bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1361: Sarcoma-relevant genetic events identified in a chimeric mouse model of sarcoma in skeletal muscle
Authors: Hettmer Simone , Lindsay Melissa C. , Langenau David M. , Wagers Amy J. 
Published: August 2012

Abstract
Background. Soft-tissue sarcomas are heterogeneous malignancies of mesodermal, non-hematopoietic origin. Ex-vivo genetic alteration (by activation of Kras(G12V) and deletion of p16INK4A/p19ARF) and intramuscular implantation of discrete mesodermal cell populations, freshly isolated from mouse skeletal muscle, results in the rapid induction of pleomorphic sarcomas. This model system can be utilized as a platform to dissect sarcoma-relevant cellular and genetic events. Methods. The molecular underpinnings of Kras; p16p19null sarcomas were evaluated by whole genome microarray in comparison to normal muscle and to previously published human rhabdomyosarcoma datasets. Upregulation of 141 candidate genes identified by bioinformatic analyses was verified using a customized RT*2 Profiler™ PCR Array (SA Biosciences). The effects of shRNA knockdown of candidate genes on sarcoma growth were evaluated in sarcoma cell lines. Results. Kras; p1619null sarcomas recapitulate gene expression signatures of human rhabdomyosarcomas and identify a conserved cluster of 144 genes that is concordantly upregulated in both mouse and human sarcomas compared to normal skeletal muscle. 74 of these 144 genes have been associated previously with human malignancies, and 28 have been linked specifically to sarcomas. PCR array validation confirmed that 104 of these genes are upregulated in mouse sarcomas compared to normal skeletal muscle, including the BMP antagonist and Shh morphogen Gremlin, previously implicated in human sarcomas (upregulated 1327-fold in mouse sarcomas vs. muscle). Gremlin knockdown in sarcoma cell lines by shRNA results in reduced proliferation, thereby implicating a functional role in sarcoma biology. Conclusions. Our studies identify a small group of genes that are upregulated in sarcomas across species and may be of fundamental importance in sarcomas. Future studies of the genes identified here will likely provide important insights into the events that drive sarcomas in muscle, and identify new targets for therapeutic intervention.
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 1361. doi:1538-7445.AM2012-1361
Abstract 1362: Developing genetically flexible mouse models of sarcoma - a novel functional genomics platform
Authors: Gupta Amar , Menezes Serena , Kabaroff Leah , Dickson Brendan , Swallow Carol , Gladdy Rebecca A. 
Published: August 2012

Abstract
Introduction: Sarcomas are a heterogeneous group of malignant neoplasms that arise from connective tissues and have a disease-specific mortality of 30-50%. Existing mouse models of sarcomagenesis utilize knockout and transgenic mice but it is unclear if fixed germline mutations recapitulate sporadic human cancer. In addition, creating germline mutant mice requires substantial time and resources. We hypothesized that delivery of oncogenes into mouse skeletal muscle using a retroviral (RCAS) system would result in sarcomagenesis and could mitigate the limitations of conventional mouse models. Methods: p16/p19 null mice expressing the retroviral receptor, TVA, under nestin (N-tva) or β-actin (BKE) promoters were used. DF1 chicken fibroblasts, infected with avian-leukosis virus vectors (RCAS) carrying combinations of oncogenes (KrasG12D, c-Myc, IGF2) or GFP alone, were delivered by injection into the hindlegs of neonatal mice and tumor development was monitored. Results: GFP-positive cells were observed following in vitro infection of cultured mouse skeletal muscle with RCAS-GFP and GFP+ myoblasts were identified from mice injected with RCAS-GFP in vivo, suggesting successful cell infection and targeted gene delivery. Sarcomas formed in 30% of p16/p19−/−xN-tva mice at the injection site with a median latency of 23.5 weeks (8-42 weeks). Several subtypes of sarcoma developed in this strain based on morphologic assessment and immunohistochemistry (S100, desmin, and smooth muscle actin). Of these, malignant peripheral nerve sheath tumor (MPNST) that overexpressed EGFR consistent with human MPNST, was the predominant subtype (55%). Although a similar tumor incidence occurred in the p16/p19−/−xBKE strain (32%), the median latency was much shorter, 10.4 weeks (7-25 weeks) and the tumor spectrum shifted to predominantly fibrosarcoma (36%) or rhabdomyosarcoma (36%). No tumors were observed in mice injected with empty RCAS vector or without inactivation of the p16/p19 locus. Gene-anchored PCR revealed retroviral vector DNA integration in 89% of N-tva and 97% of BKE tumors. KrasG12D was the most frequent oncogene isolated. Conclusions: We have generated novel models of sarcomagenesis using the RCAS-TVA system to deliver known sarcoma oncogenes into mouse hind legs with a tumor incidence of ∼30%. With optimization, we will be able to use this genetically flexible system to functionally validate novel candidate sarcoma genes.
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 1362. doi:1538-7445.AM2012-1362
Abstract 1364: Osteoprotegerin production by breast cancer cells: Regulation by NF-kappaB and role in metastasis
Authors: Weichhaus Michael , Segaran Prabu , Geerts Dirk , Connelly Linda 
Published: August 2012

