bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3115: Ephrin-dependent and -independent activities of the receptor tyrosine kinase EphB4
Authors: Yang Nai-Ying Michelle , Hooten Nikki Noren , Pasquale Elena B. 
Published: February 2011

Abstract
Recent evidence has shown that the EphB4 receptor tyrosine kinase is upregulated in various types of cancer. However, it is unclear how the EphB4 receptor may contribute to oncogenesis because its activation by its preferred ligand, ephrin-B2, appears to be low in most cancer cell types. We have found that activation of EphB4 in breast cancer cells by stimulation with exogenous ephrin-B2 Fc ligand activates a tumor suppressor pathway that inhibits cell growth and migration. Our laboratory has also recently demonstrated an ephrin-independent activity of EphB4 in breast cancer cells, which may play a role in the tumors where the ligand is absent. By using RNA interference to downregulate EphB4 in MCF-7 and MDA-MB-435 cells, we found that EphB4 inhibits integrin-mediated substrate adhesion, spreading and migration, and reduces β1-integrin protein levels. Through these effects, EphB4 expression would be expected to inhibit tumor development and growth. Ephrin binding does not appear to be important for this EphB4-dependent regulation of β1-integrin levels. Here, we show that EphB4 knock down also dramatically increases β1-integrin protein levels in PC3 prostate cancer cells. Stimulation with a soluble form of the ligand, ephrin-B2 Fc, also reduces EphB4 expression. Therefore, experiments are in progress to determine if EphB4 downregulation by ligand also results in decreased β1-integrin protein levels, besides the inhibition of integrin-mediated cell adhesion induced by EphB4 ligand-dependent signaling. Experiments are also in progress to investigate the mechanism by which EphB4 regulates integrin levels, and whether it involves regulation of mRNA levels or protein stability. Interestingly, a recent report shows that the decreased expression of EphB4 in intestinal tumors from APCmin/+ mice that lack one EphB4 allele causes increased transcription of genes involved in cell attachment to the extracellular matrix and invasion (Dopeso et al., 2009, Cancer Res 69:7430). However, an increase in β1-integrin mRNA level was not detected in this model. Therefore, it will be interesting to investigate whether EphB4 regulates integrins differently in different cancer cell types, the mechanisms involved, and the effects on cell migration and invasion.
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 3115.
Abstract 3116: Serine protease inhibitor Kazal type 1 plays a role of colon carcinogenesis through the epidermal growth factor receptor
Authors: Ida Satoshi , Ohmuraya Masaki , Tanaka Hiroshi , Watanabe Masayuki , Takamori Hiroshi , Beppu Tooru , Baba Hideo 
Published: February 2011

Abstract
Serine protease inhibitor Kazal type 1 (SPINK1: mouse homolog Spink3), which is also known as tumor associated trypsin inhibitor (TATI), is mainly produced in the acinar cells. The role of SPINK1 has been postulated to be the prevention of inadvertent proteolysis in the pancreas caused by intra-acinar premature activation of trypsinogen. SPINK1 is expressed not only in normal human pancreatic acinar cells, but also in a various cancers, including colon cancer. In the colon cancer, previous reports said high expression of SPINK1 correlates with metastasis and poor prognosis. However, the role of SPINK1 in malignant tumors remains to be elucidated. We previously demonstrated that SPINK1/Spink3 can bind to EGFR and work as a growth factor through EGFR in the pancreatic cancer, even the chronic pancreatitis. Hence, we hypothesized that SPINK1 plays a role as the growth factor for tissue repair in the inflammatory state, and if prolonged, it works to carcinogenesis in the colon tissue. We first showed that SPINK1 induced proliferation of colon cancer cell lines examined. To clarify the role in the colon cancer of SPINK1 in vivo, we use an efficient animal model for colitis-related carcinogenesis, male C57BL/6 mice were given a single intraperitoneal administration of azoxymethane (AOM), followed by a 1-week oral exposure to dextran sodium sulfate (DSS). We showed that expression of EGFR and Spink3 (its ligand) were observed in DSS induced colitis state. Sixteen weeks after injected AOM, multiple colon cancer occurred in all treated mice. In the Western blot, EGFR and Spink3 overexpressed in the whole colon tissue (cancer tissue and non-cancerous lesion), but Spink3 slightly decreased in the cancer. To determine whether Spink3 has an essential role of carcinogenesis, we further analyzed the tumor incidence of Spink3+/−mice. At 16 weeks, tumor number was 4.6 ± 0.8 (mean ± standard error) in Spink3+/+ mice and 1 ± 0.4 in Spink3+/− mice, and a significant difference was observed between the 2 groups (p&lt;0.05). To further analyze the clinical importance of SPINK1 in the development of colon cancer, we examined the expression of SPINK1 and EGFR in adenoma and adenocarcinoma. SPINK1 express in adenoma and well differentiated adenocarcinoma, but not expressed in poorly differentiated adenocarcinoma. Taken together, these results suggest that SPINK1 stimulates the proliferation of colon cancer cells through the EGFR, and especially role in early carcinogenesis in colon 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 3116.
Abstract 3117: COX-2 is a novel transcriptional target of the nuclear EGFR-STAT3 and EGFRvIII-STAT3 signaling axes
Authors: Lo Hui-Wen , Cao Xinyu , Zhu Hu , Ali-Osman Francis 
Published: February 2011

