bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 140: XIAP expression in non-small cell lung cancer cells is a key determinant of threshold to TRAIL-induced apoptotic cell death
Authors: Yang Jianhui , Xie Yili , Witasp Erika , Kwong King F. 
Published: February 2011

Abstract
Background: Intrinsic resistance to apoptosis-induction by TRAIL is found in the majority of non-small cell lung cancers (NSCLC). Previously, we have shown that intrinsic TRAIL-resistance in NSCLC cells can be markedly attenuated by transient transfection of siRNA directed against XIAP, and accordingly rendering TRAIL-resistant NSCLC cells restored TRAIL-sensitivity, with markedly enhanced apoptosis rates. The objective of the current study is to investigate the effects of XIAP overexpression in intrinsically TRAIL-sensitive lung cancer cells with respect to its threshold to apoptotic cell death.
Methods: Lentiviral p-Receiver-lv19-XIAP (GeneCopoeia, Rockville, MD) were transduced in cultured human NSCLC H460 cells to generate stable clones. Subsequently, p-Receiver-lv19-XIAP-H460 cell colonies were screened for optimal vector expression and XIAP overexpression and then propagated in culture for further analysis. Parental H460 and negative control H460-p-empty stable clone cells were used for comparisons. p-Receiver-lv19-XIAP-H460 stable clones, negative control H460-p-empty stable clones, and H460 parental cells were cultured with and without administration of TRAIL. Also, XIAP overexpression stable clones were treated with TRAIL alone, Smac mimetic AEG40730 (Vibrant Pharma, Inc., Ontario, CN), or their combination. Cellular proliferation was measured using MTT assays. Caspase activation was evaluated using Western blot analysis and caspase activity was quantified by fluorescence caspase assays.
Results: p-Receiver-lv19-XIAP-H460 stable clone cells exhibited a significant increase in protection against TRAIL-induced cell death compared to TRAIL-sensitive parental H460 and H460-p-empty cells across a spectrum of TRAIL concentrations. Also, marked reductions in caspase activation, as a result of decreased sensitivity to TRAIL, were found in p-Receiver-lv19-XIAP-H460 cells despite TRAIL administration. Rescue treatment of p-Receiver-lv19-XIAP-H460 stable clones with combination Smac mimetic AEG40730 and TRAIL was able to negate the effects of XIAP overexpression and restore intrinsic sensitivity to TRAIL-induced cytotoxicity.
Conclusions: TRAIL resistance can be conferred to intrinsically TRAIL-sensitive lung cancer cells via XIAP overexpression alone. The increased threshold to apoptotic cell death is mediated via XIAP's inhibitory effects on the canonical apoptosis pathways. However, TRAIL-sensitivity can be rescued in XIAP overexpressing lung cancer cells by combination treatment with anti-XIAP Smac mimetic and TRAIL administration. These results, along with previous work, demonstrate that XIAP is a key determinant of apoptotic cell death in lung cancer cells.
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 140.
Abstract 141: Identification of a gene silenced in rat mammary carcinomas by combination of DNA methylation microarray and chemical genomic screening
Authors: Hattori Naoko , Okochi-Takada Eriko , Yamashita Satoshi , Watanabe Naoko , Ushijima Toshikazu 
Published: February 2011