Abstract
Human breast cancer cells and tissues express the protein osteoprotegerin (OPG). While many studies have investigated the role of OPG in cancer as a mediator of bone remodeling, few studies consider its impact outside the bone microenvironment. Further investigation is therefore required into endogenous OPG expression by breast cancer cells and its effects on tumor progression. OPG can be regulated by the transcription factor NF-kappaB in several cell types. We investigated whether OPG expression in MDA-MB-231 and MDA-MB-435 breast cancer cells was regulated by NF-kappaB. Cells were treated for 24 hours with 10ng/ml TNF-alpha or 10µM thymoquinone (TQ), to stimulate or inhibit NF-kappaB activity respectively. OPG expression was measured by real time RT-PCR (mRNA) and ELISA (protein). OPG levels were increased after treatment with TNF-alpha while treatment with TQ decreased expression. We used the chick embryo metastasis model to determine the effect of OPG on metastasis. Human breast cancer cells were inoculated onto the chick chorioallantoic membrane (CAM) where they form a tumor that metastasizes to the chick tissue. Metastasis is quantified by real time PCR for Human Alu repeat DNA sequences in the chick tissue. We transfected MDA-MB-231 cells with OPG-specific siRNA which reduced OPG mRNA expression up to 72 hours post-transfection. OPG knockdown or control (non-targeting siRNA) treated cells were inoculated onto the CAM at embryonic day 9; chick tissue was harvested at day 16 and analyzed for breast cancer cell metastasis. We found a significant reduction in metastasis of the OPG knockdown cells compared to the control. We performed genome-wide mRNA microarray data analysis to determine whether OPG expression correlates with breast cancer progression in human tumor samples. OPG expression in 1809 breast cancer tissues was not correlated with prognosis. However, analyses by breast cancer subtypes showed that high OPG mRNA expression correlated with poorer prognosis in basal (p=0.0028, n=383) and also HER2 positive tumor subtypes (p=0.021, n=408). In summary, our data suggest that OPG expression in breast cancer cells is regulated by NF-kappaB, a transcription factor associated with pro-tumor effects. Our in vivo studies suggest that OPG promotes metastasis. We are currently determining the mechanism whereby OPG exerts its effects. Since OPG levels correlate with poorer prognosis in basal and HER2 positive tumors, treatment strategies targeting OPG in the primary tumor may represent a potential therapeutic strategy for these disease subytpes.
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 1364. doi:1538-7445.AM2012-1364
Abstract 1366: Development of murine models of breast cancer metastasis for the evaluation of the efficacy of TGF-β inhibitors as therapeutic agents
Authors: Biswas Tanuka , Yang Junhua , Zhao Liu , Sun LuZhe 
Published: August 2012

