bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2979: Epithelial-mesenchymal gene expression signature defines clinically relevant subtypes in epithelial ovarian cancer
Authors: Huang Ruby YJ , Tan Tuan Zea , Wong Meng Kang , Matsumura Noriomi , Lai Hung Cheng , Chung Vin Yee , Ye Jieru , Mori Seiichi , Thiery Jean Paul 
Published: August 2012

Abstract
Epithelial ovarian cancer (EOC) represents a broad and heterogeneous entity which includes different invasive behavior as well as distinct histopathological subtypes. The heterogeneity of EOC is further complicated by the fact that EOC is characterized by a high degree of genetic damages and multiple genetic alterations resulting from different mechanisms. Even within the seemingly similar histo-pathological group, molecular subtypes with different gene/pathway activations have been identified. In this study, we described a classification scheme based on in silico meta-analysis of gene expression profiling of 1,538 EOC microarray data. and identified five major robust subtypes termed Epithelial-A, Epithelial-B, Mesenchymal, Stem-A, and Stem-B that were distinctive in gene expression patterns. The epithelial subtype is hallmarked by genes known to confer epithelial characteristics, such as Keratin genes (KRT17, 14, 19, and 7), E-cadherin (CDH1), and Ep-CAM (EPCAM) and show the second best prognosis in Kaplan-Meier analysis. On the other hand, the mesenchymal subtype consists of genes such as fibronectin (FN1) and known EMT inducers ZEB1 and TWIST1. The Stem-A subtype consists of genes which confer stemness (LGR5, NCAM1). The Mesenchymal and Stem-A subtypes are linked with poorer outcomes. We further utilized a panel of 42 ovarian cancer cell lines to model EMT in vitro by performing phenotypic EMT characterization. Four EMT subgroups (epithelial, intermediate epithelial, intermediate mesenchymal, mesenchymal) representing different epithelial-mesenchymal compositions on the EMT spectrum were identified. We also demonstrated that this EMT spectrum can be used to refine the analysis of data generated in cell-based functional studies. By performing EMT-related functional assays, we found that ovarian cancer cells harbouring intermediate phenotypes are more migratory, invasive, anoikis resistant, and more spheroidogenic. We further utilized this cell line model to apply a cell line-based EMT scoring system to re-classify the 1,538 EOC microarray data. It revealed that the Mesenchymal and Stem-A subtypes were both enriched in higher mesenchymal scores. This supported the hypothesis of EMT's contribution to the aggressiveness of solid tumors. In conclusion, our results showed that EOC is sub-classified into distinct molecular subtypes correlated with clinical outcomes that are linked to EMT.
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 2979. doi:1538-7445.AM2012-2979
Abstract 299: Modulation of the leptin receptor in pancreatic cancer cells mediates tumor growth
Authors: Mendonsa Alisha , Chalfant Madeleine , Nagathihalli Nagaraj , Merchant Nipun , Gorden Lee , VanSaun Michael N. 
Published: August 2012

