bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3327: Role of microRNA221 in breast cancer stem cell expansion and induction of EMT
Authors: Ke Jia , Malik Fayaz A. , McDermott Sean , Martin Rachel , Shang Li , Korkaya Hasan , Clouthier Shawn , Ginestier Christophe , Ibarra Ingrid , Hannon Gregory J. , Wu Zhifen , Wicha Max S. , Liu Suling 
Published: August 2012

Abstract
Breast cancer can be grouped by expression profiling into categories that differ in biological and clinical characteristics. Molecular characterization of these subtypes on the basis of stem cell markers has shown that basal and claudin-low tumor bear stem cell like characteristics with a higher population of CD44+/CD24- and CD49f+/EpCAM- cells, which also display characteristics of epithelial mesenchymal tumor transition (EMT). There are several genetic and epigenetic signaling pathways that regulate the stem cell like characteristics of these subtypes. We examined the role of microRNA221 (mir-221) in sub populations of normal breast cells isolated from reduction mammoplasties as well as in cancer cell lines from different molecular subtypes of breast cancer. We found that mir-221 drives cells towards more basal subtype and induces EMT in both normal mammary cells and breast cancer cell lines. On the basis of CD49f and ESA staining in the cells isolated from normal mammary tissue, we found high mir-221 expression in the CD49f+/EpCAM- population. Furthermore, we showed that ALDH+ cells from mammospheres expressed significantly higher mir-221 compared to ALDH- cells. In order to determine the effect of mir-221 on the stem cell population, we overexpressed mir-221 in cells from primary mammospheres and showed that overexpression of mir-221 increases the CD49f+/EpCAM- population with increased expression of mesenchymal biomarkers, an effect also seen in a non-transformed breast cell line MCF10A. Overexpression of mir-221 in luminal breast cancer cell lines MCF-7 and T47D cell lines increased the proportion of CD44+/CD24- cells. Furthermore, overexpression of mir-221 significantly stimulated the tumor growth of MCF7 xenographs in NOD/SCID mice. These studies suggest that mir-221 regulates breast CSCs by promoting EMT. This may play an important role in tumor behavior and treatment resistance.
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 3327. doi:1538-7445.AM2012-3327
Abstract 3330: Functional characterization of microRNAs identified in human acute myeloid leukemia stem cells
Authors: Hermans Karin G. , Lechman Eric R. , Dick John E. 
Published: August 2012

Abstract
Human acute myeloid leukemia (AML) is organized as a functional cellular hierarchy and is sustained by a rare population of leukemia stem cells (LSC). AML is a heterogeneous disease with a relapse rate of up to 80% depending on age of the patient and AML subtype. Recent work suggests that leukemia stem cell properties influence therapy response, overall survival, and relapse of the disease. In order develop more effective novel therapies that target this rare cell population; it is imperative that we better understand LSCs at the molecular level. Although it is generally accepted that oncogenic mutations underlie cancer initiation and progression, most studies have focused on protein coding genes. However, there is increasing recognition that non-coding RNAs can also play a role in leukemogenesis. MicroRNAs (miRNAs) are a family of small non-coding RNAs that function as important regulators of the translation of protein-coding genes. In order to identify LSC specific miRNAs, we fractionated 16 primary human AML samples into four sub-populations, each of which were xenotransplanted into immune-deficient mice to evaluate in vivo leukemia initiating capacity. Global miRNA expression profiling was performed on each population and a LSC specific miRNA signature generated by supervised analysis guided by the ability to initiate leukemia in vivo. Similarly, a human cord blood derived hematopoietic stem cell (HSC) enriched miRNA signature was also established. From these lists, we selected ten promising candidate miRNAs to assess for biological function. We have initiated a functional screen to determine the role of the candidate miRNAs using both in vivo and in vitro assays. Preliminary results show that enforced expression of two miRNA candidates strongly reduced engraftment capability of HSCs over untransduced HSCs in immune-deficient recipients. Moreover, enforced expression of three additional miRNA candidates show a competitive growth advantage of transduced HSCs over untransduced HSCs and compared to controls. Also, enforced expression of one of these three miRNAs in the surrogate LSCs of a unique leukemia cell line induces a strong proliferative advantage over untransduced LSCs in an in vitro culture setting. In conclusion, thus far we have identified five miRNAs that affect hematopoietic stem cell properties. Further in vivo and in vitro analysis will determine whether these miRNAs are suitable targets for therapy.
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 3330. doi:1538-7445.AM2012-3330
Abstract 3332: Inhibition of cancer stem-like properties in malignant glioma by delivery of microRNA145 with cationic polyurethanes-PEI
Authors: Chiou Shih-Hwa 
Published: August 2012

