bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5295: Detection of VEGFA gene amplification in different neoplastic entities using four different technologies
Authors: Andreozzi MariaCarla , Vuaroqueaux Vincent , Ackermann Andreas , Schneider Sandra , Tornillo Luigi , Ruiz Christian , Fiebig Heinz Herbert , Eppenberger Serenella , Terracciano Luigi Maria 
Published: August 2012

Abstract
Background The VEGFA protein plays an important role in the induction of angiogenesis during tumor initiation and progression. The aims of the study were to investigate the presence of VEGFA gene amplification by FISH analysis on a human multi-tumor tissue microarray (MTMA) and to validate these findings on an independent human multi-tumor tissue in mouse implanted microarray (MTMA) by aCGH, SNP6 microarrays, FISH analysis and real-time PCR. Materials and Methods The VEGFA gene status was evaluated on a human MTMA (n=2,957 tissue samples) including 132 tumor entities and 31 normal tissue types. Furthermore, we reconfirmed the presence of VEGFA gene amplification as detected by FISH analysis on a second independent MTMA including 195 different tissue samples from nude mice xenograft models of 24 different human tumor types using three additional genomic techniques: array-CGH, SNP6 microarrays and real-time PCR. Results VEGFA gene amplification was detected across different tumor types. The following incidences were observed: 5.3% in colorectal carcinoma, 3.2% in endometrial carcinoma, 2.8% in gallbladder adenocarcinoma, 4.2 % in renal carcinoma, 1.5% in hepatocellular carcinoma, 4.5% in pancreas carcinoma and 4.8% in stomach carcinoma samples. Additionally, some tumors were characterized by a high polysomy. In the second independent cohort MTMA VEGFA gene amplification was detected by FISH analysis in four samples, including one non-small cell lung cancer, one sarcoma, one gastric and and breast cancer, previously classified as amplified by aCGH (100%) and SNP6 microarrays. The latter technique also revealed one “supplementary amplified sample”. All results correlated with real-time PCR (p&lt;0.05). Conclusions We detected VEGFA gene amplification in different tumor types, on a human MTMA and we confirmed our findings on an independent MTMA of human tumors implanted in mice. We demonstrated the occurrence of VEGFA gene amplification in several tumor types with an incidence of up to 5% and also we demonstrated the feasibility of four technologies for reliable VEGFA gene copy number detection. Comparison of the four technologies revealed high concordance (p&lt;0.05).
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 5295. doi:1538-7445.AM2012-5295
Abstract 5299: VEGF receptor-3 interacts with PI3K directly to regulate lymphangiogenesis
Authors: Coso Sanja , Zeng Yiping , Opeskin Kenneth , Williams Elizabeth D. 
Published: August 2012

Abstract
Dissemination of malignant cells into the regional lymph nodes is a common occurrence in many cancers. The vascular endothelial growth factor (VEGF) family is a major regulator spread of cancer to lymph nodes via induction of lymphangiogenesis. We have used primary lymphatic endothelial cells and clinical material to investigate VEGF-C/VEGF receptor (VEGFR)-3 signalling pathways. We found that treatment with VEGF-C induced activation of PI3K/Akt and MEK/Erk in lymphatic endothelial cells. Furthermore, activation of PI3K/Akt by VEGF-C/VEGFR-3 resulted in phosphorylation of P70S6K, eNOS, PLCγ1, and Erk1/2. Importantly, a direct interaction between PI3K and VEGFR-3 in lymphatic endothelial cells was demonstrated both in vitro and in clinical specimens, where it was associated with the presence of lymph node metastases in small cell carcinoma of the lung. Blocking PI3K abolished VEGF-C-stimulated lymphatic endothelial cell tube formation and migration. Our findings demonstrate that specific VEGFR-3 signalling pathways are activated in lymphatic endothelial cells by VEGF-C. The importance of PI3K in VEGF-C/VEGFR-3-mediated lymphangiogenesis provides a potential therapeutic target for tumor lymphatic metastasis.
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 5299. doi:1538-7445.AM2012-5299
Abstract 5302: Characterization the role of leukocyte cell-derived chemotaxin 2 (LECT2) in angiogenesis
Authors: Chi-Kuan Chen , Yang Ching-Yao , Chen Huei-Wen , Kuo Ming-Lian 
Published: August 2012