Abstract
Aberrant DNA methylation is deeply involved in the development and progression of human breast cancers, but its inducers and molecular mechanisms are still unclear. To reveal such inducers and analyze molecular mechanisms of methylation induction, animal models are indispensable. However, genes methylation-silenced in the animal models of breast cancer are unknown, and identification of inducers and analysis of mechanisms are hampered.
Here, to identify genes methylation-silenced in rat primary mammary carcinomas, we took a combined approach of methylated DNA immunoprecipitation (MeDIP)-CpG island (CGI) microarray and chemical genomic screening. MeDIP-CGI microarray analysis of a carcinoma cell line induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) revealed that, among 4,680 promoter CGIs analyzed, 664 were methylated in the cell line. Sixty-two of the 664 genes were re-expressed by treatment of the cell line with 5-aza-2’-deoxycytidine and trichostatin A. An unmethylated status in normal mammary glands was confirmed for 31 of the 62 genes by MeDIP-CGI microarray analyses of a pool of 4 normal mammary glands. Among 13 primary mammary carcinomas induced by PhIP, five of the 31 genes were methylated in one carcinoma or more. Among 12 primary carcinomas induced by 7,12-dimethylbenz[a]anthracene, methylation of all the five genes was also observed. RT-PCR analysis revealed that one of the five genes had high expression in normal mammary glands, but low expression in carcinomas, showing that this gene was methylation-silenced in rat primary mammary carcinomas.
In humans, the gene was expressed in mammary epithelial cells that had unmethylated DNA, and was down-regulated in three cancer cell lines that had methylated DNA. The gene was methylated in about 9% of 80 primary human breast cancers, and it was suggested that aberrant DNA methylation of this gene was a common event between rat and human breast cancers.
This is the first study of genome-wide DNA methylation analysis using rat mammary carcinomas, and the methylation-silenced gene, along with the other methylated genes, is expected to be useful as a marker in identifying inducers of aberrant DNA methylation and analyzing its molecular mechanisms.
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 141.
Abstract 1411: A novel molecular approach for head and neck cancer radiosensitization
Authors: Miyamoto Shunsuke , Wang Hui , Yamashita Taku , Li Daqing , O'Malley Bert W. 
Published: February 2011

Abstract
Purpose:
Current combined external beam radiation therapy (XRT) and chemotherapy have demonstrated as an effective treatment against advanced head and neck cancers. However, combined modality treatments often result in unacceptable levels of toxicity to the patients. It has been well-known that enhanced DNA double strand break (DSB) repairing by Mre11, Rad50 and Nbs1 (MRN) complex is one of the most important mechanisms for developing radioresistance in the tumor cells. The present study investigates if the use of targeted Rad50 disruption could sensitize the tumor cells to XRT for the treatment of human head and neck squamous cell carcinoma (HNSCC). Our goal is to establish a most effective treatment strategy while minimizing XRT morbidity for the HNSCC.
Method:
Two human HNSCC tumor cell lines, JHU012 and JHU022, and an animal model with human HNSCC were used in this study. A dominant-negative recombinant adenoviral vector containing mutant Rad50 (Ad-Rad50) was constructed. The tumors were treated with Ad-Rad50, replication-defective virus (DL312), or untreated as mock control and a 2-Gy XRT. Cell viability and tumor volume were evaluated to analyze anti-tumor activity of different treatment groups. Neutral comet assay was performed for evaluating DNA DSB damage. Apoptosis in tumor cells was studied by using immunohistochemistry.
Result:
Our study demonstrates that the transgene expression of mutant Rad50 significantly interrupts the DNA DSB repairing and increases DNA damage in the tumor cells. Increased levels of tumor cell apoptosis were found associated with combined Ad-Rad50 and XRT treatment group. The combined Ad-Rad50 and XRT treatment shows the best anti-tumor result as compared to other groups both in vitro and in vivo.
Conclusion:
The present study suggests that Ad-Rad50 gene transfer effectively interrupts DNA DSB repairing and results in radiosensitizing in the HNSCC tumor cells treated with XRT. This strategy can be further investigated in the clinic for the treatment of advanced human head and neck 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 1411.
Abstract 1417: Tumour stroma interaction and radiation resistance in pancreatic cancer
Authors: Mantoni Tine S. , Lunardi Serena , Brunner Thomas B. 
Published: February 2011