Abstract
Malignant glioma, including Glioblastoma (GBM), is the most common primary brain tumor bearing dismal prognosis. CD133 has been considered a putative marker of cancer stem cells (CSCs) in malignant cancers, including GBM. MicroRNAs (miRNAs), highly conserved small RNA molecules, may target oncogenes and become a therapeutic strategy against cancer. However, the involvement of miRNAs in GBM-associated CSCs remained mostly unclear. Using miRNA/mRNA microarray analysis, we identified that miR145 (a tumor-suppressive miRNA) expression is inversely correlated with the levels of Oct4 and Sox2 in GBM-CD133+ cells and specimens of malignant glioma. Consistently, we demonstrated that miR145 negatively regulates tumor growth of GBM by directly targeting Oct4 and Sox2 in GBM-CD133+ cells. We therefore evaluated the treatment effect of polyurethane-short branch polyethylenimine-mediated miR145 (PU-PEI-miR145) on GBM-CSCs. PU-PEI-miR145 delivery in GBM-CD133+ significantly inhibited their tumorigenic and CSC-like abilities, and facilitated their differentiation into CD133α non-CSCs. Furthermore, PU-PEI-miR145 delivery in GBM-CD133+ effectively suppressed their expressions of drug-resistance and anti-apoptotic genes, and dramatically increased the sensitivity to radiation and chemotherapeutic drugs, including temozolomide. Finally, in vivo alone delivery of PU-PEI-miR145 significantly suppressed tumorigenesis, and synergistically improved survivals in orthotopic GBM-CD133+-transplanted immunocompromised mice, combined with radiotherapy and temozolomide. Therefore, PU-PEI-miR145 is potential therapeutic approach for malignant brain tumors.
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 3332. doi:1538-7445.AM2012-3332
Abstract 3333: Cancer stem cell-mediated regulation of Myc overexpressing medulloblastoma cells on proliferation, migration and invasion
Authors: Park Jun Bum , Kim Dong Ok , Ra Yoon Hwan , Ra Young Shin 
Published: August 2012

Abstract
Medulloblastoma (MB) is the most common and malignant pediatric brain tumor. Myc amplification was frequently shown in the tumor. Hereby cancer stem cells are being issued lately was investigated whether it is associated with Myc and its contributions. MB cell lines - UW228, UW228-Myc, UW426 and UW426-Myc were used for following assays. Myc overexpressing cells of two kinds of cells were shown significantly higher proliferation rate than counterpart cells by cell proliferation assay. In particular, the extent of difference in UW228-Myc was bigger than in UW426-Myc. Using cell cycle analysis, DNA contents in both UW228-Myc and UW426-Myc were mainly accumulated in G2/M phase compared with their each control, suggesting that cells overexpressing Myc have faster proliferation rate. In addition, two UW228-Myc and UW426-Myc cells were demonstrated more increased self-renewal capacities by colony-forming assay versus UW228 and UW426, respectively. For migration and invasiveness, both Myc overexpressing cells increased in comparison with each control by wound-healing assay and invasion assay using Matrigel chamber. Interestingly UW228-Myc cells were shown nearly six times higher invasiveness than in UW228 cells. In contrast, the disparity of that in UW426 and UW426-Myc cells was just about two times. It is verified that why Myc overexpressing cells have more dominant proliferation, self-renewal, migration and invasion abilities than corresponding controls by western blot assay. The results showed strongly increased expression of migration, invasion-related markers (p-AKT, p-ERK1/2 and Rac1) and cancer stem cell-related markers (Nestin, CD133, Oct3/4 and SOX2), especially in UW228-Myc cells. In conclusion, Myc expression induces not only cell proliferative and self-renew propensities, but also migration and invasiveness by mediating cancer stem 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 3333. doi:1538-7445.AM2012-3333
Abstract 3336: The role of Notch signaling in esophageal adenocarcinoma
Authors: Wang Zhiqiang , Ranganathan Prathibha , Koshenkov Vadim , Bai Feng , Li Bin , Fei Dennis Liang , Livingstone Alan , Franceschi Dido , Martell Juan , Robbins David J. , Capobianco Anthony J. 
Published: August 2012