Abstract
Leukocyte Cell-Derived Chemotaxin 2 (LECT2) protein is expressed preferentially in the liver in a constitutive manner and secreted into bloodstream. Recently studies indicate that LECT2 potentially associated with the liver injury, repair, and regeneration, but other functions are still unknown. Angiogenesis is a process of new blood vessel formation which has essential roles in development, repair, tumor growth, invasion, and metastasis. In our previous studies, we have recently identified LECT2 as a potential tumor suppressor, correlating with decreased vascular invasion in hepatocellular carcinomas (HCC). In this study, we evaluated the function of recombinant LECT2 (rLECT2) proteins on angiogenesis by using human umbilical vein endothelial cells (HUVEC). We demonstrated a selective and significant inhibition of VEGF165-induced angiogenic activity in HUVEC by rLECT2 protein through inhibiting the proliferation, migration, and tube formation. The rLECT2 protein also suppressed VEGF165-induced angiogenesis in CAM assay and matrigel plug assay. Otherwise, we use different stage of HCC to evaluate the density, amounts, and volumes of blood vessels are associated with LECT2 protein level. Furthermore, we also evaluate the association between LECT2 protein level and the maturity of blood vessels. In conclusion, we for the first time found that LECT2 play an important role in anti-angiogenesis. Moreover, the LECT2 might have broad therapeutic applications in diseases characterized by excessive angiogenesis.
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 5302. doi:1538-7445.AM2012-5302
Abstract 5311: Transducer of Cdc42-dependent actin assembly-1 (Toca-1) promotes breast cancer invasion and metastasis
Authors: Chander Harish , Meens Jalna A. M , Truesdell Peter F. , Brien Colin D. , Everingham Stephanie L. , Craig Andrew W.B 
Published: August 2012

Abstract
Metastatic breast adenocarcinomas display activation signatures for signaling pathways like Epidermal Growth Factor Receptor (EGFR) that trigger cell motility and tissue invasion. Transducer of Cdc42-dependent actin assembly-1 (Toca-1) is an adaptor protein that promotes recruitment of actin nucleation promoting factors to cellular membranes. Although these actin regulatory proteins have been linked to breast cancer invasion, the role of Toca-1 in this process has not been reported. In this study, breast cancer cell lines with a range of invasive and metastatic properties were used, including human MDA-MB-231 cells, rat MTLn3 cells, and MTLn3-B1 cells expressing human EGFR. To test the role of Toca-1 in these cell lines, we established stable Toca-1 knock-down (KD) using lentiviral delivery of shRNAs specific for human or rat Toca-1. Here, we report that Toca-1 is expressed in highly invasive breast cancers cell lines, and that Toca-1 co-localizes with components of invadopodia. Toca-1 localizes to the filamentous actin-rich core of invadopodial protrusions in breast cancer cells that are actively degrading the extracellular matrix (ECM). In MDA-MB-231 cells, Toca-1 KD led to a significant defect in EGF-induced cell migration and invasion compared to control cells. This correlated with a significant defect in EGF- and Src-induced ECM digestion in Toca-1 KD compared to control MDA-MB-231 cells. Next, control and Toca-1 KD cells were compared in orthotopic mammary tumors that were xenografted in Rag2−/−:[[Unsupported Character - Symbol Font &#61543;]]c−/− mice. Although Toca-1 KD remained effective in primary tumors, no defects in tumor growth were observed. However, mice bearing Toca-1 KD cell tumors displayed a significant reduction in spontaneous metastases to the lung. Similar results were obtained for weakly metastatic MDA-MB-231 cells and highly metastatic MTLn3-B1 cells. In contrast, Toca-1 was not required for efficient lung seeding following tail vein injection of MTLn3-B1 cells, suggesting that Toca-1 functions at an early step in the dissemination of metastatic breast tumor cells. Taken together, this investigation identifies Toca-1 as a pro-invasive protein in breast cancer, and a potential therapeutic target to limit tumor metastasis.
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 5311. doi:1538-7445.AM2012-5311
Abstract 5316: GSK3β-dependent phosphorylation of LCRMP-1 is required for filopoda formation and tumor invasion
Authors: Wang Wen-Lung , Pan Szu-Hua , Chang Yih-Leong , Wu Chen-Tu , Chen Yuh-Ling , Hong Tse-Ming , Yang Pan-Chyr 
Published: August 2012

