bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3308: Differential expression of Notch-1 and Notch-2 correlates to invasive phenotype in bladder cancer cell lines
Authors: Gust Kilian M. , Awrey Shannon , Ettinger Susan , Li Estelle , Fazli Ladan , Black Peter C. 
Published: February 2011

Abstract
The Notch pathway plays a critical role in growth and differentiation, and is involved in cancer progression in different organ sites. Little is known about Notch in bladder cancer. In this study, we evaluated Notch-1 and Notch-2 expression in a panel of bladder cancer cell lines.
Thirteen bladder cancer cell lines with previously described invasive properties and epithelial/mesenchymal characteristics were screened for Notch-1 and Notch-2 expression by Western blot and real-time PCR. Immunohistochemistry (IHC) was performed on a tissue microarray (US Biomax, Inc., Rockville, MD) that included cores from 152 patients with bladder cancer. Alterations in gene expression after Notch-2 silencing with siRNA were measured by expression microarray in 3 cell lines. Genes that changed by at least 2-fold in all 3 cell lines were selected for further analysis. Wound healing assays were performed after treatment with Notch-2 siRNA versus scrambled siRNA. The Mann-Whitney test was performed for statistical analysis.
Epithelial cell lines with low invasive potential expressed Notch-1 at high and Notch-2 at low relative levels (P=0.03 and P&lt;0.01, respectively, compared to invasive cell lines). Highly invasive, mesenchymal cell lines expressed high levels of Notch-2 and low levels of Notch-1. These results were validated by Western blot and IHC (TMA). Microarray analysis revealed altered expression of genes related to epithelial to mesenchymal transition (EMT), protein and endosome trafficking, and cell-cell connections, when Notch-2 was silenced with siRNA. Notch-2 silencing decreased the migration of UC3 cells in the wound healing assay (P=0.02).
These results provide preliminary evidence for a role for Notch in the progression of bladder cancer and it is suggested that this may be related to EMT. Further investigation is needed to assess the suitability of Notch as a therapeutic target, and it would appear that selective inhibition of individual Notch receptors may be preferential over global inhibition.
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 3308.
Abstract 3332: Engineering functions in cell transduction domains: novel anticancer agents
Authors: Epenetos Agamemnon A. , kousparou christina , Stylianou Spyros , deonarain mahendra 
Published: February 2011

Abstract
Trojantec research has focused on the design of recombinant proteins that overcome both extracellular and intracellular limitations of other delivery systems by rapidly releasing proteins into the cytoplasm and mediating efficient nuclear translocation.
We have genetically engineered two fusion proteins; The first consisting of the Drosophila transcription factor Antennapedia (ANTP) and the truncated version of Mastermind-like (MAML) that behaves in a dominant negative (DN) fashion and inhibits Notch activation (ANTP/DN MAML) (TR4), and the second which is comprised of ANTP fused to the tumour suppressor protein p21, which is important in many key cell division processes including G1-arrest leading to apoptosis of damaged cells.
Our results indicate that drug delivery using with the ANTP cell transduction domain induces apoptosis, abolishes colony formation in soft agar, and inhibits tumor growth in mice, without organ or systemic toxicity. These studies establish TR1 and TR4 as new cancer therapeutic agents in clinical applications.
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 3332.
Abstract 336: Blockade of CCN6 (WISP3) activates growth factor-independent survival and resistance to anoikis in human mammary epithelial cells
Authors: Huang Wei , Gonzalez Maria E. , Toy Kathy , Banerjee Mousumi , Kleer Celina G. 
Published: February 2011

