bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2470: Clinically used selective aldosterone blocker attenuates hepatocarcinogenesis via angiogenesis inhibition in rats
Authors: Noguchi Ryuichi , Yoshiji Hitoshi , Ikenaka Yasuhide , Kaji Kosuke , Shirai Yusaku , Fukui Hiroshi 
Published: February 2011

Abstract
Hepatocellular carcinoma (HCC) is now a major health problem. Since the high-risk group of either primary or secondary HCC development seems to be clearer than in the other types of tumors, it is likely that chemopreventive agents will be beneficial in improving the prognosis of HCC. In addition to assessment of tumor growth, recent studies have demonstrated that angiogenesis plays a pivotal role in the hepatocarcinogenesis process. Although several anti-angiogenic agents have already been employed in the clinical practice, most patients show adverse reactions with new drugs. An alternative approach may be to find a clinically available compound that also exhibits anti-angiogenic activity for which the safety of long-term administration has been proven. We previously reported that angiotensin-II (AT-II) was a prerequisite for hepatocarcinogenesis. Suppression of AT-II by angiotensin-converting enzyme inhibitor attenuates hepatocarcinogenesis via-suppression of neovascularization in the clinical practice. Recent studies have also suggested possible involvement of aldosterone (Ald) in neovascularization. The aim of our current study was to elucidate the effect of the clinically used eplerenone, a selective Ald blocker (SAB), on the rat hepatocarcinogenesis especially in conjunction with angiogenesis. We employed the rat hepatocarcinogenesis model, induced by feeding the rats on a choline-deficient, L-amino acid-defined diet without any carcinogen (CDAA model). The effects of SAB on the development of liver enzyme (namely, the placental form of glutathione-S-transferase (GST-P))-altered pre-neoplastic lesions and angiogenesis were examined. We also performed an in-vitro study to elucidate the possible mechanisms involved. Treatment with SAB markedly inhibited GST-P-positive lesions along with suppression of neovascularization. The hepatic vascular endothelial growth factor (VEGF) was also significantly attenuated. Our in-vitro study showed that Ald augmented both proliferation and tubule formation of the endothelial cells, and that SAB inhibited both activities in a dose-dependent manner via inhibition of phosphorylation of the extracellular signal-regulated kinase 1/2. These results indicated that, as well as AT-II, Ald plays a pivotal role in hepatocarcinogenesis, and that augmentation of angiogenesis is involved. Since SAB is already widely used in the clinical practice with proved safety, this drug may represent a potential new strategy for chemoprevention against HCC in the future.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2470.
Abstract 2472: The role of aging T-cells in prostate cancer development
Authors: Angulo Alejandra De , Jolly Christopher A. , Faris Robert , Cavazos David , Salcedo Ramona , Apte Shruti , Chen Cindy , deGraffenried Linda A. 
Published: February 2011

Abstract
As men age past 40, their chance of developing prostate cancer increases exponentially each year. The mechanism by which age influences the risk of prostate cancer remains largely unknown, hindering the development of effective preventive interventions. As one ages, there are significant changes in immune response regulation and outcome. This includes an age-related loss of appropriate T cell function. This loss of appropriate T cell function is associated with a change from anti-inflammatory to pro-inflammatory cytokine production as well as decreased appropriate immune surveillance. We hypothesize that one mechanism by which age increases the risk for prostate cancer may be through these alterations in immune response by the T cells. To date, the specific contribution of an aging immune system to prostate cancer initiation and progression has been difficult to determine because of the lack of appropriate model systems to evaluate this phenomena. We have recently begun studies investigating the contribution of an aging T cell population to prostate cancer progression using a highly unique and innovative animal model, the glycerol-3-phosphate acyltransferase-1 (GPAT-1) knock out mouse. The GPAT-1 KO young mouse has a T cell phenotype which mimics old wild type mice. We have recently initiated a series of in vitro studies to evaluate the effects of exposure of sera from GPAT KO mice on pro-inflammatory signaling in LNCaP prostate cancer cells. Exposure to sera from young GPAT KO mice resulted in strong induction of NF-κB activity in LNCaP cells compared to both the sera from the age-controlled wild type mice and the sera-free conditions. We are currently evaluating the significance of this NF-κB induction as well as the induction of other pro-inflammatory pathways by the GPAT KO mouse sera in promoting a more aggressive phenotype in our cancer cells. Additionally, LNCaP cells exposed to conditioned media from stimulated T-cells from the GPAT KO mice demonstrated induction of Akt phosphorylation. Previous studies have shown an important role for NF-kB and Akt in promoting inflammation and survival in prostate cancer cells. Currently, we are evaluating how GPAT KO mouse sera might promote a more aggressive phenotype in LNCaP prostate cancer cells. These studies would be the first to demonstrate a specific modulation of prostate cancer signaling by sera from mice that directly reflect an aging T cell phenotype suggesting that age-related loss of appropriate T cell function might contribute to the increased risk for prostate cancer in the elderly.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2472.
Abstract 2473: Effects propolis on inflammation-related rat colon carcinogenesis induced by DMH and DSS
Authors: Obo Yumi , Sokuza Yui , Wei Min , Kakehashi Anna , Tei Keiko , Wanibuchi Hideki 
Published: February 2011