Abstract
Background: Pancreatic cancer is the fourth leading cause of cancer death with a five year survival rate around 5%, which has not changed in 30 years. Obesity and increased abdominal adipose tissue independently correlate with an increased relative risk for the development of pancreatic cancer. These conditions have been associated with altered levels of adipokines, or adipose secreted cytokines. Circulating serum levels of the adipokine leptin are increasesddramatically in obese patients as well as in high fat diet induced obese mice. Leptin has been shown to induce oncogenic signaling in breast and prostate cancer. We have previously shown an increase in orthotopic pancreatic tumor size in high fat diet induced obese mice compared with regular diet control mice. We hypothesize that leptin signaling mediates pancreatic tumorigenesis. Methods: Leptin receptor status was determined in human as well as murine pancreatic cell lines. Leptin stimulated cell proliferation was determined using a modified BrdU assay. Leptin receptor levels were knocked down in human and murine pancreatic tumor cells using a shRNAmir approach. Leptin receptor shRNA Panc02 knockdown cells were injected orthotopically into the pancreas of C57/Bl6J mice on regular or high fat diet to determine the contribution of leptin to pancreatic tumor growth. Results: We have detected the long form of the leptin receptor in five human and four murine pancreatic cancer cell lines. In vitro administration of leptin stimulated proliferation of Panc1 and CFPAC1 cell lines, which was abrogated with co-incubation of a leptin antagonist. To better understand the mechanism of leptin-mediated signaling, we studied downstream targets and identified a significant increase in phosphorylation of STAT3 in Panc1, BXPC3 and CFPAC1 cell lines after leptin treatment. Orhtotopic injection of leptin receptor shRNA Panc02 cells into normal and obese mice showed a markedly diminished tumor growth in obese mice when compared to the nonsilencing control Panc02 cell growth in obese mice. Conclusion: These results implicate leptin as a mediator of pancreatic tumorigenesis and suggest that leptin activation is mediated in part through STAT3 signaling. Knockdown of the leptin receptor results in inhibition of high fat diet associated tumor growth in vivo.
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 299. doi:1538-7445.AM2012-299
Abstract 3005: Characterization of a lung cancer growth factor, LASEP1 as a serological and prognostic biomarker and a therapeutic target
Authors: Takano Atsushi , Nakamura Yusuke , Daigo Yataro 
Published: August 2012

Abstract
To identify molecules that might serve as biomarkers or targets for the development of novel molecular therapies, we have been screening genes encoding transmembrane/secretory proteins that are up-regulated in lung cancers, using cDNA microarrays. During this process, we identified a secreted protein, LASEP1 (lung cancer-associated serum protein 1) as a candidate. Immunohistochemical staining using tumor tissue microarrays consisting of 374 non-small cell lung cancers (NSCLC) revealed that LASEP1 protein was frequently over-expressed in lung cancers; positive staining of LASEP1 was observed in 210 (56.1%) of 374 NSCLC, while that was observed in 9 (69.2%) of 13 small cell lung cancers (SCLC). In addition, a strong LASEP1 positivity was associated with poor prognosis for patients with NSCLC (P&lt;0.001 by log-rank test), and multivariate analysis confirmed its independent prognostic value. Serum LASEP1 levels were higher in NSCLCs as well as SCLCs patients than in healthy volunteers. The proportion of serum LASEP1-positive cases was 127 (38.6%) of 329 lung cancers, while 4 (3.9%) of 102 healthy volunteers were falsely diagnosed. Furthermore, treatment of lung cancer cells with siRNAs against LASEP1 suppressed its expression and resulted in growth suppression of the lung cancer cells; on the other hand, induction of exogenous expression of LASEP1 conferred growth-promoting activity and enhanced the cell mobility in vitro. Interestingly, the growth activity of the LASEP1-positive cells was neutralized by addition of originally developed anti-LASEP1 monoclonal antibodies into their culture media. The systemic administration of the anti-LASEP1 antibody to LASEP1-positive tumor-implanted mice significantly suppressed tumor growth without any adverse events. We found a receptor (LASEPR) which interacts with LASEP1 on lung cancer cell surface and is essential for the growth of cancer cells. The data suggest that the LASEP1-LASEPR interaction could promote the cancer cell growth in an autocrine manner. LASEP1 is a potential serological and prognostic biomarker and a therapeutic target for lung cancer.
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 3005. doi:1538-7445.AM2012-3005
Abstract 3010: IL-6 enhances migration and ICAM-1 expression of human oral squamous cell carcinoma involves IL-6 receptor signaling pathway
Authors: Yen Wei-Lin , Chuang Jing-Yuan , Tang Chih-Hsin 
Published: August 2012