Abstract
Preclinical models are elemental in understanding drug efficacy and safety in vivo. Many existing models of breast cancer metastasis use immune compromised animals, which are not appropriate for the evaluation of novel therapeutics that modulate host immune response such as inhibitors of transforming growth factor-β (TGF-β) signaling pathway. TGF-β has been shown to be a major immune modulator as well as a major driver in epithelial-mesenchymal transition, which is believed to result in tumor invasion and metastasis. In the current study we characterized a pair of murine mammary cell lines derived from PyMT tumors in C57Bl/6 mice with respect to the effect of TGF-β on their malignant phenotypes. These cell lines, named Py-230 and Py-8119, represent luminal epithelial and mesenchymal cell populations respectively in the tumor. In vitro characterization revealed differences in viability, motility, and transcriptional activation in response to treatment with TGF-β. Py-230 cells were growth inhibited and exhibit epithelial-mesenchymal transition upon treatment with TGF-β whereas Py-8119 was non-responsive to TGF-β in these assays. These observations were consistent with higher Smad activation by TGF-β in Py230 cells than in Py-8119 cells. Furthermore, intra cardiac injections were performed using luciferase-and GFP-transfected PyMT cells in syngeneic animals, which were then treated with either placebo or TβRI KI (kinase inhibitor for TGF-β receptor I). A preliminary study with Py-230 cell-injected mice indicates that TβRI KI treatment appears to enhance bone metastasis. This outcome will be compared with the effect of TβRI KI on the metastatic potential of Py-8119 in our future studies. We believe that the development of mouse models of tumor metastasis using murine mammary cells in a syngeneic background will help illustrate the efficacy of TGF-β inhibitors in abrogating metastasis in an immune competent environment and also allow determining the optimal dose and time of this novel intervention.
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 1366. doi:1538-7445.AM2012-1366
Abstract 1369: Mouse models of clinical oligo- and poly-metastatic progression
Authors: Zhang Qingbei , Yang Xinan , Shen Jikun , Salama Joseph K. , Khodarev Nikolai , Hasselle Michael D. , Huang Yong , Fan Hanli , Khan Sajid A. , Darga Thomas E. , Hoffma Robert M. , Chmura Steve , Lussier1 Yves A. , Weichselbaum Ralph R. , Weichselbaum Ralph R. , Xing Rosie Hongmei 
Published: August 2012

Abstract
We previously proposed a metastatic state defined by a limited number of metastases, termed oligometastasis(es). These limited metastases may be cured by metastasis-directed treatments in contrast to widespread metastatic disease. While many animal models of polymetastases exist, an oligometastasis(es) model is lacking. Here, we report the first mouse xenograft model of oligometastasis(es) employing the MDA-MB-435 human tumor that maintains a stable oligometastatic phenotype in vivo. We also developed an MDA-MB-435 polymetastatic progression model in which the pattern of dissemination induced poly-foci in the lung, or to multiple anatomic sites including lung, heart, muscle, pleura, bone and peritoneal cavity. We performed microRNA expression profiling from distinct lung metastases of oligometastatic and polymetastatic animals. MicroRNA expression distinguished oligometastatic cell lines from those of polymetastatic, and accurately identified oligometastatic patients from a prior clinical study who failed to develop widespread metastases (p=0.005). These findings form the basis for investigating mechanisms underlying the specific metastatic pattern of individual cancers.
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 1369. doi:1538-7445.AM2012-1369
Abstract 137: Molecular networks regulated by tumor suppressive microRNA-375 in head and neck squamous cell carcinoma
Authors: Kinoshita Takashi , Hanazawa Toyoyuki , Nohata Nijiro , Kikkawa Naoko , Fuse Miki , Chiyomaru Takeshi , Yoshino Hirofumi , Enokida Hideki , Nakagawa Masayuki , Okamoto Yoshitaka , Seki Naohiko 
Published: August 2012