Abstract
Background
Pancreatic ductal adenocarcinoma (PDAC) is characterised by a strong desmoplasmic reaction where the stromal compartment encounts for up to half the tumour volume. The enriched stroma is believed to be a contributing factor to the poor therapeutic response of PDAC, which is reflected in only 13% surviving the first year after diagnosis. A central mediator of the desmoplastic reaction is the pancreatic stellate cells (PSC). Signalling between PSC and tumour cells stimulates proliferation and migration of both cell types as well as secretion of extracellular matrix (ECM) proteins by the PSC. We aim to gain a better understanding of the crosstalk between PSC and tumour cells and how this affects tumour cell response to ionising radiation.
Methods
We have set up a co-culture system, which allow studies of tumour cells directly and indirectly co-cultured with PSC. Clonogenic survival assays were used to assess the radiosensitivity of mono- and co-cultured tumour cells. We also use in vivo mouse models to study the effects of PSC on tumour proliferation and tumour regrowth in response to radiation.
Results and conclusion
We demonstrate that PSC promote radioprotection and stimulate proliferation in pancreatic tumour cells in both direct and indirect co-culture. This is a PSC specific response as fibroblasts do not have a radioprotective effect on the tumour cells. Our in vivo studies of xenograft tumours in mice likewise demonstrate PSC dependent radioprotection and increased tumour proliferation. The kinetics of DNA repair in tumour cells were investigated but showed no changes in the presence of PSC and was therefore concluded not to form part of this radioprotective response. Previous studies have shown that cell adhesion to ECM proteins by integrin molecules mediates resistance to genotoxic stress. We here show that abrogating β1-integrin signalling by means of a blocking antibody results in a significant decrease in the PSC mediated radioresistance in tumour cells. Taken together we here demonstrate for the first time that PSC promote radioprotection of pancreatic tumour cells in vitro and in vivo. Our data points towards a role of β1-integrin signalling in this radioprotective response.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
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 1417.
Abstract 1420: Inhibition of platelet-derived growth factor receptor tyrosine kinase reduces tumor growth and metastasis in an orthotopic nude mice model of human gastric cancer
Authors: Sumida Tomonori , Kitadai Yasuhiko , Onishi Mayu , Ohara Eiji , Shinagawa Kei , Tanaka Miwako , Kodama Michiyo , Tanaka Shinji , Yasui Wataru , Chayama Kazuaki 
Published: February 2011

Abstract
Background: Recent studies have revealed that platelet-derived growth factor (PDGF) plays a role in promoting progressive tumor growth in several organs; however, whether PDGF plays a role in gastric cancer is undetermined. We examined whether inhibition of PDGF receptor (PDGF-R) tyrosine kinase signaling by imatinib affects tumor growth and metastasis of human gastric cancer cells in an orthotopic nude mouse model.
Methods: TMK1 human gastric cancer cells were injected into the gastric wall of nude mice. Groups of mice (n=10 each) received saline (control), low-dose imatinib (50 mg/kg/day), high-dose imatinib (200 mg/kg/day), cancer chemotherapeutic agent irinotecan (5 mg/kg/week), or imatinib (50 mg/kg/day or 200 mg/kg/day) and irinotecan in combination for 28 days. Tumor growth and metastasis were assessed. Resected tumors were analyzed immunohistochemically.
Results: Carcinoma-associated fibroblasts (CAFs) within gastric tumors expressed high levels of PDGF-R; cancer cells did not. Treatment with imatinib alone did not inhibit tumor growth and metastasis; however, treatment with irinotecan alone or combined with imatinib (single-agent therapy or relative control) significantly inhibited tumor growth. Only treatment with high-dose imatinib and irinotecan in combination inhibited lymph node and peritoneal metastasis. Immunohistochemically, only imatinib alone or in combination with irinotecan significantly decreased the stromal reaction, pericyte coverage of tumor microvessels, and microvessel area. These effects were marked in the high-dose imatinib group.
Conclusion: Administration of PDGF-R tyrosine kinase inhibitor in combination with irinotecan appears to impair the progressive growth of gastric cancer cells by blockade of PDGF-R signaling pathways in CAFs and pericytes on the tumor vasculature.
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 1420.
Abstract 1425: Dasatinib reverses the phenotype of cancer associated fibroblasts (CAFs) to a normal fibroblast (NAF) like phenotype
Authors: Schmid Jens O. , Haubeiss Silke , Mürdter Thomas E. , Friedel Godehard , van der Kuip Heiko , Aulitzky Walter E. 
Published: February 2011

