bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 461: Identification of COX-2 as a major actor of the transcriptomic adaptation of endothelial and tumor cells to cyclic hypoxia: impact on angiogenesis and metastases
Authors: Daneau Géraldine , Boidot Romain , Martinive Philippe , Feron Olivier 
Published: February 2011

Abstract
Purpose: Cyclic hypoxia in tumors originates from heterogeneities in red blood cell flux and influences tumor cells but also endothelial cells lining tumor blood vessels. Whether pO2 fluctuations, in particular transient reoxygenation periods, alter the well-known hypoxia-inducible factor (HIF)-dependent gene program is largely unknown. Experimental design: We compared the transcriptomic profiles of endothelial and tumor cells exposed to cyclic hypoxia vs continuous hypoxia to uncover a possible differential impact on angiogenesis and metastases. Results: Microarray analyses identified early genes that were selectively induced by cyclic hypoxia in endothelial cells. Among them, we focused on PTGS2 since the observed increase in mRNA expression led to a significant increase in the expression and the activity of COX-2 (the protein product of PTGS2). HIF-1α was shown to be stabilized by cyclic hypoxia (despite reoxygenation periods) and to favor COX-2 induction, as validated by the use of echinomycin and HIF-1α targeting siRNA. Using a specific COX-2 inhibitor and a dedicated COX-2-targeting siRNA, we documented that COX-2 accounted for the higher endothelial cell survival and angiogenic potential conferred by cyclic hypoxia. Cyclic hypoxia also led to a preferential COX-2 induction in tumor cells and, contrary to continuous hypoxia, fostered a higher metastatic take of pre-challenged tumor cells. Conclusions: Our study documents that PTGS2/COX-2 is part of a cyclic hypoxia gene signature and largely accounts for the unique phenotype of endothelial and tumor cells exposed to fluctuations in pO2, thereby offering new perspectives for the clustering of tumors expressing COX-2 together with other cyclic hypoxia-responsive genes.
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 461.
Abstract 4613: Targeting ER-KDM1 axis to sensitize therapy resistant breast cancer cells to hormonal therapy
Authors: Cortez Valerie , Nair Sujit S. , Tekmal Seshidar Rao , Vadlamudi Ratna K. 
Published: February 2011

Abstract
Estrogen-induced breast carcinogenesis is characterized by global changes in histone modifications. KDM1 (also known as LSD1) a histone demethylase enzyme, plays a key role in establishing specific histone methylation marks at ERα target gene promoters. Emerging evidence suggests histone methylation imposes ligand dependency; and deregulation of this epigenetic pathway potentially contributes to hormonal independence and adaptive resistance in breast cancer. Our study examined the therapeutic efficacy of pargyline, a KDM1 inhibiting drug, and evaluated the therapeutic benefit to curb growth of therapy resistant breast cancer cells. We used several model cell lines shown to exhibit resistance to hormonal therapy including MCF7-HER2, MCF7-Tam, MCF7-Ca-LTLT, MCF7-PELP1 and parental MCF7 cells as controls. Reporter gene assays showed KDM1 enhanced ERα- mediated transcription in therapy resistant cells. KDM1 functionally interacts with ERα coregulator PELP1 and is co-recruited with PELP1 to ERα target genes. Pargyline treatment substantially inhibited ERα transactivation functions. ChIP analysis revealed distinct activating histone methylation modifications at growth regulatory ERα target genes in aggressively growing and therapy resistant breast cancer cells. Breast cancer models treated with pargyline facilitated reversal of the observed specific modifications and thereby inhibited the growth of breast cancer cells in vitro and in vivo nude mice models. Pargyline also showed significant effect in blocking local estrogen synthesis via alterations in histone methylation modifications at the aromatase promoter. Combinational therapy using three agents that: (a) block ERα's nuclear actions (tamoxifen or letrozole), (b) ERα's extranuclear actions (dasatinib) and (c) ERα's epigenetic modifications (pargyline) showed most promising therapeutic effect compared to single agent therapy on the growth of therapy resistant cells. Our results suggest that histone methylation modifications play a role in therapy resistance and validate the therapeutic potential of pargyline in combinational therapies. Collectively, our results suggests targeting KDM1 axis with pargyline in combination with current endocrine therapies will have better therapeutic effect and may inhibit or delay development of hormonal resistance. This study is funded by Komen grant KG090447.