Abstract
BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide. In spite of considerable advances in multimodality therapy including surgery, radiotherapy and chemotherapy, the overall five-year survival rate for patients with HNSCC is around 40%. Understanding of the molecular oncogenic pathway underlying HNSCC could significantly improve diagnosis, therapy, and disease prevention. Our microRNA (miRNA) expression signatures of hypopharyngeal squamous cell carcinoma (SCC), maxillary sinus SCC and esophageal SCC revealed that the expression of microRNA-375 (miR-375) was significantly reduced in cancer tissues. In this study, we investigated the functional significance of miR-375 and explored novel molecular networks regulated by miR-375 in HNSCC. METHODS: Cell proliferation assay was performed to investigate the functional significance of miR-375 and its target genes in HNSCC cell lines. Genome-wide gene expression analysis was performed to identify the molecular networks of miR-375 by microarray technique. The expression levels of miR-375 target genes were verified using quantitative real-time RT-PCR in HNSCC clinical specimens. A luciferase reporter assay was used to identify the actual binding site between miR-375 and its candidate target genes. RESULTS: Restoration of miR-375 significantly inhibited cancer cell proliferation in HNSCC cells. Genome-wide molecular targets search and TargetScan database indicated that homocysteine-inducible, endoplasmic reticulum stress-inducible, ubiquitin-like domain member 1 (HERPUD1), lactate dehydrogenase B (LDHB), PC4 and SFRS1 interacting protein 1 (PSIP1), metadherin (MTDH) and solute-carrier family 7, member 11 (SLC7A11) were the candidate genes of miR-375 target. Among them, the expression levels of LDHB and MTDH were significantly up-regulated in clinical HNSCC tumor specimens compared with adjacent normal epithelium. Luciferase reporter assay showed that LDHB and MTDH were directly regulated by miR-375. Silencing of these genes studies demonstrated significant inhibition of cell proliferation in HNSCC cells. CONCLUSIONS: miR-375 functions as a tumor suppressor in HNSCC. LDHB and MTDH are directly regulated by miR-375. These genes may function as oncogenes and contributed to cell proliferation in HNSCC. Tumor suppressive miR-375 and its target oncogenes may provide new insights into the molecular networks of HNSCC.
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 137. doi:1538-7445.AM2012-137
Abstract 1370: Tumor endothelial cells acquire drug resistance by MDR1 upregulation via VEGF signaling in tumor microenvironment
Authors: Akiyama Kosuke , Ohga Noritaka , Hida Yasuhiro , Kawamoto Taisuke , Sadamoto Yoshihiro , Ishikawa Shuhei , Maishi Nako , Akino Tomoshige , Kondoh Miyako , Matsuda Aya , Inoue Nobuo , Shindoh Masanobu , Hida Kyoko 
Published: August 2012

Abstract
Tumor endothelial cells (TECs) are therapeutic targets in antiangiogenic therapy. Contrary to the traditional assumption, it has been reported that TECs can be genetically abnormal and might acquire drug resistance. In this study, mouse TECs and normal ECs (NECs) were isolated to investigate drug resistance of TECs and the mechanism by which it is acquired. TECs were more resistant to paclitaxel with upregulation of multidrug resistance 1 (MDR1) mRNA, which encodes the P-glycoprotein, compared to NECs. Normal human microvascular ECs (HMVECs) were cultured in tumor-conditioned medium (tumor CM) and were found to become more resistant to paclitaxel through MDR1 mRNA upregulation and nuclear translocation of Y-box-binding protein 1 (YB-1), which is an MDR1 transcription factor. Vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) and Akt were activated in HMVECs by tumor CM. We observed that tumor CM contained a significantly high level of VEGF. A VEGF receptor kinase inhibitor, Ki8751, and a PI3K/Akt inhibitor, LY294002, blocked tumor CM-induced MDR1 upregulation. MDR1 upregulation via the VEGF/VEGFR pathway in the tumor microenvironment is one of the mechanisms of drug resistance acquired by TECs. We observed that VEGF secreted from tumors upregulated MDR1 through VEGFR2 and Akt activation. This is a novel mechanism of acquisition of drug resistance by TECs in a tumor microenvironment.
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 1370. doi:1538-7445.AM2012-1370
Abstract 1373: Preclinical activity of axitinib and its associated change of serum biomarkers in nasopharyngeal carcinoma (NPC)
Authors: Hui Edwin Pun , Lui Vivian WY , Hui Connie WC , Lau Cecilia PY , Loong Herbert HF , Wong Cesar SC , Wong Eric CH , Chan Anthony TC 
Published: August 2012