Abstract
LCRMP-1, a novel isoform of CRMP-1, can promote cancer cell migration, invasion and associates with poor clinical outcome in patients with non-small cell lung cancer (NSCLC). However, the underlying mechanisms for regulation of LCRMP-1 in cancer cell invasiveness remain still obscure. Here, we report that GSK-3β can phosphorylate LCRMP-1 at Thr-628 in consensus sequences and this phosphrylation is crucial for function of LCRMP-1 on filopodia formation and cancer cell invasion. Impediment of Thr-628 phosphorylation attenuates the effects of LCRMP-1 to form filopodia and promote cancer invasion; simultaneously, kinase-dead GSK-3β diminishes regulation of LCRMP-1 on cancer cell invasion. Furthermore, we also found that patients with low-level inactive GSK-3β expression and high-level LCRMP-1 expression have worse overall survival than those with high-level inactive GSK-3β expressions and low-level LCRMP-1 expressions (P&lt; 0.0001). Collectively, these results demonstrate that GSK-3β-dependent phosphorylation of LCRMP-1 provides an important mechanism for regulation of LCRMP-1 on cancer cell invasiveness and clinical outcome.
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 5316. doi:1538-7445.AM2012-5316
Abstract 5381: Activation and frequency of myeloid subsets in peripheral blood is associated with clinical outcome in prostate cancer patients treated with Prostate GVAX and anti-CTLA4
Authors: Stam Anita G.M. , Santegoets Saskia , Scheper Rik , Lougheed Sinéad , Gall Helen , Jooss Karin , Sacks Natalie , Hege Kristen , Lowy Israel , Cuillerot Jean-Marie , Gerritsen Winald , van den Eertwegh Alfons , de Gruijl Tanja 
Published: August 2012

Abstract
Blockade of the CTLA-4 immune checkpoint can enhance anti-tumor responses and prolong survival, but it can also lead to the development of severe and potentially life-threatening immune-related adverse events (IRAE). To avoid unnecessary exposure to this risk, it is essential to identify biomarkers that correlate with clinical activity and can be used to recognize and select patients that will benefit from immune checkpoint blockade. We therefore performed extensive immune monitoring in a phase I/II dose escalation/expansion trial of combined Prostate GVAX (a GM-CSF-secreting allogeneic prostate cancer vaccine) and antiCTLA-4/ipilimumab immunotherapy in patients with Castration Resistant Prostate Cancer (CRPC). Here we report on the effects of the treatment on circulating myeloid cells and the identification of potential myeloid-related biomarkers. The GVAX/ipilimumab combination was clinically active with PSA declines of more than 50% in 5, and PSA stabilizations in 12 of 28 patients. Regressing bone and lymph node metastasis were observed in 2/5 PR patients. Flowcytometric monitoring of myeloid subsets in peripheral blood before and after Prostate GVAX/ipilimumab treatment revealed some striking differences between patients who benefited from therapy and patients who did not. Significant treatment-induced decreases of conventional and plasmacytoid Dendritic Cell subsets (cDC and pDC, respectively) were observed, which were paralleled by increased DC activation and recruitment to the vaccination sites. Treatment-induced activation of BDCA1/CD1c+ cDC and 6-sulfo LacNAc+ inflammatory DC was associated with significantly prolonged over-all survival (OS). In contrast, increased frequencies of CD11b+CD14−CD15+ granulocytic myeloid-derived suppressor cells (MDSC) and high pre-treatment levels of CD14+HLA-DRlo/− monocytic MDSC were associated with reduced OS. Together with similar analyses of T cell subsets, these studies have yielded an immune profile with predictive value for clinical outcome. The profile is characterized by pre- or on-treatment activation of immune effector subsets and low frequencies of regulatory/suppressive subsets. It may thus provide a potentially useful tool for patient selection and should be validated as such in other patient groups treated by antiCTLA-4 blockade.
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 5381. doi:1538-7445.AM2012-5381
Abstract 539: A preclinical model to evaluate the risk of increased dietary fat consumption and prostate cancer progression
Authors: Kobayashi Yasuyuki , De Velasco Marco A. , Hatanaka Yuji , Yamamoto Yutaka , Tanaka Motoyoshi , Masahiro Nozawa , Shimizu Nobutaka , Yoshimura Kazuhiro , Kodama Mitsuyama , Yoshikawa Kazuhiro , Nishio Kazuto , Uemura Hirotsugu 
Published: August 2012