Abstract
CCN6 is a secreted cysteine rich matricellular protein (36.9 kDa) that exerts growth inhibitory functions in breast cancer. Reduction or loss of CCN6 protein has been reported in invasive carcinomas of the breast with lymph node metastasis and in inflammatory breast cancer. However, the mechanism by which CCN6 loss promotes breast cancer growth remains to be defined. In the present study we developed lentiviral mediated shRNA knockdown of CCN6 in nontumorigenic mammary epithelial cells MCF10A and HME. We discovered that CCN6 knockdown protects mammary epithelial cells from apoptosis and activates growth factor-independent survival. In the absence of exogenous growth factors, CCN6 knockdown was able to promote growth under anchorage independent conditions and triggered resistance to detachment-induced cell death (anoikis). Upon serum starvation, CCN6 knockdown was sufficient for activation of the phosphatidylinositol 3-kinase/Akt pathway. Growth factor-independent cell survival was stunted in CCN6 knockdown cells when treated with either human recombinant CCN6 protein or the phosphatidylinositol 3-kinase inhibitor LY294002. Targeted inhibition of Akt isoforms revealed that the survival advantage rendered by CCN6 knockdown requires specific activation of Akt-1. The relevance of our studies to human breast cancer is highlighted by the finding that low CCN6 protein levels are associated with upregulated expression of phospho-Akt-1 (Ser473) expression in 21% of invasive breast carcinomas. These results enable us to pinpoint one mechanism by which CCN6 controls survival of breast cells mediated by the PI3K/Akt-1 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 336.
Abstract 338: Enhanced cetuximab and radiosensitization with src inhibition in head and neck cancer
Authors: Li Chunrong , Iida Mari , Dunn Emily , Wheeler Deric L. 
Published: February 2011

Abstract
The epidermal growth factor receptor (EGFR) is a ubiquitously expressed receptor tyrosine kinase (RTK) that initiates a spectrum of signaling pathways that promote cell proliferation, differentiation, migration, motility, and metastasis. The EGFR has been strongly linked to the etiology of head and neck squamous cell carcinoma (HNSCC). The first major phase III clinical trial combining cetuximab with radiation in HNSCC confirmed a strong survival advantage for patients on the cetuximab arm. It has recently been reported, however, that cetuximab and radiation can induce EGFR to the nucleus where it can enhance resistance to both of these therapeutic modalities. In this report we sought to determine how to block cetuximab and radiation induced translocation of EGFR to the nucleus to increase the efficacy of this therapeutic regimen in HNSCC.
We utilized three established HNSCC lines, SCC1, SCC6 and SCC1483 and measured nuclear translocation of the EGFR after treatment with cetuximab, radiation or the combination. Both cetuximab and radiation treatment could induce nuclear translocation of the EGFR in all SCC lines tested. Strikingly, time course analysis indicated that cetuximab could stimulate movement of the EGFR to the nucleus within one hour where it maintained its present for greater than 96 hours. Conversely, radiation could stimulate EGFR translocation to the nucleus within 0.5 hours, but returned to baseline levels within four hours. Both cetuximab and radiation treatment of SCC lines led to the phosphorylation of tyrosine 845 (Y845) of the EGFR. Y845 is phosphorylated specifically by the non-receptor tyrosine kinase Src and/or its family of kinases (SFKs). Blockade of SFKs by dasatinib could abrogate cetuximab and radiation induced EGFR translocation to the nucleus indicating that SFKs are crucial for the movement of the EGFR to the nucleus. In addition, pre-treatment of HNSCC cells with dasatinib, followed by cetuximab and radiation enhanced the suppression of ERK activity in all three SCC cell lines. Furthermore, combining dasatinib with cetuximab/radiation treatment exhibited additive inhibitory effects on cell growth or clonogenic formation. These data suggest that both cetuximab and radiation can induce EGFR to the nucleus and blockade of SFKs using dasatinib can abrogate this translocation. Collectively these findings may suggest that dasatinib can limit EGFR translocation to the nucleus and may enhance radiotherapy plus cetuximab in HNSCC.
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 338.
Abstract 3390: Cas-L promotes migration, invasion and recurrence in human lung cancer
Authors: Kondo Shunsuke , Iwata Satoshi , Inoue Yusuke , Yamada Taketo , Morimoto Chikao 
Published: February 2011