Abstract
Background: We have previously demonstrated promising activity of sunitinib, a multi-targeted tyrosine kinase inhibitor (TKI) against vascular endothelial growth factor (VEGF) receptor, platelet-derived growth factor receptor (PDGFR), c-kit and RET, in preclinical models of NPC (Invest New Drugs 2011:1123-31). However, the significant host related toxicity encountered in a phase 2 clinical trial of NPC patients has limited its clinical efficacy (Ann Oncol 2011:1280-7). Axitinib is a highly selective TKI of VEGF receptor 1, 2 and 3. Selectively targeting a single growth factor receptor pathway provides the potential to rationally adjust dosages and combine drugs directed at specific parts of the pathway to minimize toxicity and achieve the optimum therapeutic benefit. Methods: In vitro cytotoxicity of axitinib was evaluated by MTT assay in five NPC cell lines (C666-1, CNE-2, HK1-LMP1, HNE-1, HONE-1-EBV). In vivo activity was tested in two representative NPC xenograft models (CNE-2 and HK1-LMP1). We also studied treatment induced changes in tumor histology, microvessel density (MVD) and murine serum biomarkers. Results: All NPC cell lines tested except C666-1 were sensitive to axitinib with IC50 of 0.8-7 µM and maximum growth inhibition of 45-87%. In vivo, axitinib demonstrated significant tumor growth inhibition (fractional tumor volume reduction of 32-63% for axitinib treated mice versus 0-10% for vehicle control), reduced MVD and induced extensive tumor necrosis with no significant host toxicity in mice. There were significant increases in serum murine-derived VEGF and SDF-1α and decrease of sVEGFR-2 in axitinib treated tumor bearing mice as compared to vehicle treated controls. Conclusion: Axitinib demonstrated potent in vitro and in vivo activity in NPC preclinical models. Host derived serum proteins may serve as potential biomarkers of drug activity. A phase 2 clinical trial of axitinib in NPC is on-going (NCT01249547) to validate these findings in patients. Acknowledgement: supported by a direct grant (2041496) from CUHK. Axitinib was provided by Pfizer Inc.
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 1373. doi:1538-7445.AM2012-1373
Abstract 1374: Cross-resistance and sensitivity of sunitinib resistant tumor cells
Authors: Gotink Kristy J. , Broxterman Henk J. , de Haas Richard R. , Rovithi Maria N. , Pili Roberto , Verheul Henk MW 
Published: August 2012

Abstract
Background: Resistance to sunitinib, a multi-targeted anti-angiogenic tyrosine kinase inhibitor (TKI) approved for clinical use in advanced renal cell cancer, gastrointestinal stromal tumors and pancreatic neuroendocrine tumors, represents a major clinical problem. Previously we have shown that tumor cells acquire resistance in vitro by continuous incubation with sunitinib and found that acidic lysosomal sequestration of sunitinib mediates its resistance. In this study, we investigated whether sunitinib resistant tumor cells are cross-resistant to other clinically relevant inhibitors and whether agents interfering with lysosomal function can modulate resistance. Methods: Continuous exposure to sunitinib for more than 12 months resulted in drug resistance in 786-O (RCC) and HT-29 (colorectal cancer) cell lines. Using these cells, cross-resistance to other clinically available TKIs such as sorafenib, pazopanib and erlotinib, and to the mTOR inhibitor everolimus, was determined in proliferation assays (MTT). In addition, modulation of sunitinib resistance by the lysosomal inhibitors (LIs) chloroquine and bafilomycin A1 was studied using proliferation assays. The effect of LIs on phosphorylation of key signaling proteins was determined by western blotting. Results: Compared to parental cell lines, proliferation assays revealed that sunitinib resistant cell lines were cross-resistant to pazopanib and erlotinib, while no significant decrease in sensitivity to sorafenib or everolimus was observed. Both chloroquine and bafilomycin A1 were able to modulate sunitinib resistance. Western blot analysis revealed that phosphorylation of key signaling proteins including Akt and p44/42-MAPK was inhibited in sunitinib resistant cells upon co-incubation with chloroquine, while sunitinib alone did not inhibit phosphorylation of these kinases. Conclusion: We found that sunitinib resistant tumor cells are cross-resistant to pazopanib and erlotinib, but remain sensitive to sorafenib and everolimus. Furthermore, combination with the lysosomal inhibitor chloroquine resulted in inhibition of key signaling proteins in sunitinib resistant cells. Taken together, we envision that these findings are relevant for clinical treatment strategies in patients with renal cell cancer resistant to sunitinib.
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 1374. doi:1538-7445.AM2012-1374