Abstract
Cancer associated fibroblasts (CAFs) show a molecular and functional phenotype that is different from their normal counterparts (normal fibroblasts, NAFs). It is a well established phenomenon that these modified and activated fibroblasts possess permissive and promoting properties for epithelial tumor cells and therefore play a central role in tumor progression, metastasis, and probably also in sensitivity to antitumor agents. We asked whether CAFs could be reverted back pharmacologically to normal homeostasis by inhibiting PDGFR signalling.
We therefore evaluated the efficacy of the FDA approved PDGFR inhibitor Dasatinib on proliferation and gene expression profile of CAF strains isolated from different lung carcinoma specimens. Dasatinib significantly reduced proliferation without inducing cell death in all 40 CAF strains investigated. Genome-wide microarray analysis of 9 CAF strains cultivated in presence or absence of Dasatinib identified 491 genes whose expression was significantly changed at least twofold. 104 of these encoded cell cycle related proteins with a great majority of 97 being down-regulated by Dasatinib. To determine the relevance of the differentially regulated genes in Dasatinib treated cells, we compared the Dasatinib expression signature to the previously described signatures of NAFs and CAFs derived from breast cancer patients (Sadlanova et al., 2008). Importantly, 102 of the 491 genes regulated by Dasatinib were also shown to be differentially expressed in CAFs versus NAFs. The expression of 72 of the genes we identified as down-regulated by Dasatinib was also reduced in NAFs compared to CAFs (p&lt;0.0001 in Fisher's exact analysis). In addition, 30 genes identified as up-regulated by Dasatinib were also found to be elevated in NAFs compared to CAFs (p&lt;0.0001 in Fisher's exact analysis).
In summary, our data suggest that Dasatinib may reverse the cancer-activated phenotype of CAFs to a normal fibroblast like phenotype. Dasatinib treatment may therefore also reverse the tumor-promoting properties of CAFs.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
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 1425.
Abstract 143: Global DNA methylation level in whole blood and risk of non-Hodgkin lymphoma
Authors: Kim Hee Nam , Tran Huong Thi Thanh , Li Yu , Kim Nan young , Lee Il-Kwon , Kim Yeo-Kyeoung , Yang Deok-Hwan , Lee Je-Jung , Shin Min–Ho , Park Kyeong-Soo , Chung Ik-Joo , Cho Sang-Hee , Choi Jin-Su , Hyeoung-Joon Hyeoung-Joon 
Published: February 2011

Abstract
Global DNA hypomethylation may result in chromosomal instability and cancer risk. This study was performed to determine the association between DNA hypomethylation in derived from whole blood and non-Hodgkin lymphoma. We analyzed DNA of 506 NHL and 1680 control subjects at Chonnam National University Hwasun Hospital, Korea. Global DNA methylation levels were assessed using bisulfited-PCR pyrosequencing of long interspersed nuclear element-1 (LINE-1). All participants were subsequently categorized into quartiles by mean % in control. When the highest quartile was considered as a reference category (Q4), the following adjusted odds ratios (OR) and 95% confidence intervals (95% CI) were observed for decreasing methylation quartiles OR(Q3)=2.36 (95% CI:1.40-3.97); OR(Q2)=4.67 (95% CI: 2.89-7.55) and OR(Q1)=17.56 (11.19-27.56).
This is, to the best of our knowledge, the first study to show that global DNA hypomethylation was significantly associated with increased for NHL risk in a large case-control study. These findings suggest that global methylation levels in genomic DNA may be play important role in the NHL risk.
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 143.
Abstract 1433: Tumor-associated fibroblasts increase HNSCC invasion in the presence of carcinogen NNK via activation of EGFR and c-Met
Authors: Kim Joseph , Panahandeh Mary , Thomas Sufi M. 
Published: February 2011