Abstract
Propolis has been reported to have anti-inflammatory, anti-oxidative and anti-tumor effects. The purpose of the present study is to evaluate the effects of propolis on inflammation-related rat colon carcinogenesis induced by 1,2-dimethylhydrazine (DMH) and dextran sodium sulfate (DSS). Six week-old F344 males rats were divided into 3 groups of 20 rats each. All rats were given subcutaneous injections of DMH at dose of 40 mg/kg/b.w. twice in the first week, and followed by 1% DSS in drinking water for 1 week. After 1 week of DSS treatment, groups of rats were fed diet containing 1% ethanol-extracted propolis (EEP), 1% water-extracted propolis (WEP) or basal diet for 29 weeks. The average numbers of Tubular adenocarcinoma were 2.2 ± 3.5, 0.4 ± 0.6 and 1.2 ± 1.7/rat in basal diet group, EEP and WEP groups, respectively. There were significant difference in the number of Tubular adenocarcinoma between basal diet group and EEP or WEP groups. The present research indicated that EEP exerts suppression effect on inflammation-related rat colon carcinogenesis induced by DMH and DSS.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2473.
Abstract 2475: Effect of mTOR inhibition by rapamycin on promotion of skin tumors in BK5. Aktwt transgenic mice
Authors: Rho Okkyung , Jiang Guiyu , Sandifer Allyson , DiGiovanni John 
Published: February 2011

Abstract
Akt is a serine/threonine kinase involved in a variety of cellular responses including cell survival and proliferation. It has been shown that PI3K/Akt signaling is frequently altered (upregulated) in human cancers. mTOR is one of the Akt downstream signaling pathways that regulates protein synthesis, cell growth and proliferation. mTOR exists in two complexes, mTORC1 and mTORC2. Our laboratory previously reported that tumor promoters including TPA, okadaic acid (OA), and chrysarobin (CHRY) activate epidermal Akt after topical treatment of mouse epidermis and mouse primary cultured keratinocytes. Activation of Akt during tumor promoter treatment leads to enhanced downstream signaling including mTORC1 pathways. BK5. Aktwt transgenic mice where Akt is overexpressed in basal epidermis were significantly more sensitive to two-stage carcinogenesis, showing tumors with a much shorter latency, considerably larger in size, and enhanced progression of papillomas to SCCs. Importantly, Akt transgenic mice showed significant elevations in several downstream signaling pathways both in the absence and presence of TPA, including mTORC1 activity. Collectively, the studies with transgenic mice overexpressing Akt in epidermis (BK5.Aktwt) have suggested that activation of mTORC1 signaling may contribute to the process of skin tumor promotion. In this study, we have examined the ability of rapamycin, a known inhibitor of mTOR, on mTORC1 signaling in relation to its effect on TPA-induced epidermal cell proliferation and skin tumor promotion. Rapamycin given at doses of 1 μmol, 100 nmol, 20 nmol, and 5 nmol 30 min prior to 6.8 nmol TPA treatment inhibited mTORC1 activity in a dose-dependent manner. Notably, in a multiple treatment regimen (4 applications of rapamycin and TPA over a two week period) high doses of rapamycin significantly inhibited TPA-induced Akt phosphorylation at serine 473 as well as mTORC1 signaling in a dose dependent way, suggesting mTORC2 inhibition induced by prolonged high dose rapamycin treatment. The ability of rapamycin (at doses of 100, 20, and 5 nmol per mouse) to inhibit skin tumor promotion by TPA in BK5. Aktwt transgenic mice was compared with wild-type mice. Rapamycin significantly reduced TPA promotion in BK5.Aktwt mice, however, it was less effective compared to similar doses used in wild-type mice. The data demonstrate that rapamycin, although less effective, still retained significant inhibitory activity toward TPA promotion even when Akt and mTOR activities were elevated. These data demonstrate an important role for mTOR signaling in skin tumor promotion of TPA.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2475.
Abstract 2480: Role of Stat1 in epithelial carcinogenesis
Authors: Bozeman Ronald , Abel Erika , DiGiovanni John 
Published: February 2011