Abstract
Oral squamous cell carcinoma(SCC) has a striking tendency to migration and metastasize. Interleukin-6(IL-6) has been implicated in the promotion of many cancers proliferation and migration. Intercellular adhesion molecule-1(ICAM-1), a member of the immunoglobulin supergene family, is an inducible surface glycoprotein that mediates adhesion-dependent cell-to-cell interactions. However, the effects of IL-6 in migration and ICAM-1 expression in human oral cancer cells are largely unknown. We found that IL-6 increased migration and ICAM-1 expression in human oral cancer cells. Using a specific inhibitor and genetic inhibition of IL-6 receptor, we discovered that the IL-6 receptor is involved in migration and ICAM-1 expression of human oral cancer cells. IL-6-mediated migration and ICAM-1 up-regulation were attenuated by inhibitor of Syk, JNK and AP-1. Activation of the Syk, JNK and AP-1 signaling pathway occurred after IL-6 stimulation. IL-6 induced AP-1 activity was inhibited by Syk and JNK inhibitor. Our results indicated that IL-6 enhances the migration of human oral cancer cells by increasing ICAM-1 expression through the IL-6 receptor, Syk, JNK and AP-1 signal transduction pathway.
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 3010. doi:1538-7445.AM2012-3010
Abstract 3070: Activated EGFR and PPARδ regulate MUC1 expression in human uterine and pancreatic cancer cell lines
Authors: Dharmaraj Neeraja , Carson Daniel D. 
Published: August 2012

Abstract
The high molecular weight, transmembrane mucin, MUC1 is expressed at high levels in many epithelial tumors including endometrial and pancreatic cancers. Aberrant glcosylation and overexpression of MUC1 make tumor cells poorly adherent, protect tumor cells from the host immune system, promote metastases from primary sites and enhance resistance to chemotherapeutic drugs. MUC1 has three distinct domains: an extracellular domain (ECD) composed of a tandem repeat region rich in serine, threonine and proline; a transmembrane domain (TM) and; a short cytoplasmic tail domain (CT) involved in a variety of signal transduction events. Epidermal Growth Factor Receptor (EGFR/erbB) family members regulate cell growth and survival in both normal and cancer cells. MUC1 interacts with erbB receptors and also affects downstream signaling pathways in a EGFR-ligand dependent manner. We previously demonstrated that the Peroxisome Proliferator Activated Receptor ≤ (PPARδ) agonist rosiglitazone severely inhibits progesterone stimulated MUC1 expression (Wang et al. 2010. Mol. Endocrinol. 24: 1368-1379). Two independent approaches were used to determine if rosiglitazone as well as EGFR tyrosine kinase inhibitor, AG1478 reduced MUC1 expression in a high MUC1-expressing cell line, HES; the uterine adenocarcinoma cell line, HEC-1A; and in the human pancreatic adenocarcinoma cell lines, HPAFII and CAPAN2. EGFR activation by Epidermal Growth Factor (EGF) stimulated MUC1 protein expression (1.5-2 fold) in both uterine and pancreatic cancer cells. The PPARδ agonist, rosiglitatzone, markedly (&gt; 90%) reduced EGFR-driven MUC1 expression detected by antibodies directed against the MUC1 ECD and CT. Preliminary studies indicate that rosiglitazone effects on EGFR-driven MUC1 expression is indirect. Furthermore, rosiglitazone treatments enhanced EGFR degradation via the lysosomal degradation pathway in the presence of EGF-family ligands in both uterine and pancreatic cancer cell lines. A combination of biochemical and molecular biological assays have been used to identify the transcriptional and signal transduction pathways activated by EGFR, leading to increased MUC1 expression and the impact of AG1478 and rosiglitazone on these events. Understanding the molecular basis of how these agents reduce MUC1 expression may offer novel therapeutic avenues to improve cancer chemotherapies.
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 3070. doi:1538-7445.AM2012-3070
Abstract 3072: HER2 signaling affects SRC-3 phosphorylation and gene regulatory potential within the cistrome
Authors: Nikolai Bryan C. , Smith Carolyn L. , O'Malley Bert W. 
Published: August 2012