Abstract
Prostate cancer (PCa) is a common disease in older men that is highly associated with various dietary factors including the increased consumption of fats, red and processed meats. Although results from large clinical studies have shown inconsistent findings with regards to obesity and prostate cancer-related mortality, increasing evidence has suggested a link between obesity and an increase in prostate cancer-specific mortality. To better understand the effects of increased dietary fat in prostate carcinogenesis, we developed a preclinical model using prostate-specific PTEN conditional knockout mice. This model is based on the conditional inactivation of PTEN in the prostate to alter PI3K/Akt/mTOR signaling, resulting in a stage-specific development and progression of cancer, with the ability to further develop castrate-refractory prostate cancer in a manner similar to humans. We previously showed that consumption of a high-fat diet (13.6% high fat plus N-nitroso-N-methylurea) for 75 weeks augmented prostate cancer progression in PTEN-mutant mice resulting increased metastases and decreased survival. To determine the molecular mechanisms involved in tumor promotion we randomized PTEN-mutant mice with non-castrate and castrate refractory prostate cancer to a high fat diet for 50 weeks. Chronic consumption of a high-fat diet results in increased tumor growth compared to controls. Mice fed a high fat diet showed increased levels of circulating adipokines and pro-inflammatory cytokines that include leptin, TIMP-1 IL-6, IL-10, IL-11 IGF-II, HGF and LIF. Mice fed the high fat diet also showed increased levels of tumor cell proliferation, transcriptional Stat-3 activation and neovascular angiogenesis. These findings provide evidence for the tumor promoting effects of a high fat diet and establish a preclinical model for the future development of novel chemopreventive strategies.
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 539. doi:1538-7445.AM2012-539
Abstract 5395: The E3 ligase Itch and deubiquitinase Cyld act together to regulate Tak1 and inflammation
Authors: Poojary Venuprasad K. , Ahmed Neesar , Zeng Minghui , Polin Lisa , Sinha Indrajit , Wei Wei-Zen , Rathinam Chozha V. , Flavell Richard , Massoumi Ramin 
Published: August 2012

Abstract
Chronic inflammation has been strongly associated with tumor progression, but the underlying mechanisms remain elusive. Our previous studies have achieved important new insights into key regulatory mechanism in the immune system mediated by the ubiquitin ligase, Itch, whose deficiency results in inflammatory disorders and pulmonary inflammation (Venuprasad K et al. Nat. Immunol. 2008, Venuprasad K. et al. J.Clin. Invest. 2004). We demonstrate that E3 ligase Itch and deubiquitinase Cyld formed a complex via interaction through ‘WW-PPXY’ motifs. The Itch-Cyld complex sequentially cleaved K63-linked ubiquitin chains and catalyzed Lys48-linked ubiquitination on TGF-beta activated kinase 1(Tak1) to terminate inflammatory signaling. Itch or Cyld deficiency resulted in sustained Tak1 activation and elevated production of proinflammatory cytokines by bone marrow derived macrophages (BMDMs). Tak1 selective inhibitor, (5Z)-7-Oxozeaenol abrogated Tak1 activation and production of proinflammatory cytokines by Itch-/- and Cyld-/- BMDMs. Similarly, ectopic expression of a catalytically inactive dominant-negative (Tak1-K63W) inhibited elevated cytokine production by Itch-/- and Cyld-/- BMDMs. Reconstitution of wild-type Cyld but not the mutant Cyld(Y485A), which cannot associate with Itch, blocked sustained Tak1 activation and proinflammatory cytokine production by Cyldα/β BMDMs. Deficiency in Itch or Cyld led to chronic production of tumor-promoting cytokines by tumor-associated macrophages and aggressive growth of lung carcinoma. Thus, we have identified an Itch-Cyld-mediated regulatory mechanism in innate inflammatory cells.
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 5395. doi:1538-7445.AM2012-5395
Abstract 540: Increased growth and malignant transformation of human prostate epithelial cells by chronic exposure to arsenic and estrogen
Authors: Treas Justin N. , Singh Kamaleshwar P. 
Published: August 2012

