bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4362: RBM3 overexpression promotes cancer stem cell expansion through activation of Notch-1 signaling
Authors: Ramalingam Satish , Subramaniam Dharmalingam , Jensen Roy A. , Anant Shrikant 
Published: June 2012

Abstract
Cancers are heterogeneous population of cells, a minor portion of which exhibit stem-like characteristics. Recent evidence suggests that these Cancer Stem Cells (CSCs) are responsible for tumor behavior. Recently, we reported that RNA binding protein RBM3 is overexpressed in various tumors of epithelial origin and downregulating its expression results in inhibition of tumor growth. Moreover, RBM3 affects the proliferation of CD34+ hematopoietic stem cell. Overexpression of RBM3 induces NIH-3T3 cells to transform and grow in an anchorage independent manner, and form tumors in athymic nude mice suggesting RBM3 is a proto-oncogene. Given these observations, we sought to determine whether RBM3 expression affects CSCs in solid tumors and its function in tumor initiation and/or metastasis. We have recently demonstrated that Doublecortin like Kinase-I (DCAMKL-1/DCLK1), a microtubule-associated kinase is a marker of quiescent intestinal stem cells. Immunohistochemical analyses of the NIH3T3-RBM3 tumors demonstrated an increase in the number of DCLK-1+ stem cells. Using fluorescence-activated cell sorting, we were able to isolate these DCLK-1+ stem cells from the bulk of the tumor and grow them in tissue culture dishes. We have named these cells as RNA binding protein-Induced Cancer Stem Cells (RICSCs). We next determined the stemness of the DCLK-1+ RICSCs. For this, we performed serial dilutions of the RICSCs starting at 10,000 cells and injected them into the flanks of nude mice. Even when 500 cells were injected, a primary tumor was observed at about 10 weeks; the histological analysis of the tissues revealing metastatic lesions in the lung, liver, bone and spleen. Recent studies with mammary and neuroectodermal tumors have suggested that inappropriate Notch activation promotes self-renewal and transformation of progenitor cells. We observed that there was a significant upregulation of activated Notch-1 expression in the NIH-3T3-RBM3 RICSCs. Inhibition of Notch-1 with a specific inhibitor, DAPT resulted in the arrest of RICSC-mediated tumor growth in nude mice. These data demonstrate that Notch signaling is essential for self-renewal in stem cells thereby affecting tumor growth. Taken together, these data imply that overexpression of RBM3 results in increased dedifferentiation into cancer stem cells that have an aggressive metastatic phenotype. These CSCs have great potentials for aiding in our understanding of oncogenesis and metastatic cascades.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4362. doi:10.1158/1538-7445.AM2011-4362
Abstract 4363: Inhibitory efficacy of curcumin ± stem cell specific RNAi on the growth of tumorospheres in vitro: Assay development and mechanisms of action
Authors: Kantara Carla , Sarkar Shubhashish , Swiercz Rafal , Ullrich Robert , Singh Pomila 
Published: June 2012