Abstract
Emerging evidence indicate novel modes of EGFR signaling, notably, one involves EGFR nuclear translocalization and subsequent gene activation. To date, however, the significance of the nuclear EGFR pathway in glioblastoma (GBM), the most frequent and deadliest brain malignancy in adults, is unknown. Here, we report that EGFR and its constitutively activated variant EGFRvIII undergo nuclear translocalization in GBM cells, in which the former event requires EGF stimulation and the latter is constitutive. To gain insight into the impact of nuclear EGFR on gene expression in GBM, we created isogenic GBM cell lines, namely, U87MG-vector, U87MG-EGFR and U87MG-EGFRdNLS that, respectively, express the control vector, EGFR and nuclear-entry defective EGFR with a deletion of the nuclear localization signal (NLS). Microarray analysis shows that 19 genes, including, cyclooxygenase-2 (COX-2), to be activated in U87MG-EGFR cells but not in U87MG-EGFRdNLS and U87MG-vector cells. Subsequent validation studies indicate that COX-2 gene is expressed at higher levels in cells with EGFR and EGFRvIII than those with EGFRdNLS and EGFRvIIIdNLS. Nuclear EGFR and its transcriptional co-factor STAT3 associate with the COX-2 promoter. Increased expression of EGFR/EGFRvIII and activated STAT3 leads to synergistic activation of the COX-2 promoter. Promoter mutational analysis identified a proximal STAT3-binding site that is required for EGFR/EGFRvIII-STAT3 mediated COX-2 gene activation. In GBM tumors, an association exists between levels of COX-2, EGFR/EGFRvIII and activated STAT3. Together, these findings indicate the existence of the nuclear EGFR/EGFRvIII signaling pathway in GBM and its functional interaction with STAT3 to activate COX-2 gene expression, thus linking EGFR-STAT3 and EGFRvIII-STAT3 signaling axes to pro-inflammatory COX-2 mediated pathway.
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 3117.
Abstract 3118: Platelet-derived growth factor-D contributes to aggressiveness of breast cancer cells by up-regulation of Notch and NF-κB signaling pathways
Authors: Ahmad Aamir , Kong Dejuan , Wang Zhiwei , Ali Raza , Banerjee Sanjeev , Sarkar Fazlul H. 
Published: February 2011