Abstract
Aberrant expression and/ or activity of STATs 1, 3, and 5 have been reported in multiple human cancers as well as in murine models of tumorigenesis. Previous work performed in our lab demonstrated a critical role for Stat3 in mediating the initiation and promotion stages of epithelial multi-stage carcinogenesis in mouse skin. In light of these findings, we have begun investigating the role of other STATs, particularly Stat1, in multistage skin carcinogenesis using both wild-type and Stat1 knockout (KO) mice. Western blot analyses revealed that topical application of the skin tumor promoters 12-O-tetradecanoylphorbol-13-acetate (TPA) and chrysarobin induced phosphorylation of Stat1 in mouse epidermis. In addition, following treatment with chrysarobin, the level of total Stat1 protein was also dramatically elevated. To further investigate the role of Stat1 during epithelial carcinogenesis, Stat1 KO mice and wild-type littermates were initiated with 25 nmol DMBA and promoted with either 6.8 nmol TPA or 220 nmol chrysarobin. No significant differences were observed in either tumor incidence or multiplicity when TPA was used as the promoting agent, suggesting that Stat1 does not play a significant role in TPA-mediated skin tumor promotion. In contrast, Stat1 KO mice exhibited a dramatic reduction in both tumor multiplicity and incidence as compared to wild-type littermates when chrysarobin was used as the promoting agent. Additionally, following topical treatment with chrysarobin, Stat1 KO mice had a reduced epidermal proliferative response. To further investigate the impact of Stat1 deletion on chrysarobin-induced tumor promotion, Stat1 KO mice and wild-type controls were treated topically with chrysarobin and the inflammatory response was assessed. Stat1 KO mice displayed a significant reduction in Cox-2 induction compared to wild-type controls. Preliminary findings also showed that Stat1 KO mice have reduced immune cell influx following chrysarobin treatment. To investigate the potential role of reactive oxygen species (ROS) in the effects of chrysarobin on Stat1 activation, the dorsal skin of FVB mice were pre-treated topically with the anti-oxidants ascorbyl palmitate and α-tocopherol acetate. Topical application of α-tocopherol acetate significantly attenuated the epidermal proliferative response and Stat1 activation suggesting that chrysarobin-mediated generation of ROS may play a role in its effects on Stat1 during tumor promotion. Additional studies are underway to further determine the mechanistic basis for the role of Stat1 in chrysarobin-mediated tumor promotion. Supported by NIH grant CA 76520.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2480.
Abstract 2483: Transgenic mice to evaluate the role of S-adenosylmethionine decarboxylase in skin carcinogenesis
Authors: Shi Chenxu , McCloskey Diane E. , Pegg Anthony E. , Feith David J. 
Published: February 2011

Abstract
To evaluate the role of S-adenosylmethionine decarboxylase (AdoMetDC) and altered polyamine levels in mouse skin carcinogenesis, we utilized the tetracycline-regulated system to produce conditional expression of AdoMetDC in basal keratinocytes. AdoMetDC is a key enzyme in polyamine biosynthesis and it catalyzes the decarboxylation reaction converting AdoMet to dcAdoMet. dcAdoMet provides the aminopropyl groups for the synthesis of the higher polyamines spermidine and spermine from the precursor putrescine. Therefore, elevated AdoMetDC activity may promote the synthesis of higher polyamines at the expense of putrescine, and increased putrescine levels are tightly linked to tumor promotion in mouse skin. AdoMetDC activity is also known to be induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). To make the DNA construct for microinjection, human AdoMetDC cDNA was inserted into the TetO vector followed by an internal ribosome entry site and luciferase coding sequence. Potential founder mice were crossed to mice with skin-specific expression of tetracycline-regulated transcriptional activator (tTA) directed by bovine keratin 5 (K5) promoter elements to generate K5-tTA/TetO-AdoMetDC bitransgenic mice. Transgene expression has been characterized by in vivo bioluminescent imaging of luciferase activity, in vitro luciferase activity as well as AdoMetDC activity assay and Western blotting in 7 week old mice. In bitransgenic mice, AdoMetDC is constitutively expressed in the skin and expression can be repressed by exposure to the tetracycline analogue doxycycline (Dox). In untreated bitransgenic mice generated from two founder lines, we saw a massive increase in luciferase activity and these mice have a thin fur phenotype. Minimal transgene expression is detected in either single transgenic TetO-AdoMetDC or Dox-treated bitransgenic mice. Untreated bitransgenic mice from one founder line exhibit a 7.2- fold increase in AdoMetDC activity in epidermis, a 7.8-fold increase in dermis, and dcAdoMet levels are also elevated by 8.0-fold in dermis. Effects of AdoMetDC overexpression on TPA induced polyamine biosynthesis and susceptibility to 7,12-dimethylbenz(a)anthracene/TPA carcinogenesis are now being investigated. These mice with regulated AdoMetDC expression in the skin provide a valuable model system to evaluate the role of AdoMetDC and polyamines in skin carcinogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2483.
Abstract 2488: γ-Secretase inhibitor blocks cell proliferation in gastric cancers through mitotic arrest and apoptotic cell death
Authors: Shin Ji Young , Yi HwaJung , Chun Kyung-Hee 
Published: February 2011