Abstract
Colorectal cancer (CRC) is the third most common cancer and leading cause of cancer related deaths in the Unites States. Several therapies are currently being used to treat the disease but recurrence remains a challenge. It is believed that cancer stem cells (CSCs) may be resistant to currently used radiation and chemotherapeutic treatments, and may thus be the likely cause of relapse. It is postulated that CSCs may arise from normal adult stem cells and, therefore, preventing aberrant proliferation of stem/progenitor cells and/or targeting CSCs may improve treatment outcomes. However, to-date, there are no assays for examining response of ‘stem cells’ in vitro. Therefore one of our goals was to isolate stem cells from colorectal cancers, and establish stem/progenitor cell bioassays to examine inhibitory efficacy of chemo preventive agents and stem cell specific siRNA. In recent years, several putative stem/progenitor cell markers have been identified, including DCAMKL-1, CD44 and LGR5. Curcumin is being used in clinical trials for treating CRCs. For our studies we chose to isolate CSCs using the above indicated stem cell markers, each of which expresses an extracellular domain. We successfully isolated stem cell populations enriched in the indicated markers, and established tumorospheres from a colon cancer cell line (HCT-116); these growths are selective for stem cells, and can therefore be used in bioassays for examining inhibitory efficacy of drugs on stem cells in vitro. We examined the inhibitory efficacy of curcumin±DCAMKL-1 siRNA against growth of HCT-116 tumorospheres. Spheres were fixed and stained for DCAMKL-1, CD44, and LGR5, and examined by fluorescence confocal microscopy. The effect on growth signaling pathways was quantified by Western Blot analysis. Our results reveal that both DCAMKL-1 siRNA and curcumin exert inhibitory effects on growth of HCT-116 tumorospheres, and reduce relative expression levels of NFκBp65 and β-catenin in tumorospheres. Importantly, DCAMKL-1 siRNA potentiated inhibitory potency of Curcumin. In conclusion, we have successfully established in vitro methods for examining proliferative/inhibitory efficacy of various molecules on the biology and response of cancer stem cells, which can be expected to impact cancer treatment strategies. This work is supported by NIH grants CA97959 and CA114264 to PS and NASA grants NNX09AM08G and NNJ04HD83G to RU.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4363. doi:10.1158/1538-7445.AM2011-4363
Abstract 4364: TR4 for the treatment of human neoplasms: Novel antiNotch agent
Authors: Epenetos Agamemnon A. , Kyprianou Spyros , Colucci Silvia , Kousparou Christina , Deonarain Mahendra 
Published: June 2012

Abstract
It has been widely demonstrated that the Notch receptor signaling pathway is required for regulation and differentiation of stem cells in many tissues cell types. It is also well established that aberrant Notch signaling can lead to several human forms of cancer, including leukaemia, breast, colon, skin, cervical, and lung cancer, making Notch an attractive target for new cancer therapies. It has become clear that one of the major therapeutic targets in the Notch pathway is the cleavage of four Notch receptors, in which gamma-secretase inhibitors play a role. Unfortunately inhibition of γ-secretase complex is accompanied by many serious side effects.
In order to avoid the side effects associated with γ-secretase inhibitors and achieve an improved therapeutic effect, a more selective Notch inhibition is desirable. We have genetically engineered a fusion protein, 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 the Notch transactivation complex. This fusion protein, (ANTP/DN-MAML) or TR4, has been tested for its ability to target tumor cells in vitro and in vivo.
Our results indicate that targeting Notch signaling with the ANTP/DN-MAML (TR4) suppresses Notch activation, translocates into nucleus and inhibits tumor growth in mice, without significant organ or systemic toxicity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4364. doi:10.1158/1538-7445.AM2011-4364
Abstract 4367: IP6: A potential novel therapy for cancer stem cells
Authors: Nata Toshie , Tran Hieu Cong , Bryant Joseph L. , Ateh Eugene , Lunardi-Iskandar Yanto , Vucenik Ivana 
Published: June 2012

Abstract
Background and Aims: We recently discovered that inositol hexaphosphate (IP6), a new anticancer agent, killed malignant cancer stem cells (CSC) such as: CD133+, CD44+ and CD24+ cells via apoptotic pathways, but did not kill normal epithelial cells, fibroblasts, lymphocytes and macrophages. The effects of IP6 on malignant CSC have not been known. To clarify the molecular mechanism of IP6 destruction of CSC cells, we studied its effects in several CSC from malignant KS-Y1, B-NHL, prostate cancer (PCA) and breast cancer (BCA) cell lines. Methods and Results: CSC were isolated from KSY-1, B-NHL/HIV Tg26 mice, PCA and BCA cancer cell lines using magnetic beads conjugated with MoAbs and analyzed by flow cytometry for CD133, CD44 and CD24 cells. CSC cells were cultured using liquid and semisolid techniques for tumorigenesis assay and were treated with IP6 at doses of 100, 300 and 500 µg/ml, untreated (PBS) and control treatment with 10-100 µg/ml of Taxol. Cell viability was determined by trypan blue at 1 hr-24 hrs. FACS analyses were performed for apoptotic activities by detection of death molecules such as Annexin V-FITC and PI-CD95, and apoptosis assessed by 3D confocal microscopy. Significant killing of malignant CSC with IP6 in a dose-dependent manner were shown ex vivo in proliferation/differentiation tumorigenesis assay, in quantitative/qualitative FACS analyses and 3D confocal microscopy. In contrast, Taxol molecule with doses 10-100 µg/ml did not kill the CSC. Since it is known that CSC are resistant to Taxol treatment and radiation therapy, and IP6 significanly decreased proliferation and induced apoptosis in malignant and metastatic CSC, the results from our experiments suggest that IP6 may be an excellent new drug for treatment of CSC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4367. doi:10.1158/1538-7445.AM2011-4367
Abstract 4371: Optimal drug concentration screening and evaluation in cancer stem cells & 3D tumor stem cell cultures drug response assays in association with clinical efficacy for melanoma cancer stem cell
Authors: Passarini Jenna , Cleary John Patrick , Kumar Preetham , Newton Trisha , Shankar Sharmila , Sharma Cristian , Sharma Michael , Punzalan Rubio R. , Sharma Bhuvesh K. , Sharma Sherven , Gill Parkash , Srivastava Rakesh K. , Sharma Jay P. 
Published: June 2012