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 4613.
Abstract 4617: Novel antiestrogens, SS1020 and SS5020, for breast cancer therapy and prevention
Authors: Shibutani Shinya , Suzuki Naomi , Liu Xiaoping , Kim Hyo Jeong , Laxmi Y. R. Santosh , Okamoto Yoshinori 
Published: February 2011

Abstract
Tamoxifen (TAM) is widely used as a first-line endocrine therapy for breast cancer patients and as a prophylactic agent for women at high risk of developing this disease. Long-term administration of TAM has serious side effects, including endometrial cancer. These side-effects are due to the DNA damaging and/or estrogenic action of the drug. Raloxifene (RAL) approved as a chemopreventive agent for postmenopausal women at high risk for invasive breast cancer retains an estrogenic action. The poor bioavailability of RAL requires high doses to obtain an efficacy equivalent to that achieved with TAM. Several other antiestrogens developed were dropped out from the clinical trials due to their undesirable effects on the uterus. Therefore, development of new antiestrogen alternatives, but free of genotoxic and estrogenic potential, having significant antitumor potential beyond TAM and RAL is urgently required. SS1020 and SS5020 were developed as a new triphenylethylene antiestrogen and benzopyran antiestrogen, respectively, in our laboratory. Although TAM is a hepatic carcinogen and produces a high level of DNA damage in rats, both SS1020 and SS5020 did not produce such DNA damage. Unlike TAM and RAL, SS1020 and SS5020 had no detectable uterotrophic activity in OVX-rats treated even with a high dose (10 mg/kg). These indicate that SS1020 and SS5020 are free of genotoxic and estrogenic activities. The antitumor potential of SS1020 or SS5020 against 7,12-dimethyl-benz(a)anthracene-induced mammary carcinoma in rats and human MCF-7 breast cancer xenograft in athymic nude mice was superior to that of TAM and RAL. SS1020 has a much higher bioavailability than RAL, endowing it with higher antitumor potential than RAL. In addition, the development of estrogen-induced mammary tumor in rats was completed inhibited by dietary intake of SS1020, indicating that this compound has preventive potential. Taken together, SS1020 and SS5020 lacking genotoxic and estrogenic actions have anti-breast cancer activity superior to that of TAM and RAL. Both SS1020 and SS5020 are safer and more effective antiestrogen candidates for breast cancer therapy and prevention.
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 4617.
Abstract 4639: Prognostic significance and molecular associations of CDKN2A (p16) promoter methylation and loss of expression in colorectal cancer
Authors: Shima Kaori , Nosho Katsuhiko , Baba Yoshifumi , Cantor Mami , Giovannucci Edward L. , Fuchs Charles S. , Ogino Shuji 
Published: February 2011

Abstract
Background: p16 (CDKN2A/Ink4a) is a cyclin-dependent kinase inhibitor and functions as a tumor suppressor. CDKN2A promoter methylation and gene silencing are associated with the CpG island methylator phenotype (CIMP) in colorectal cancer. However, prognostic significance of CDKN2A methylation or loss of p16 expression independent of CIMP status has not been studied.