Abstract
Steroid Receptor Coactivator-3 (SRC-3/AIB1) is a potent transcriptional coregulator for nuclear receptors and other transcription factors and is often amplified or overexpressed in tumors. The growth promoting effects of SRC-3 involve its ability to integrate extracellular signals into discrete patterns of gene expression. SRC-3 is regulated by various post-translational modifications, including multiple phosphorylations that define a combinatorial code that tailors SRC-3 activity in response to specific signaling stimuli. HER2 is a member of the ErbB receptor tyrosine kinase family of growth factor receptors and is often associated with cancer. Clinical studies show that breast cancer patients with tumors expressing high levels of both HER2 and SRC-3 have reduced disease-free survival, and SRC-3 phosphorylation is influenced by HER2. The current study seeks to define the effect of HER2 signaling events on SRC-3 activity in breast cancer cells. HER2 knock down using siRNA affects multiple kinase pathways, as evidenced by decreased AKT and c-Raf phosphorylation. HER2 knockdown causes the isoelectric point of SRC-3 to shift, suggesting that post-translational modification of SRC-3 is actively altered by HER2 signaling. Reduction of SRC-3 phosphorylation in HER2-depleted cells also was evident using a phospho-specific antibody to SRC-3. Expression microarray analysis revealed that many genes are altered by HER2 knockdown. Parsing the microarray with SRC-3 ChIP-seq data identified genes that are coordinately regulated by a HER2/SRC-3 signaling axis. Collectively, this work describes transcriptomic and cistromic mechanisms for oncogenic cooperation between HER2 and SRC-3 and identifies key genes that contribute to proliferation of breast cancer 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 3072. doi:1538-7445.AM2012-3072
Abstract 3076: p53 homologue p63 trans-activates epidermal growth factor (EGF) receptor and 14-3-3α and thus promotes tumorigenesis and chemoresistance in pancreatic cancer
Authors: Danilov Alexey V. , Srivastava Amitabh , Feofanova Elena V. , Humphries Leigh Ann , Direnzo James , Korc Murray 
Published: August 2012

Abstract
Pancreatic cancer is the 4th leading cause of cancer-related mortality in the United States. Despite these statistics, progress in therapy of pancreatic cancer has been slow. p53 tumor suppressor pathway is altered in 50-75% of pancreatic cancer tumors. However, the role of p53 homologs p63 and p73 has not been well studied. We previously reported that p63 is expressed in pancreatic cancer cell lines and contributes to their motility and invasion. Here we tested expression of p63 in resected tumors and investigated its role as a transcription factor in pancreatic cancer. Expression of p63 was determined by immunohistochemistry in 20 resected tumor samples (15 - adenocarcinoma, 5 - squamous) using pan-p63 (clone 4A4) and ΔNp63-specific antibodies; and by immunoblotting, real-time quantitative and semi-quantitative PCR in 5 pancreatic cancer cell lines. p63 levels were manipulated employing transient overexpression and lentiviral approaches. We studied cell doubling times, motility in a wound assay and invasiveness in Matrigel chambers in the presence or absence of epidermal growth factor (EGF). Functional reporter and chromatin immunoprecipitation assays were performed to study the effects of p63 on selected promoters. We found that the p53 homolog p63 was expressed in resected pancreatic cancer samples. Pancreatic tumors with squamous differentiation showed strong diffuse expression of p63, whereas adenocarcinomas without squamous component had a focal expression of p63 (ΔNp63). In pancreatic cancer cell lines, p63 protein levels were high in 3/5 tested cell lines and ΔNp63α was the predominantly expressed variant. By contrast, TAp63 was not detected while p73 was barely detectable in 2/5 cell lines. Ectopic expression of ΔNp63α in PANC-1 cells (which had low endogenous p63) and shRNA-mediated knockdown in T3M4 cells (with high endogenous p63) indicated that ΔNp63α promoted anchorage-dependent and independent growth, motility and invasion, and enhanced resistance to cisplatin-induced apoptosis. Motogenic effects of ΔNp63α were augmented in presence of EGF. ΔNp63α augmented the EGF receptor expression in pancreatic cancer cells via transcriptional regulation and potentiated EGF-mediated activation of ERK, Akt and JNK signaling. 14-3-3α transcription was also positively regulated by ΔNp63α and we have previously shown that 14-3-3α contributes to chemoresistance in pancreatic cancer. Thus, p53 homolog ΔNp63α is expressed in pancreatic cancer, where it enhances tumor progression and chemoresistance via trans-activation of EGF receptor and 14-3-3α.
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 3076. doi:1538-7445.AM2012-3076
Abstract 308: Tumor hypoxia promotes tolerance and angiogenesis via CCL28 and Treg cells
Authors: Facciabene Andrea , Coukos George 
Published: August 2012