Abstract
Lung cancer is the most common cause of cancer mortality world wide. Surgical intervention is currently the most effective treatment modality for non-small cell lung cancer (NSCLC) confined to the thorax. The relapse rate among patients with early-stage NSCLC is 40% within 5 years after potentially curative treatment. Adjuvant chemotherapy is added to standard therapy, but the efficacy is limited. To identify molecular subtypes associated with outcome facilitates selecting patients who can be offered an additional treatment option
Crk-associated substrate lymphocyte type (Cas-L) is a docking protein that is heavily tyrosine phosphorylated via β1 integrins and growth factor dependent signals in cancer cells and lymphocytes. Cas-L plays a role in biologically regulatied cell attachment, migration, invasion, apoptosis and cell cycle and also plays a role in the development of metastatic capability in cancer. Cas-L protein is identified with an essential switch for pro-metastatic behavior in tumors. Cas-L mRNA and protein expression were elevated in a significant percentage of metastatic melanomas and that this elevated Cas-L expression was required for the metastatic process. Here in, we showed the potential role of Cas-L in the phosphorylation and downstream signaling of epidermal growth factor (EGF) receptors in NSCLC. Cas-L is involved in EGF-stimulated migration and invasion of NSCLC cells. Additionally, we suggest that phosphorylation of Cas-L and the SH3 domain of Cas-L, and binding with docking proteins such as Src kinase and FAK, are necessary for EGF-stimulated migration and invasion.
An in vivo mouse model showed Cas-L over-expression to promote tumorgenesis and metastasis. In clinical samples, our results show that Cas-L promotes invasion in N2 lymph nodes (p≡0.02), pathological lymphatic invasion (p≡0.01) and pathological venous invasion (p≡0.001). Furthermore, Cas-L is associated with recurrence (Hazard ratio 4.24, 95%CI 1.93-9.26; p&lt;0.001) and prognosis (Hazard ratio 5.35, 95%CI 1.98-14.50, p≡0.001).
In conclusion, Cas-L may be useful in selecting patients for adjuvant chemotherapy and serve as an important therapeutic target in NSCLC, as a recurrence marker.
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 3390.
Abstract 3397: The role of Pdef in mammary development, tumorigenesis and metastasis
Authors: Findlay Victoria J. , Watson Patricia M. , Feldman Ron J. , Sigmon Stacey A. , Gong Yong Z. , Moussa Omar , Sypropoulos Demetri D. , Turner David P. , Watson Dennis K. 
Published: February 2011

Abstract
ETS proteins represent one of the largest families of transcription factors with diverse functions that activate or repress the expression of genes that are involved in various biological processes, including cellular proliferation, differentiation, development, transformation and apoptosis. The ETS family gene, PDEF (prostate derived ets factor), is expressed in normal epithelial tissues including prostate, breast, colon and bladder. Significantly, PDEF protein is present in non-invasive cancers but reduced or absent in most invasive cancers. By re-expression and knock-down of PDEF in cancer cell lines, we and others have shown that PDEF target genes control aspects of the metastatic process, including cell growth, migration and invasion. We hypothesize that PDEF is important for normal developmental processes and that loss of PDEF regulatory networks is a key event in the development of invasive cancer. To study the function of Pdef in vivo, we generated mice with constitutive Pdef knockout (Pdef −/−). Specific stages of mammary development were examined, including early-pubescent (5 week), virgin adult (8 week), pregnancy (days 7.5 and 13.5), lactation (days 1 and 7) and involution (day 7). Inhibition of the development of the ductal tree and an increase in ductal side branching and terminal end bud proliferation was observed in 5-8 week old virgin Pdef −/− mice. TGFβ1 and ERα are required for development of the ductal tree during puberty and mRNA levels for both are reduced in the
Pdef −/− mice at 5 and 8 weeks of age. Incomplete lobuloalveoli development was observed in Pdef −/− pregnant and lactating mice, although no phenotypic effects were observed in the resultant pups. To explore the role of Pdef in mammary tumor progression and metastasis, we generated mice expressing the MMTV-PyMT or MMTV-Neu oncogene in wild type and Pdef −/− backgrounds. No impact of Pdef dosage upon tumor incidence or growth was observed in the PyMT model; however, initial tumor formation was delayed by 4 weeks (8.9 vs. 4.8) and time from tumor initiation to sacrifice was 3 weeks longer (29.4 vs 26.4) in the Pdef −/− Neu model. Significantly, an increase in lung metastasis was observed in the Pdef −/− mice in both the PyMT and Neu models. Thus, loss of Pdef in vivo is associated with defects in mammary development and increased metastasis in mouse models of breast cancer, suggesting Pdef is a metastasis suppressor.
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 3397.
Abstract 3398: Double-faced Sema3E-PlexinD1 signaling inhibits tumor growth but promotes metastatic spreading
Authors: Casazza Andrea , Capparuccia Lorena , Finisguerra Veronica , Mazzone Massimiliano , Comoglio Paolo M. , Tamagnone Luca 
Published: February 2011