Abstract
Optimal drug concentration screening and evaluation in Cancer stem cells & 3D Tumor Stem Cell cultures Drug Response assays in association with Clinical efficacy for Melanoma Cancer Stem Cell.
Three-dimensional (3D) culture of cancer cell lines has long been advocated as a better model of the malignant phenotype that is most closely related to tumorigenicity in vivo. Moreover, new drug development requires simple in vitro models that resemble the in vivo situation more in order to select active drugs against solid tumors and to decrease the use of experimental animals. The induction of chemotherapy or concomitant chemoradiotherapy has been used to increasingly to improve survival, and organ preservation. This approach encounters significant morbidity and mortality. Therefore reliable chemosensitivity assays are needed to accurately predict the response to chemotherapy and guide the selection and treatment of cancer patients. The purpose of this study is to examine and evaluate optimum drug candidates in vitro chemosensitivity on patient tumor tissues directly in culture and on their Cancer stem cell cultures. The tumor samples obtained after surgery or biopsy, were placed immediately in Celprogen Tumor Transportation Media and shipped at 4-8 OC for processing. Tissues were washed with 1X PBS solution and aseptically cut into 0.5mm sections and cultured in 6 well tissue culture plates with an insert pre-coated with ECM. All cancer cell types remain viable and maintain their native architecture for at least 14 days and incorporated DNA measured by adding EdU(5-ethynyl-2’-deoxyuridine) to the culture. The efficacy of various therapeutic agents targeting major pathways (wnt, Notch, PI3K, MAPK, STAT) and chemotherapy agents were tested using DNA uptake and TUNNEL assay anti-cancer agents was calculated according to the inhibition index. The same compounds were tested for utilizing the patient's Melanoma Cancer stem Cell Cultures established with Celprogen's Media and ECM. Among the 300 compounds tested Adria, Taxol, DTIC, Thalidomide, Paclitaxel, Abraxane, Ertibux and Velcade were not effective against Melanoma Cancer Stem cell (CSC). We were able to show 3 compounds that were effective against Melanoma CSC targeting selected pathways.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4371. doi:10.1158/1538-7445.AM2011-4371
Abstract 4378: Defining the role of mammary stem cells and progenitor cells in the development of estrogen-induced mammary cancer in the rat
Authors: Ding Lina , Shull James D. 
Published: June 2012