Abstract
Platelet-derived growth factor-D (PDGF-D) has been suggested to be associated with progression of several human malignancies; however, its role in breast cancer progression has not been investigated. We found that PDGF-D expressing breast cancer cell lines MDA-MB-231 and SUM-149 are more aggressive compared to the cell lines with little or no expression of PDGF-D, such as MDA-MB-468 and MCF-7 cells. In order to test our hypothesis that PDGF-D influences cell proliferation, invasion and metastasis mediated by the activation of Notch and NF-κB signaling, we over-expressed PDGF-D in MDA-MB-468 and MCF-7 by cDNA transfection as well as silenced it in MDA-MB-231 and SUM-149 cells using PDGF-D siRNA, for mechanistic studies. We found that PDGF-D over-expression increased cell proliferation while its silencing resulted in decreased cell proliferation and increased induction of apoptosis. PDGF-D expression correlated with the activated expression of several members of Notch-signaling, namely, Notch-1, Notch-4 and Jagged-1, and attenuation of PDGF-D levels led to the inactivation of Notch signaling. PDGF-D over-expression was also found to induce the expression of mesenchymal markers (Vimentin and ZEB-2) concomitant with decreased expression of epithelial marker E-cadherin, which appears to be one of the mechanism by which PDGF-D may contribute to the aggressiveness of breast cancer cells. Since NF-κB plays a crucial role in Notch signaling as well as in the processes of epithelial-mesenchymal transition (EMT), we studied the effect of PDGF-D signaling on the DNA binding activity of NF-κB. We found that PDGF-D over-expression led to increased expression of Notch-1 and increased the DNA binding activity of NF- κB whereas the silencing of PDGF-D reduced the expression of Notch-1 and also reduced the DNA binding activity of NF-κB, suggesting that PDGF-D is upstream of Notch and NF-κB signaling pathways. These results were also consistent with the expression and activity of MMP-9 and VEGF, as well as invasive characteristics. From these results, we conclude that PDGF-D plays an important role in breast tumor aggressiveness and this process is mechanistically linked with Notch-1 and NF-κB signaling.
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 3118.
Abstract 3121: A novel molecular mechanism for HER2-induced sustained signaling and transformation
Authors: Zhou Xiandong , Ahmed Naushin , Agazie Yehenew M. 
Published: February 2011

Abstract
HER2 overexpression in breast and other tumors leads to an aggressive disease state and poor prognosis for patient survival. It is believed that increased cell growth and survival signaling induced by HER2 is responsible for the aggressive disease state and unfavorable outcome. The peculiarity of HER2 among the four EGFR family members is that even a modest expression leads to cell transformation, while similar expression of the other members does not. But how HER2 overcomes the receptor regulatory mechanism to induce constitutive signaling and cell transformation is virtually unknown. Here, we show that HER2 induces distinctive EGFR autophosphorylation that disfavors c-Cbl and RasGAP, but favors Gab1/2, PLCγ, SHP2 and PI3K interactions. We further show that HER2 expression leads to reduced interaction of Grb2 with EGFR-HER2 complexes, an effect that further reduces the interaction c-Cbl. The inefficient interaction of c-Cbl confers receptor resistance to EGF-induced degradation, while the reduced interaction with RasGAP leads to an increase in the half live activated Ras. Therefore, the molecular mechanism by which HER2 confers sustained signaling and cell transformation is by inducing distinctive receptor autophosphorylation that favors receptor recycling and prolon
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 3121.
Abstract 3126: Tumor heterogeneity in glioblastoma is an active process driven by a mutant EGFR-induced paracrine circuit
Authors: Inda Maria-del-Mar , Bonavia Rudy , Sah Dinah WY , Vandenberg Scott , Brennan Cameron , Johns Terrance G. , Hadwiger Philipp , Tan Pamela , Cavenee Webster K. , Furnari Frank B. 
Published: February 2011

Abstract
Amplification and mutation of the epidermal growth factor receptor gene (EGFR), resulting in the common and oncogenic EGFRvIII (ΔEGFR) variant, is a signature pathogenetic event in GBM. Strikingly, despite its greater biological activity than wildtype EGFR (wtEGFR), only a minority of cancer cells in the primary tumor possess the hallmark ΔEGFR lesion, while the remainder of cancer cells express wtEGFR. We hypothesized that the ΔEGFR-expressing subpopulation provides enhanced tumorigenicity to the entire tumor cell population through a paracrine mechanism. Using a combination of mixed tumor engraftments and biochemical analysis of paracrine factors and signaling pathways activation, we determined that human glioma tissues, glioma cell lines, glioma stem cells and primary mouse astrocytes, that express ΔEGFR each secrete IL-6 and/or LIF cytokines. This then prompts a novel interaction between the receptor that is common to these cytokines, gp130, and wtEGFR in neighboring cells that express amplified levels of EGFR, resulting in co-receptor activation and tumor growth enhancement. Ablating IL-6, LIF or gp130 uncouples this cellular cross-talk and potently attenuates tumor growth enhancement. These findings demonstrate that the heterogeneity which characterizes GBM, and perhaps other tumors with this feature, does not occur stochastically, but instead can be an actively maintained feature and illuminates a heterotypic cancer cell interaction of potential therapeutic significance.
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 3126.
Abstract 3128: mTOR expression and activity patterns in gastroenteropancreatic neuroendocrine tumors
Authors: Kasajima Atsuko , Pavel Marianne , Darb-Esfahani Silvia , Noske Aurelia , Stenzinger Albrecht , Sasano Hironobu , Dietel Manfred , Denkert Carsten , Röcken Christoph , Wiedenmann Bertram , Weichert Wilko 
Published: February 2011