Abstract
Semaphorins comprise a wide family of secreted and membrane-bound signals, originally found in neural development, and then implicated in a range of functions: from angiogenesis, to the immune response, to cancer progression. We have previously shown that high-affinity semaphorin receptors are found in the families of the plexins and of the neuropilins. Moreover, additional molecules interact with semaphorin receptors in cell-context dependent manner, featuring a complex scenario of multiple potential signaling pathways. The role of semaphorin signaling in tumor progression is currently under close scrutiny; it is known that cancer cells release semaphorins regulating their own behavior as well as that of cells in the tumor microenvironment, such as endothelial cells and recruited leukocytes.
In this work, we focused on the function of Semaphorin 3E (Sema3E) and its high affinity receptor PlexinD1, and on their potential role to regulate cancer progression. Here we found that Sema3E and PlexinD1 are highly expressed in human metastatic tumors. Moreover, we provided experimental evidences that Sema3E released by tumor cells is a double-faced signal, acting via two distinctive signaling pathways. In paracrine manner, Sema3E-PlexinD1 signaling can elicit endothelial cell repulsion, thereby reducing vessel density and tumor growth. Conversely, Sema3E autocrine signaling in tumor cells thrusts their invasiveness, trans-endothelial migration, and metastatic spreading, through the trans-activation of PlexinD1-associated oncogenic kinases. Notably, by silencing the endogenous expression of either Sema3E or PlexinD1 the metastatic potential of cancer cells is significantly reduced, identifying this pathway as a major driver of the metastatic spreading. In sum, Sema3E autocrine signaling in cancer cells is crucially implicated to induce a metastatic behavior, and it appears as a promising target for strategies aimed at blocking tumor metastasis.
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 3398.
Abstract 3410: Discovery of prognostic factors in Ewing's sarcoma family of tumors by use of Intercohort co-analysis of public gene expression datasets
Authors: Bennani-Baiti Idriss M. , Lawlor Elizabeth R. , Cooper Aaron , Kauer Maximilian , Ban Jozef , Aryee Dave N.T , Kovar Heinrich 
Published: February 2011