Abstract
Both Arsenic and 17β-estradiol have been shown to induce growth and neoplastic formations in prostate epithelial cells. Estrogens are involved in prostate development and function at several stages. Arsenic has mild estrogenic properties. However, the effects of the co-exposure to physiologically relevant doses of these two chemicals on human prostate epithelial cells are not known. We hypothesize that as compared to the individual exposure, the co-exposure to arsenic and estrogen will potentiate the cell growth and transformation in prostate epithelial cells. Therefore, the objective of this study was to examine the effects of chronic exposure to arsenic and estrogen both individually and in combination on neoplastic transformations and increase cell growth. Human prostate epithelial cells, RWPE-1 were treated for 6 months with sodium-meta arsenite and 17β-estradiol both alone and in combination at concentrations of 100 pg/mL and 100 ng/mL. These treated cells were maintained further for 3 months in culture media without arsenic or estrogen supplementation. The effects of these compounds on cell growth were determined by cell count and MTT assay, and malignant transformation of cells was determined by anchorage independent growth assay on soft agar. The mitogenic effects of these chemicals were further confirmed at molecular level by cell cycle analysis using flow cytometry and gene expression analysis by quantitative real time PCR. The result of this study revealed that chronic exposure to arsenic and estrogen causes increased cell proliferation and induces cell transformation as observed in colony formation assay. The combination of these two chemicals had potentiating effects on cell growth and transformation of RWPE-1 cells. The increased percentage of cells in S-phase and increased expression of CyclinD1 as well as the anti-apoptotic gene Bcl2 further confirmed the mitogenic potential of these two chemicals in RWPE-1 cells. The present findings of increased growth and transformation of arsenic and estrogen treated cells and epigenetic changes observed in these cells together suggest that these carcinogenic chemicals induce malignant transformation in prostate epithelial cells at least in part through epigenetic mechanisms.
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 540. doi:1538-7445.AM2012-540
Abstract 5468: Transgenic mice ectopically express miR-31 in basal keratinocyte, exhibit high potential for oral tumorigenesis
Authors: Lin Shu-Chun , Tseng Ssu-Hsueh 
Published: August 2012

Abstract
Oral squamous cell carcinoma (OSCC) is one of the leading causes of cancer mortality in the world. Despite that numerous advances have resulted in better control of patient morbidity, overall survival for OSCC has remained low for the past decades due to relapse and metastases. Besides, resistance to conventional therapeutic modalities stands for another important cause of treatment failure. OSCC adopts multiple genetic alterations for pathogenesis including activation of EGFR, AKT and hypoxia pathway, and other oncogenic events. Novel targeting therapy against these alterations in rodent tumors genetically resemble human tumors may confer tremendous abrogation benefits. MiRNAs are small non-coding RNAs mediating the translational repression of target mRNAs. miR-31 is among the most eminently up-regulated miRNAs in OSCC. Our works defined that miR-31 ablated expression of the HIF regulatory factor FIH (factor-inhibiting hypoxia-inducible factor) to activate hypoxia signaling and up-regulate VEGF, which contributed to OSCC pathogenesis. We established K14-GFP-miR-31 transgenic mouse lines in this study. GFP and miR-31 were detected in basal and suprabasal layers of the squamous epithelium of skin, oral cavity and esophagus in these transgenic mice. The transgenic mice exhibited higher potential for tumor induction on oral tongue and esophagus by 4-nitroquinoline 1-oxide treatment than wild type mice. The tumors induced in transgenic mice expressed more abundant K14, miR-31, VEGF and Ki-67 than tumors in wild type mice. The preneoplastic lesions on oral tongues of transgenic mice were also in more advanced stages in contrast to counterparts in wild type mice. Spontaneous occurrences of tumors in transgenic mice are being observed to insight additional oncogenic alterations essential for OSCC pathogenesis. We identified the high sensitivity of this transgenic mouse model for chemical carcinogen-induced oral tumorigenesis, and this model will be developed to select drugs or targeting strategies to facilitate human OSCC interception.
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 5468. doi:1538-7445.AM2012-5468