Abstract
Recently, novel small molecules targeting the mammalian target of rapamycin (mTOR) have been successfully tested for the treatment of endocrine neoplasias. Since these drugs will certainly be used as routine therapeutics in the near future, it is surprising that information on the exact expression patterns of mTOR and its downstream target 4EBP1 in endocrine tumors is still lacking.
We investigated expression of mTOR and total as well as phosphorylated 4EBP4 in specimen of endocrine tumors by immunohistochemistry and correlated our findings with clinicopathologic variables and patient prognosis.
We found that 61 (61.6%), 92 (92.2%), 79 (79.8%) and 69 (69.7%) out of 99 neuroendocrine foregut and midgut tumors were positive for mTOR, 4EBP1, cytoplasmic phospho-4EBP1 (p-4EBP1) and nuclear phospho-4EBP1, respectively. mTOR, 4EBP1 and p-4EBP1 (either cytoplasmic or nuclear) expression was higher in foregut tumors than in midgut tumors. Expression of mTOR was higher in foregut tumors with distant metastases (p=0.035) when compared to their locally restricted counterparts. 4EBP1 as well as p-4EBP1 (either cytoplasmic or nuclear) expression was associated with higher Ki-67 positivity and thereby proliferative activity.
mTOR expression and activity as measured by phosphorylation of its downstream target 4EBP1 vary considerably in dependence of tumor location and metastatic status. We hypothesize that differences in mTOR expression patterns and/or activity might predict response to mTOR inhibitors which should be taken into account when future clinical trials with these substances are being planned.
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 3128.
Abstract 3131: IGF-I regulates Cyr61-induced breast cancer cell growth and migration
Authors: Sarkissyan Suren , Sarkissyan Marianna , Wu Yanyuan , Koeffler H Phillip , Vadgama Jaydutt V. 
Published: February 2011

Abstract
Cysteine-rich 61 (Cyr61) is a protein involved in wound healing, regulation of extracellular matrix microenvironment, and in tumor invasion. Data from our laboratory and others have shown that highly invasive cancer cells have high Cyr61 transcriptional levels as compared with non-invasive cells. Recent studies from our laboratory have shown that IGF-I (insulin growth factor I) is involved in activating the PI3/Akt pathway, and this may increase Cyr61 expression. We have hypothesized that IGF-I induces tumor invasion by upregulating Cyr61 through Akt phosphorylation (pAkt). In the current study, several breast cancer cell lines, MDA-MB231, BT474, MCF-7, SKBR3 were used; two of which were stably transfected with active Akt1(SKBR3/AA and MCF-7/AA) and dominant negative Akt1 (SKBR3/DN and MCF-7/DN). To determine Cyr61 expression in response to IGF-I, cells were treated with IGF-I and Cyr61 expression was examined by RT-Real time PCR. To determine cell invasiveness in relation to Cyr61 expressions and IGF-I induction, a migration assay was used. Our result showed that Cyr61 expression was significantly higher in MDA-MB231 cells. SKBR3/AA and MCF-7/AA had increased levels of Cyr61, while SKBR3/DN and MCF-7/DN had decreased levels of Cyr61 compared to SKBR3 and MCF-7. Furthermore, IGF-I (100ng/ml) increased Cyr61 expression significantly and cells with high level of Cyr61 increased invasiveness. In summary, active Akt was associated with the IGF-I induced Cyr61, which caused breast cancer cell migration and invasion. Hence, Cyr61 may be a potential therapeutic target for treatment of invasive breast tumors.
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 3131.
Abstract 3132: Proliferative effects of FGF1 on ovarian cancer cells correlate with FGFR4 over expression and are mediated by MAPK/ERK signaling
Authors: Zaid Tarrik , Thompson Melissa S. , Wong Kwong-kwok , Yeung Tsz-Lun Yeung , Yeung Zachary , Yates Melinda S. , Birrer Michael J. , Mok Samuel C. 
Published: February 2011