Abstract
Gastric cancer is one of the most common cancers with mortal malignancy. Most patients with advanced gastric cancer have been treated with anti-cancer chemotherapies such as fluorouracil (5-FU), cisplatin and anthracycline which block mitotic cell division and induce consequent apoptotic cell death. However, there are needed novel gastric therapies and/or develop the new agents to overwhelm the resistance for traditional chemotherapeutic agents. Recent studies have reported that the Notch signaling pathway is associated with human gastric cancer and other cancers. Notch receptors are transmembrane proteins which are cleaved by protelolytic emzymes (gamma-secretase) and release their intracellular domain (ICD) upon activation status by ligand binding. In previous reports, notch intracellular domain (NICD) turns on target genes which are related with tumorigenesis such as COX-2, c-Myc and Snail in cancers, including gastric cancer cells. Thus we speculated that the blockage of notch signal would be useful strategy for chemotherapy of gastric cancers. We initially showed that Notch receptors and ligands are expressed in various gastric cancer cells through RT-PCR and western blotting. We also confirmed that Notch signals are activated in gastric cancer cells by Notch reporter gene analysis. Furthermore, GSI treatment reduced cell survival rate in gastric cancer cells, including AGS, SNU1, SNU601, and SNU638 cells. We observed G2/M mitotic arrest and subG1 arrest by GSI treatment in gastric cancer cells, accompanying with the increase of mitotic gene cyclin B1, cdc2, p21, and apototic caspase-3 activation. To demonstrate the effect of p21 increasing by GSI treatment, cell proliferation and G2/M cell cycle arrest was inhibited by GSI treatment in Myr-AKT lentivirus infection cell. Also, p21 and cyclinB1 protein levels were not increased after rapamycin treatment in Myr-AKT lentivirus infection cell. Collectively, these results suggest that GSI, which block Notch signal, would be a potential therapeutic drug in gastric cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2488.
Abstract 249: A Sleeping Beauty screen in mice identifies Zmiz1 as a candidate cancer gene in human squamous cell carcinomas
Authors: Rogers Laura M. , Swick Brian L. , Meyerholz David K. , Dupuy Adam J. 
Published: February 2011

Abstract
Cutaneous squamous cell carcinoma (SCC) is the second most frequent cancer in the United States, with over 250,000 new cases diagnosed annually. Current treatments rely upon surgical excision of the cancerous tissue. Often, however, surgical removal can be difficult for patients because tumors commonly develop on sun-exposed surfaces such as the face, ears, and hands. In addition, a low percentage of patients exhibit aggressive metastases that are not easily removed and often result in death. A deeper understanding of the underlying genes involved in disease initiation and progression will be essential for the development of nonsurgical treatments. A recent Sleeping Beauty (SB) transposon insertional mutagenesis screen identified Zmiz1 as a candidate cancer gene in cutaneous SCCs. Intriguingly, over 90% of SB-induced skin SCCs harbored mutations within the Zmiz1 gene, predicted to cause overexpression of an N-terminally truncated protein, which we named Zmiz1mut. Immunohistochemistry (IHC) analysis of SB-induced SCCs revealed aberrant nuclear Zmiz1 localization in tumor samples, while nuclear staining was absent in normal mouse skin. Importantly, nuclear Zmiz1 was also detected in ∼70% of human SCC tumors analyzed by IHC, indicating that aberrant Zmiz1 expression may also play a role in human disease. Furthermore, we have discovered that Zmiz1 nuclear staining is present in a significant percentage of breast, colon, and ovarian cancers.
The purpose of this study is to determine the functional significance of Zmiz1 mutation in cutaneous SCC. To this end, we engineered transgenic mice that express Zmiz1mut in a Cre-dependent manner. We crossed these mice to a K14-Cre strain to induce Zmiz1mut expression in the skin. Offspring inheriting both alleles proved to be tumor-prone, with over 80% of these animals developing SCC. These data confirm that Zmiz1 has oncogenic potential in the skin. Sequencing analysis of cDNA from tumors produced by our Zmiz1mut transgenic model uncovered no mutations in either p53 or H-Ras_mutations that are observed in other mouse models of skin cancer. IHC was also performed on tumor sections. As before, we observed a strong nuclear staining pattern in the tumors induced by Zmiz1mut expression, leading us to hypothesize that nuclear accumulation of Zmiz1 plays an active role in tumorigenesis. Current efforts are focused on further characterization of our unique skin cancer model and discovering the driving force behind nuclear accumulation of Zmiz1.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 249.