Patients and Methods: Utilizing 940 colorectal cancers (stage I-IV) in two independent cohort studies (the Nurses’ Health Study and the Health Professionals Follow-up Study), we quantified DNA methylation in the CDKN2A promoter real-time PCR (MethyLight) and detected hypermethylation in 269 tumors (29%). By immunohistochemistry, we detected loss of p16 (CDKN2A) expression in 25% (200/804) of tumors. We also analyzed DNA methylation in LINE-1 and 7 other CpG islands (CACNA1G, CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1); microsatellite instability (MSI); KRAS, BRAF and PIK3CA mutations; and expression of β-catenin, p53, p21, p27, cyclin D1, fatty acid synthase (FASN), and cyclooxygenase-2 (PTGS2, COX-2).
Results: In multivariate logistic regression analysis, CDKN2A methylation was independently associated with CIMP-high [adjusted odds ratio (OR) 41.6; 95% CI, 21.6-80.0; vs. CIMP-0], CIMP-low (adjusted OR 5.66; 95% CI, 3.75-8.53; vs. CIMP-0), and COX-2 negativity (adjusted OR 0.46; 95% CI, 0.29-0.74; COX-2 -positive vs. negative). Both CDKN2A promoter methylation and loss of p16 were significantly associated with high overall mortality in univariate Cox regression analysis [hazard ratio (HR), 1.31; 95% CI, 1.07-1.60; p=0.009 (CDKN2A methylation), HR, 1.30; 95% CI, 1.03-1.63; p=0.026 (loss of p16)] but not in multivariate analysis [HR, 0.79; 95% CI, 0.57-1.09; p=0.14 (CDKN2A methylation), HR, 1.00; 95% CI, 0.79-1.27; p=0.98].
Conclusion: Both CDKN2A promoter methylation and loss of p16 expression in colorectal cancer are not independently associated with patient survival. However, CDKN2A promoter methylation is independently associated with CIMP and COX-2 negativity.
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 4639.
Abstract 4660: Double combination array analysis detected A kinase anchor protein 12 (AKAP12) gene as a new tumor suppressor gene of hepatocellular carcinoma
Authors: Hayashi Masamichi , Nomoto Syuji , Kanda Mitsuro , Okamura Yukiyasu , Fujii Tsutomu , Sugimoto Hiroyuki , Takeda Shin , Nakao Akimasa 
Published: February 2011

Abstract
Background Hepatocellular carcinoma (HCC) is the fifth most common malignancy and is caused environmental and genetic factors. However, little is known about the genetic characteristics of HCC cells. In this study, we investigated a novel tumor suppressor gene in HCC by double combination array method, consisting of both expression array analysis and karyotyping analysis of single-nucleotide polymorphism (SNP) array, using the same surgical specimen. Methods We performed double combination array analysis of the HCC sample from a 68-year-old woman with chronic hepatitis type C. The Affymetrix HGU133A and HGU133B was used for expression profiling and the Affymetrix GeneChip Mapping 500K array was used for SNP array. We verified the identified gene by using HCC cell lines and 48 primary HCC tissues of patients who had undergone hepatectomy at our hospital. Results AKAP12 gene expression was decreased in tumor tissue by the expression array analysis. This gene is said to produce a structurally diverse protein associated with protein kinase A, which blocks tumor cell growth and invasion. The copy number at locus 6q24-q25 did not show chromosomal deletion by the SNP array analysis. This gene was also revealed to have a CpG rich promoter region. We could recognize promoter hypermethylation by sequence analysis of the HCC cell lines. Furthermore, AKAP12 gene expression was reactivated after 5-aza-2′-deoxycytidine (5-aza-dC) treatment. As for the 48 HCC samples, 41 cases (85%) showed promoter hypermethylation by methylation specific PCR. In these cases, the values of AKAP12 gene expression in tumor tissues, which were examined by quantitative real-time PCR, were significantly lower (P = 0.0001) than those in adjacent non-cancerous tissues. Finally, we evaluated the downregulated status of AKAP12 and the clinico-pathological findings. The downregulated cases were correlated with poor overall survival rate, although the diffenrence was not significant (P = 0.115). Conclusion Our double combination array method successfully detected a tumor suppressor gene of HCC which has yet to be identified. The downregulation of AKAP12 gene occurred by promoter hypermethylation and correlated with poor prognosis.