Abstract
Substantial data implicate both estrogens and progestins in the etiology of breast cancer. However, the mechanisms through which these steroid hormones elicit their effects on breast cancer risk have not been elucidated. The ACI rat serves as a unique model for investigating the mechanisms through which estrogens and progestins contribute to breast cancer development and for defining the genetic bases of inherited risk of breast cancer. When treated with physiologic levels of 17β-estradiol (E2), female ACI rats develop mammary cancer at an incidence that approaches 100%. Interestingly, rapid development of mammary cancer in E2 treated ACI rats is dependent upon progesterone. The mammary cancers that develop in E2 treated ACI rats are estrogen dependent, frequently exhibit non-random patterns of genome instability, and are invasive. Because each of these phenotypes is also commonly exhibited by breast cancers in humans, the ACI rat appears to be highly relevant to the study of breast cancer etiology. Whereas female ACI rats are highly susceptible to E2-induced mammary cancer, female Brown Norway (BN) rats are resistant. Genetic studies performed by our laboratory localized a total of six quantitative trait loci (QTL), designated Emca3 through Emca9, that account for a large fraction of inherited susceptibility in F2 progeny generated in intercrosses between ACI and BN rats. The purpose of this study is to test the hypothesis that ACI and BN rats exhibit differences in the responsiveness of their mammary stem cell (MaSCs) and/or progenitor cell (MaPCs) populations to E2 and/or progesterone. By using a combination of markers CD31, CD45, CD24, CD29 and fluorescence-activated cell sorting, we have identified four distinct populations of mammary cells. To quantify the numbers of MaSC and MaPC in these populations, we are evaluating the ability of the basal (Lin-CD24+CD29high) and luminal (Lin-CD24+CD29low) cell populations to form colonies when cultured in vitro and to generate mamamry gland outgrowths when transplanted into the interscapular fat pad of recipient syngenaic or (ACIxBN)F1 rats. Any observed differeces in MaSC and/or MaPC number or function will be evaluated further using a set of congenic rat strains that harbor BN alleles across an individual Emca locus on the ACI genetic background.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4378. doi:10.1158/1538-7445.AM2011-4378
Abstract 4380: CD133/prominin-1 modulates epithelial-mesenchymal transition, stemness and tumorigenicity of oral squamous cell carcinoma-derived cancer initiating
Authors: Chen Yu-Syuan , Lo Jeng-Fan 
Published: June 2012

Abstract
Background: Oral squamous carcinoma cell (OSCC) is a lethal cancer with clinical, pathological, phenotypical and biological heterogeneity. Tumor initiating cells (TICs), which are responsible for tumor growth and coupled with epithelial-mesenchymal transition (EMT), have been identified. We have also identified the subpopulation of oral cancer derived tumor initiating cells (OC-TICs), and observed the upregulation of CD133 in OC-TICs. Others demonstrate that CD133 is phosphorylated by Src and Fyn tyrosine kinases. However, the molecular function of CD133 in OC-TICs remains unclear. Herein we determined the critical role of CD133, an important TICs marker, in the maintenance of stemness characteristics and tumorigenic phenotype of OC-TICs.
Methods: Stable overexpression and knockdown of CD133 expression in OSCCs and OC-TICs was achieved by lentiviral-mediated system. Consequently, we elucidated the epithelial-mesenchymal transition, the stemness properties and tumorigenicity of OSCCs and OC-TICs with CD133 down-regulation or overexpression, respectively. Consequently, we investigated the role of Src and and Fyn tyrosine kinases in CD133 mediated signaling pathway.
Results: Stable over-expression of CD133 induced epithelial-mesenchymal transition, enhanced tumorigenicity and enhanced the TICs properties in OSCCs. In contrast, lentiviral knockdown of CD133 significantly reduced the self-renewal ability, side population cells, and stemness genes in OC-TICs. Additionally, down-regulation of CD133 enhanced the differentiation capability but inversely diminished “stemness” gene expression of OC-TICs. Of note, knockdown of CD133 lessened tumorigenicity of OC-TICs both in vitro and in vivo. Furthermore, over-expression of CD133 increased phosphorylation of Src and Erk1/2.
Conclusion: We showed that CD133 contributes to the epithelial-mesenchymal transition and the maintenance of stemness and tumorigenicity of OC-TICs. In addition, Src and Erk1/2 activation was involved in CD133 modulating phenotype. Overall, silencing CD133 might be a potential therapeutic target for OSCC by eliminating TICs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4380. doi:10.1158/1538-7445.AM2011-4380
Abstract 44: Towards novel marker discovery from phylogenetic analysis of heterogeneous tumor samples
Authors: Subramanian Ayshwarya , Shackney Stanley , Schwartz Russell 
Published: June 2012