Abstract
Tobacco smoking is a major risk factor for head and neck squamous cell carcinoma (HNSCC); one of the leading causes of cancer mortality. Nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) a major product of cigarette smoke and is a well known carcinogen. Approximately 20 − 40% of former smokers continue to smoke 1 year post-HNSCC diagnosis. The role of NNK in tumor progression remains unknown. We hypothesize that exposure to carcinogens such as NNK contributes to the invasive and metastatic ability of HNSCC. In addition we believe it affects the surrounding stromal tissue, facilitating tumor progression. In order to examine the effects of NNK on HNSCC and stomal fibroblast invasion, we used Matrigel-coated transwell invasion chambers, where the cells were plated on top of the Matrigel for 24 h following which the invaded cells were fixed, stained, and counted. Our data demonstrate that NNK (10 nM) increases invasion in both HNSCC cells as well as surrounding stromal fibroblasts though Matrigel. Further, we demonstrate that NNK treatment resulted in activation of the epidermal growth factor receptor (EGFR) and c-met in HNSCC cells. EGFR activates downstream molecules increasing HNSCC invasion. Inhibition of EGFR using the EGFR specific antibody cetuximab abrogates NNK-induced invasion in HNSCC cells. Neutralizing antibodies to HGF abrogates NNK induces invasion in the presence of tumor associated stromal fibroblasts. These findings provide important insights into mechanism whereby NNK contributes to tumor progression. Further, inhibition of EGFR abrogates NNK-mediated invasion of HNSCC and may facilitate loco-regional spread of the disease.
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 1433.
Abstract 1436: Interleukin-17A stimulates expression of chemokines and cytokines in prostatic epithelial cells via nuclear factor-kappaB and extracellular signal-regulated kinase pathways
Authors: You Zongbing , Ge Dongxia , Liu Sen 
Published: February 2011

Abstract
T helper 17 (Th17) cells secret interleukin-17A (IL-17A) and interleukin-17F. Th17 cells and IL-17A are increased in prostate tumors. The role of IL-17A in prostate cancer is not clear. The objective of this in-vitro study was to investigate the effects of IL-17A on prostatic epithelial cells. Cell growth assay, Western blot, and real-time quantitative reverse transcription- polymerase chain reaction (qRT-PCR) analysis were used to measure the effects of IL-17A on the immortalized normal human prostatic epithelial cell lines (RWPE-1 and pRNS-1-1), human high-grade prostatic intraepithelial neoplasia (PIN) cell line, human prostate cancer LNCaP cell line, and mouse prostate cancer TRAMP-C1 cell line. We found that recombinant human IL-17A (20 ng/ml) did not affect cell growth rate in any of the prostatic cell lines studied. IL-17A did not significantly activate Nuclear Factor-kappaB (NF-kappaB) or Extracellular signal-Regulated Kinase (ERK) signaling pathway in RWPE-1, pRNS-1-1, or PIN cells. IL-17A activated NF-kappaB and/or ERK signaling pathways in LNCaP and TRAMP-C1 cells. When IL-17RC (receptor of IL-17A) was overexpressed in PIN and LNCaP cells, activation of NF-kappaB or ERK signaling pathway by IL-17A was significantly enhanced. IL-17A modestly induced mRNA expression of chemokines (CXCL1 and CXCL2) in RWPE-1, pRNS-1-1, and PIN cells. IL-17A induced mRNA expression of chemokines (CXCL1, CXCL2, CCL2, CCL5, CCL7, and CCL20) and cytokine IL-6 in LNCaP cells. In mouse TRAMP-C1 cells, IL-17A induced mRNA expression of chemokines (CXCL1, CXCL2, CXCL5, CCL2, and CCL5) and cytokine IL-6. When IL-17RC was overexpressed in PIN and LNCaP cells, chemokine expression was significantly enhanced. Our findings suggest that although IL-17A has no effects on cell growth in-vitro, it may modulate the stroma-epithelial interaction in tumor microenvironment in-vivo via stimulation of expression of chemokines and cytokines.
Acknowledgement: DoD W81XWH-05-1-0567, NIH/NCRR 2P20 RR020152-06, and LCRC Fund.
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 1436.