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 4660.
Abstract 4679: Integrin and FAK signaling regulate ARHI-induced autophagy
Authors: Lu Zhen , Liao Warren S. , Suh Grace K. , Bast Robert C. 
Published: February 2011

Abstract
Autophagy selectively degrades cellular proteins, protein aggregates and organelles, providing energy in a nutrient deprived environment. We have reported that re-expression of ARHI, a maternally imprinted Ras-related tumor suppressor gene that is down regulated in more than 60% of ovarian cancers, induces autophagy. Persistence for ARHI-induced autophagy for several days is lethal for ovarian cancer cells in culture. In xenografts, however, ARHI-induced autophagy does not kill ovarian cancer cells, but rather is required to maintain a dormant state in the absence of a vascular supply. When ARHI is downregulated in vivo, previously dormant xenografts grow promptly and outgrowth of cancers is inhibited by treatment of dormant cancer cells with chloroquine. Growth factors (IGF-1, IL-8, VEGF) and ECM components (fibronectin) in the cancer microenvironment can rescue ovarian cancer cells from ARHI-induced autophagic death in cell culture. Rescue was associated with partial reversal of ARHI-mediated inhibition of PI3K signaling and AKT and mTOR activity. Consequently, we have hypothesized that both autophagy and survival factors (IGF-1, fibronectin) are required to maintain dormancy, where autophagy provides energy for avascular xenografts and survival factors prevent autophagic death by partially reversing inhibition of PI3K signaling. Here, we show that re-expression of ARHI in SKOv3 ovarian cancer cells inhibited integrin β1 expression and decreased FAK activation, stimulated by fibronectin and growth factors (IGF-1). Consistent with the importance of ECM, addition of fibronectin, a receptor for αvβ1 integrin, induced FAK activity and diminished ARHI-induced autophagy; whereas addition of neutralizing antibody against integrin β1 decreased FAK and Akt activities, enhancing autophagy. Autophagy induced by ARHI is dramatically reduced in cells that overexpress FAK and knockdown of FAK by RNA interference enhances ARHI-induced autophagy in ovarian cancer cells cultured on fibronectin. Our results suggest that the ECM and growth factors in the tumor microenvironment function to coordinate the activities of integrin β1, FAK and Akt to regulate ARHI-mediated autophagy, contributing to the survival of dormant ovarian 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 4679.
Abstract 4683: Coexistence incidence and clinicopathologic characteristics of gastrointestinal stromal tumors with gastrointestinal carcinoma
Authors: Wen Li , Ren Xu-gong , Huang Yan-li 
Published: February 2011

Abstract
Objective Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumors of the digestive tract. The coexistence with other gastrointestinal carcinoma is unique. The aim of this study was to investigate the coexistence of GIST with other primary gastrointestinal carcinoma and its clinicalpathologic features. Methods 113 patients had been diagnosed as GIST in three local hospitals from 2002 to 2008. The surgical specimens were analyzed with an immunohistochemical panel that included staining for CD117, CD34, SMA and Ki-67. Results 16.8 % of (19 of 113) patients with GIST were co-diagnosed as gastrointestinal carcinoma. The average age at diagnosis was 57 years (range, 43 to 66), two years older than that of the patients only with GIST (range, 43 to 71). The patients with the coexistence of GIST and gastrointestinal carcinoma included 11 males and 8 females. The male-to -female ratio was 1.38:1, which is higher than that of the patients of GIST without the carcinoma (1.24:1). 