Abstract
Objectives: To identify the effect of FGF1 on cell proliferation in ovarian cancer and endothelial cells, its relation to FGFR4 over expression and signaling pathways involved
Methods: Amplification of FGFR4 on 5q31-35, which was previously shown to be associated with poor survival in patients with advanced stage high-grade serous ovarian cancer (HGSC), was validated by quantitative PCR in 52 HGSC. Association between DNA copy numbers of FGFR4 and FGF1 located on the same segment was performed by Spearman correlation analysis. Over expression of FGFR4 protein was confirmed in ovarian cancer cell lines and tissue by western blot analysis and immunohistochemistry, respectively. Endogenous FGF1 production by several ovarian cancer cell lines in conditioned medium was quantified using ELISA. Effect of exogenous FGF1 on cell proliferation of high and low-FGFR4 expressing ovarian cancer cell lines and an immortalized microvascular endothelial cell line was determined by WST-1 assay. Signaling pathways activation was screened by treating ovarian cancer cell lines and endothelial cells transduced with six different transcription response elements using the Cignal-Lenti reporter system with exogenous FGF1.
Results: FGFR4 was amplified and over-expressed in a majority of ovarian cancer cell lines and tumor tissue and FGFR4 DNA copy number was significantly correlated with that of FGF1 (r=0.4, p=0.04). Endogenous FGF1 production was detected by ELISA in 2 of 5 screened ovarian cell lines. FGF1 significantly induced cell proliferation in high FGFR4 expressing ovarian cancer cells (20%, p&lt;0.001) and in endothelial cells (15%, p&lt;0.001); but not in low FGFR4 expressers. Significant activation of MAPK/ERK signal transduction pathways was noted after treatment of ovarian(1.43 fold, P &lt; 0.001) and endothelial(1.33 fold, P &lt; 0.001) cell lines transduced with the Cignal-Lenti reporter system.
Conclusions: Our report provides preliminary evidence that poor survival associated with FGF1 amplification and over expression appears to be mediated through FGFR4, which is also amplified and over-expressed in ovarian cancer cell. In addition, FGF1 produced by ovarian cancer cells may exert both autocrine and paracrine effect on cancer cells and endothelial cells through the activation of MAPK/ERK pathway. These data suggests that new regimens targeting FGF1, FGFR4 and downstream signaling pathways may improve ovarian cancer patient survival.
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 3132.
Abstract 3135: Segregation of non-R132H mutations in IDH1 in distinct molecular subtypes of glioma
Authors: Bralten Linda B. , Gravendeel Lonneke AM , Kloosterhof Nanne K. , van Marion Ronald , Dubbink Hendrikus J. , Dinjens Winand , Bleeker Fonnet E. , Hoogenraad Casper C. , Michiels Erna , Kros Johan M. , van den Bent Martin , Smitt Peter AE Sillevis , French Pim J. 
Published: February 2011

Abstract
Mutations in the gene encoding the isocitrate dehydrogenase 1 gene (IDH1) occur at a high frequency (up to 80%) in many different subtypes of glioma. In this study, we have screened for IDH1 mutations in a cohort of 496 gliomas. IDH1 mutations were most frequently observed in low grade gliomas with 395G&gt;A (R132H) representing &gt;90% of all IDH1 mutations. Interestingly, non-R132H mutations segregate in distinct histological and molecular subtypes of glioma. Histologically, they occur sporadically in classic oligodendrogliomas and at significantly higher frequency in other grade II and III gliomas. Genetically, non-R132H mutations occur in tumors with TP53 mutation, are virtually absent in tumors with loss of heterozygosity on 1p and 19q and accumulate in distinct (gene-expression profiling based) intrinsic molecular subtypes. The IDH1 mutation type does not affect patient survival. Our results were validated on an independent sample cohort, indicating that the IDH1 mutation spectrum may aid glioma subtype classification. Functional differences between R132H and non-R132H mutated IDH1 may explain the segregation in distinct glioma subtypes.
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 3135.