Abstract
Computational methods based on phylogenetics, or the inference of evolutionary trees, have been useful for inferring likely pathways of tumor progression, but their use has been limited by our inability to precisely characterize the mutational states of individual cells in heterogeneous tumor samples. We describe a novel approach to tumor phylogenetics using computationally inferred sub-populations of cells derived from whole-genome data on heterogeneous tumor samples. We previously proposed a strategy for computationally separating cell types from heterogeneous tumor samples and inferring genome-wide profiles of RNA expression or DNA copy number for these discrete cell populations from profiles of the full tumor samples. In the present work, we extend this method by showing how one can use these computationally inferred cell states to identify markers informative of progression state and use them in phylogenetic analysis of tumor samples. We demonstrate the approach on a publicly available data set of array comparative genome hybridization (aCGH) data profiles applied to sectioned ductal breast carcinomas (Navin et al., 2010; NCBI GEO GSE16672). Our approach begins by applying our previously described method for cell type separation to generate inferred profiles of six cell types, and computationally inferring virtual aCGH profiles for these types. We then scan over sliding windows of 20 consecutive probes per window, identifying windows for which probe values are significantly aberrant relative to diploid by a modified chi-squared test (p-value 0.001 with Bonferroni correction), and merging overlapping windows to identify phylogenetically informative amplicons. We then identify, for each amplicon, those components that have significantly aberrant copy number by Gaussian test with diploid mean (p-value 0.001). Finally, the identified amplicon states for the inferred cell types, as well as an additional all-diploid normal type, are used as input for a maximum parsimony phylogenetic tree reconstruction using the PAUP package with 300 bootstrap replicates. The method applied to the Navin et al. data identified 15 amplicons phylogenetically informative for breast tumor progression. Bootstrap replicates from the phylogenetic tree reconstruction reveal a robust grouping of cell states into three distinct subgroups and suggest several possible progression pathways by which the identified amplicons may successively accumulate in particular breast cancer sub-types. Continuing work will examine robustness of the inferred markers and pathways to independent data sources.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 44. doi:10.1158/1538-7445.AM2011-44
Abstract 4402: Triple negative breast cancer progression is impacted by NR4A orphan nuclear receptor signaling
Authors: Llopis Shawn D. , Singleton Brittany , Williams Christopher 
Published: June 2012

Abstract
PURPOSE: Despite the lack of an increased rate of breast cancer occurrence among African-American women, African-American women suffer greater mortality due to breast cancer as compared with other ethnic groups. A key factor in decreased survival among African American women may be the elevated occurrence of triple negative (ER-/PR-/HER2-) breast cancers. The negative response makes these patients ineligible for hormonal therapy or Her2 targeted therapies, often leaving cytotoxic chemotherapeutic strategies. The NR4A subfamily of orphan nuclear receptors have the potential to serve as distinct, specific pharmacological targets which can directly affect apoptosis and be exploited to design highly selective, less toxic regimens in triple negative breast cancer phenotypes. DESIGN METHOD: Using cell lines derived from MB468 cells, crystal violet staining and Alamar blue assays for cell viability, Western blot for protein expression, PCR for gene expression, and fluorescence microscopy for immunohistochemical staining and xenograft studies were performed. RESULTS: Breast tumor microarrays demonstrate that NR4A2 is highly expressed in the nucleus of normal, but not malignant breast epithelial cells. shRNA-mediated silencing of NR4A2 in triple negative breast cancer cells leads to increased proliferation. Studies also reveal shRNA-silencing of NR4A2 expression mediated partial resistance to doxorubicin, while overexpression leads to cell cycle arrest. Additionally, gene expression arrays show that overexpression of NR4A2 induces expression of angiogenic factors, and suppresses markers associated with epithelial-mesenchymal transition. CONCLUSION: These studies suggest that NR4A2 is a viable pharmacological target in triple negative breast cancer and may prove an effective means to address the disparity in survival rates of African-American women as compared to other ethnicities.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4402. doi:10.1158/1538-7445.AM2011-4402