26.3% GIST with the carcinoma was found in the esophagus (5 of 19) and 73.7% in the stomach (14 of 19) and non in the intestine. In contrast, only 5.3% GIST without the carcinoma was found in the esophagus (5 of 94) which was less incidence in the esophagus than that of coexistence of GIST and the carcinoma (P &lt; 0.05), 84.0% in the stomach and 10.6% in the intestine, which higher incidence in the intestine than that of coexistence of GIST and the carcinamo (P &lt; 0.05). The mean diameter of 19 GISTs with the carcinoma was 1.91 cm (range, 0.6 to 3.8 cm) smaller than that of 94 GISTs without the carcinoma (5.42 ± 6.17 cm, p &lt; 0.05). 15.8% of the patients with coexistences of GIST and the carcinoma showed lower dysplasia, whereas 41.5 % of GIST patients without the carcinoma had the dysplasia and 33.0 % was malignant (p &lt; 0.05). The average mitotic count in GIST with the carcinoma was 0.74/high-power field (HPF) (range, 0-4/HPF), and much less than that (3.78/HPF) of GIST without the carcinoma (range, 0 to 53/HPF, P &lt; 0.05). The average proliferative index (positive number of Ki-67/HPF) of GIST with the carcinoma was 7.16/HPF (range 0 to 22) and less than that (19) of GIST without the carcinoma (range, 0 to 107). Conclusion 16.8% of GIST was co-diagnosed with gastrointestinal carcinoma. More coexistence of GIST and the carcinoma occurred in the esophagus. The GIST with the carcinoma was less proliferative and aggressive than the GIST without the Carcinoma.
[Key words] gastrointestinal stromal tumor; pathology; carcinoma
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 4683.
Abstract 4688: A relationship between environmental tobacco smoke (ETS) and epidermal growth factor receptor (EGFR) mutations in never smoker patients with non-small cell lung cancer
Authors: Lee Young Joo , Cho Byoung Chul , Choi Hye Jin , Lee Jin Gu , Kim Joo-Hang 
Published: February 2011

Abstract
Purpose
The etiology of EGFR-mutant lung cancer remains unknown. The high incidence of EGFR mutations are observed in life-time never smokers. We investigated whether the risk factors of lung cancer in never smoker may be associated with a mutant-EGFR dependent carcinogenesis. Especially, we focused on the effect of ETS on EGFR-mutant lung cancer.
Patients and Methods
We enrolled 179 consecutive never smokers who were newly diagnosed with NSCLC. The history of ETS exposure was obtained with a standardized questionnaire that included exposure period, place, and duration. The nucleotide sequences of exons 18-21 on EGFR gene were determined using nested PCR amplification. Those patients with an exon 19 deletion and exon 21 point mutations were selected as a subgroup with activating mutations for further analysis.
Results
The median total smoker-year of patients with ETS exposure was higher than that of those without (25 years vs. 15 years; P = 0.002). The incidence of EGFR mutations was significantly lower in patients with ETS exposure than in those without (38.5% vs. 61.4%; P = 0.008). The proportion of exon 19 mutation was lower in patients with ETS exposure (59.6% vs. 81.5%; P = 0.050). In a logistic regression model that adjusted for gender and histology, an adjusted odds ratio (AOR) for the risk of EGFR mutations with exposure to ETS was 0.40 (95% confidential interval [CI], 0.20-0.81; P = 0.011). In quartile groups based on total smoker-year, the AORs for the lowest- to highest-quartile groups were 0.59 (95% CI, 0.23-1.49), 0.50 (0.17-1.50), 0.48 (0.20-1.18), and 0.22 (0.08-0.62) (Ptrend = 0.028). The period and place of ETS exposure had no different effect on the incidence of EGFR mutations. Patients with ETS exposure showed a lower response rate to EGFR tyrosine kinase inhibitors than did patients without ETS exposure (24.6% vs. 44.8%; P = 0.053).
Conclusions
Exposure to ETS is negatively associated with the incidence of EGFR mutations in lung cancer in never smokers. There was an inverse trend between the cumulative dose of ETS exposure and the frequency of EGFR mutations. A mutant-EGFR-dependent carcinogenesis may be different from a tobacco-smoke-associated 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 4688.