV were indistinguishable from wild type cells. We also found Src kinase, a downstream signal transducer of ITAM signaling is activated in the MMTV expressing cells, and MMTV induced apoptosis resistance was completely restored by Src inhibitor PP2. Our results show that MMTV suppress apoptosis through ITAM mediated Src tyrosin kinase signaling. The studies in signaling pathways and apoptosis resistance induced by ITAM containing proteins in nonhematopoietic cells could lead to the development of effective treatment of cancers in which ITAM-mediated signaling plays a role.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-68. doi:1538-7445.AM2012-LB-68
Abstract SY10-01: Uncovering the cellular origin of skin cancers
Authors: Blanpain Cedric 
Published: August 2012

Abstract
Stem cells (SCs) are responsible for tissue homeostasis and repair. SCs have been hypothesized to be the cells at the origin of cancer. However, for the vast majority of cancers, the cell at the origin of tumor initiation is still unknown. Two epithelial skin cancers are frequent in human populations: the basal cell carcinoma (BCC) and the squamous cell carcinoma (SCC).
We developed new genetic approaches to identify the cells at the origin of BCC and SCC in mice. Using mice conditionally expressing constitutively active Smoothened mutant (SmoM2) or KRas mutant (G12D), we activated hedgehog or Ras signaling in different cellular compartments of the skin epidermis, and determined from which epidermal compartments oncogene expression induces cancer formation. Using clonal analysis, we found that SmoM2 induced BCC arise from long-term resident progenitor cells of the interfollicular epidermis. In contrast, expression of mutant KRas in hair follicle bulge stem cells (SCs), but not in their transient amplifying progeny, led to benign squamous skin tumor (papilloma). Whereas no malignant tumor was observed following KRasG12D expression alone, expression of KRasG12D combined with the loss of p53 induced invasive SCC formation (3). Our studies uncover the cells at the origin of SmoM2 induced BCC and and Kras induced SCC in mice and demonstrate that expression of differentiation markers in tumor cells is not necessary predictive of the cancer initiating cells.
We have now developed novel strategy to isolate by flow cytometry oncogene targeted cells at different time following oncogene expression and determined the molecular changes associated with tumor initiation and malignant progression. The functional relevance of these genes is currently investigated using gain and loss of function in mice. These new results and the relevance of these findings to human skin cancers will be presented.
Acknowledgement This work is supported by Welbio, the FNRS, the program d'excellence CIBLES of the Wallonia Region, Fondation Contre le Cancer, the European Research Council (ERC) and the EMBO Young Investigator Program.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY10-01. doi:1538-7445.AM2012-SY10-01