Abstract
Cancer genomics can help uncover genes that may serve as indicators of tumor susceptibility, progression, or treatment outcome, as exemplified by studies of adult tumors for which large cohorts are readily available. Childhood cancers comprise a large number of low-incidence histogenetically and molecularly distinct neoplasms, rendering population-based genomic studies unrealistic for these diseases. In recent years, several small-size cohort childhood cancer genomic studies have been published. We report here a novel analytical approach, named intercohort co-analysis or Ican, whereby gene expression significance is inferred from gene expression levels in biologically relevant normal tissues, and gene-disease association significance is assessed in each individual cohort. Next, only genes found to be consistently significant in all cohorts are considered as putative markers of specific disease states. We tested Ican in Ewing's sarcoma (ESFT), a family of tumors that lacks a reliable molecular prognostic or metastasis indicator. We report here that this approach revealed a high intercohort gene expression significance variability, and identified CXCR4 and CXCR7, two chemokine receptors known to correlate to metastasis and/or to poor prognosis mostly in adult cancers, as significantly and consistently associated with ESFT subsets. Accordingly, we show for the first time that CXCR4 expression marks metastatic ESFT and that of CXCR7 serves as a predictor of adverse patient survival. We submit these findings as a proof-of-principle that Ican of publicly available gene expression profiles can yield genes with predictive value for the progression or outcome of low-incidence diseases. We further submit that this approach is poised to gain momentum as many journals now request the mandatory contribution of gene expression profiles to public repositories. These policies, along with the growing number of cancer gene expression profiling investigations, we predict, will swiftly drive upward the number of publicly available low-incidence disease expression datasets, and consequently, of Ican applications.
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 3410.
Abstract 3419: NOS1 imparts a survival benefit to PAX-FKHR expressing alveolar rhabdomyosarcomas
Authors: Bajaj Sheetal V. , Shahbazian Violette , Anderson Michael J. , Triche Timothy J. 
Published: February 2011

Abstract
BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood and adolescence. Based on histology, two major forms are identified: embryonal and alveolar. Molecularly, these tumors are classified as translocation-positive alveolar RMS (ARMS, characterized by PAX3-FKHR or PAX7-FKHR chimeric fusions), translocation-negative alveolar RMS (nARMS), and embryonal RMS (ERMS). The PAX-FKHR oncogenes have been shown to be responsible, in part, for the aggressive clinical behavior and poor outcome of ARMS. It is thus important to identify biomarkers in this subgroup that can be used as potential therapeutic targets.
METHODS: Using Affymetrix Human Exon 1.0 ST (HuEx) microarrays, genome-wide expression profiles were generated on primary tumors from RMS patients accrued on COG treatment protocols. Data analysis was performed using institutional software (Genetrix) by standard classification methods. Expression of neuronal nitric oxide synthase (NOS1) was validated by qPCR, immunoblot and immunohistochemistry. A functional relationship, if any, to PAX-FKHR was determined by qPCR after siRNA-mediated knockdown of PAX-FKHR in ARMS cell lines and stable transduction of PAX-FKHR into an ERMS cell line. Further, shRNA targeting NOS1 using a lentiviral delivery system was used for functional NOS1 studies in ARMS cell lines.
RESULTS: Expression analysis revealed that NOS1 is highly expressed in ARMS with a PAX3 or PAX7 translocation. Little expression was found in nARMS, ERMS or normal muscle. This was confirmed by qPCR and immunoblotting in two independent groups of primary tumors and RMS cell lines. PAX-FKHR knockdown resulted in decreased expression of NOS1 and its corresponding protein in ARMS cell lines. PAX-FKHR expression in an ERMS cell line induced the expression of NOS1 and its corresponding protein where the native cell line showed no corresponding expression. Further, targeting NOS1 using shRNA in ARMS cell line caused decreased NOS1 expression leading to poor cell survival and cell death.
CONCLUSIONS: NOS1 is over-expressed in the more aggressive PAX3 or PAX7 ARMS when compared to translocation-negative RMS. Its expression appears to be regulated by PAX-FKHR, a tumor specific chimeric gene that has been implicated in regulating the malignant phenotype of ARMS. It seems to play an important role in the survival of these tumor cells. Taken together, these observations suggest that NOS1 is a downstream effecter of PAX-FKHR mediated oncogenesis and an essential factor for tumor cell survival that could be a therapeutic target, using suitable small molecule therapy.
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 3419.