Abstract
Although immune mechanisms can suppress tumor growth, tumors establish potent and overlapping mechanisms that mediate immune evasion. Emerging evidence suggests a link between tumor immune tolerance and angiogenesis. Hypoxia, a condition known to drive tumor angiogenesis, results in release of damage-associated molecular pattern molecules, which can trigger tumor immune rejection. Thus, counter-activation of tolerance mechanisms at the site of tumor hypoxia would be a critical condition to maintain immunologic escape of tumors. However, a direct link between tumor hypoxia and tolerance through the recruitment of regulatory cells has not been established. We hypothesized that tumor hypoxia induces expression of chemotactic factors promoting tolerance. Here we show that tumor hypoxia promotes T regulatory (Treg) cell recruitment via the CCL28 chemokine, which in turn promotes tumor tolerance and angiogenesis. Thus, peripheral immune tolerance and angiogenesis are intimately connected and cooperate to sustain tumor growth.
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 308. doi:1538-7445.AM2012-308
Abstract 3096: ICAD deficiency in human colon cancer and predisposition to colon tumorigenesis in mice: Linkage to resistance to apoptosis and susceptibility to genomic instability
Authors: Errami Youssef , Brim Hassan , Naura Amarjit , Kim Hogyoung , Jihang Ju , Xu Ming , Zhang Jianhua , Valle Luis Del , Boulares Hamid 
Published: August 2012

Abstract
We previously showed that DNA fragmentation factor, which comprises a caspase-3-activated DNase (CAD) and its inhibitor (ICAD), may influence the rate of cell death by generating PARP-1-activating DNA breaks. Here we tested the hypothesis that ICAD-deficient colon epithelial cells (CECs) exhibiting resistance to death stimuli may accumulate additional genetic modifications, leading to a tumorigenic phenotype. We show that ICAD deficiency is highly associated with colon malignancy in humans. Upon DNA damage caused by a low dose of irradiation, ICAD-/- cells acquire a tumorigenic phenotype. CECs derived from ICAD-/- mice showed a marked resistance to death induced by the colon carcinogen dimethylhydrazine (DMH) in vitro and in mice. Such resistance was associated with a decrease in PARP-1 activation. In an animal model of DMH-induced colon tumorigenesis, ICAD-/- mice developed significantly higher numbers of tumors with markedly larger sizes than the wild-type counterparts. Interestingly, the phenotype of the ICAD-/- mice was not associated with a significant increase in the precancerous aberrant crypt foci suggesting a link to tumor progression rather than initiation. More importantly, ICAD deficiency was associated with severe genomic instability, constituting most prominently of amplifications but with sizable deletions as compared to the wild-type counterparts affecting several cancer-related genes including RAF-1, GSN, LMO3, and Fzd6 independently of p53. Our results present a strong case for involvement of ICAD deficiency in colon carcinogenesis and show that apoptosis and genomic instability may comprise the means by which such deficiency may contribute to the process of increasing susceptibility to carcinogen-induced tumorigenesis.
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 3096. doi:1538-7445.AM2012-3096