Abstract
Background: The Notch signaling pathway plays a critical role in embryonic development and carcinogenesis. Aberrant Notch signaling has been linked to a wide variety of cancers. Activation of Notch pathway can either suppress or promote tumors depending on the cell type and context. However, the role of the Notch pathway in the pathogenesis and development of esophageal adenocarcinoma (EAC) is poorly understood. Objective: Elucidate the role of NOTCH signaling pathway in EAC. Methodology: In this study, the expression of Notch components in EAC tissues, matched non-tumor esophageal mucosa and normal esophagus tissues, EAC cell lines (FLO-1, JH-EsoAd1, OE19 and OE33) and 3 primary esophageal normal epithelial cells were assessed by quantitative RT- PCR, western blot analysis, immunofluorescence and immunohistochemistry. The effect of blocking as well as ectopic activation of the Notch pathway on the proliferation, colony formation, and gene expression were also characterized. Results: The aberrant activation of Notch signaling was observed in human EAC clinical samples. Expression of most Notch pathway components was elevated in EAC. The expression of activated NOTCH1 also associated with the differentiation grade of EAC. We found that blocking Notch activity by gamma-secretase inhibitors(GSI) affects the proliferation and/or survival of EAC cell lines and human EAC samples ex vivo cultures. In contrast, this effect was not observed in human esophageal epithelial cell line, Het-1A. However, we observed that activation of Notch signaling by NOTCH1icd could promote colony formation in Het-1A cells. Conclusions: Our results showed that Notch signaling promotes the growth and pathogenesis of EAC. Therefore, Notch signaling pathway could be a promising therapeutic target for treatment of human EAC.
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 3336. doi:1538-7445.AM2012-3336
Abstract 3338: Characterization of glucose transporter 3 in head and neck cancer initiating cells
Authors: Chen Yu-Syuan , Lo Jeng-Fan 
Published: August 2012

Abstract
Background: Head and Neck squamous cell carcinoma (HNSCC) is a lethal cancer with clinical, pathological, phenotypical and biological heterogeneity. Cancer initiating cells (CICs) exhibit self-renewal and promote tumor progression capacity. We have also identified the subpopulation of head and neck cancer initiating cells (HN-CICs), and observed the upregulation of Glucose Transporter 3(Glut3) in HN-CICs by differential systemic analyses. However, the role of Glut3 in HN-CICs metabolism alternation remains unclear. Herein we determined the critical role of Glut3, a novel CICs marker, in the maintenance of stemness characteristics and tumorigenic phenotype of HN-CICs. Methods: Stable overexpression and knockdown of Glut3 expression in HNSCCs and HN-CICs was achieved by lentiviral-mediated system. Consequently, we elucidated the stemness properties and tumorigenicity of HNSCCs and HN-CICs with Glut3 down-regulation. Consequently, we investigated the role of Glut3 in metabolism regulation of cancer initiation cells. Results: Lentiviral knockdown of Glut3 significantly reduced the self-renewal ability and cancer initiation cell marker Grp78 expression in HN-CICs. Additionally, down-regulation of Glut3 enhanced the differentiation capability but inversely diminished “stemness” gene expression of HN-CICs. Of note, knockdown of Glut3 lessened tumorigenicity of HN-CICs both in vitro. Conclusion: We showed that Glut3 contributes to the maintenance of stemness and tumorigenicity of HN-CICs. In addition, the expression of Glut3 was involved in HN-CICs metabolism. Overall, silencing Glut3 might be a potential therapeutic target for HNSCC by eliminating CICs.
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 3338. doi:1538-7445.AM2012-3338
Abstract 3342: Tumor-initiating cells in human glioblastoma are heterogeneous populations which reside in distinct environmental niches
Authors: Piccirillo Sara Grazia Maria , Spiteri Inma , Sottoriva Andrea , Marko Nicholas , Tavare' Simon , Collins Peter , Watts Colin 
Published: August 2012

Abstract
We previously demonstrated that it is possible to objectively interrogate human glioblastoma (GBM) by using 5-aminolevulinic acid (5-ALA), an endogenous intermediate of the porphyrin biosynthesis pathway. It acts as a prodrug that is metabolised intracellularly leading to the selective accumulation of the fluorescent molecule protoporphyrin IX (PpIX) in tumor cells. Tumor tissue resection is then performed on a fluorescence-guided basis allowing direct visualization of tumor tissue and diffusely infiltrative disease. This approach gave us the possibility to identify and characterize tumor compartments in GBM. We have now interrogated tumor compartments based on PpIX fluorescence. Our results demonstrate that: 1) cells residing in the tumor margin do not resemble the “cancer stem cell” phenotype but are tumorigenic to some extent, 2) the margin tissue expresses markers of apoptosis, 3) fluorescence material is present in the SVZ of 65% of our GBM (n=65 patients) and it is possible to isolate TICs from these SVZs. These cells are phenotypically similar to those isolated from the tumor mass and possess all the “cancer stem cell” cardinal features, 4) SNP analysis of SVZ tissue samples reveals distinct genetic aberrations, 5) TICs in the SVZ reside in a pro-angiogenic environment. Further characterization of niches in tumor edges and SVZ as well as response to chemotherapeutic agents is in progress to highlight intra-tumoral heterogeneity of TICs.
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 3342. doi:1538-7445.AM2012-3342
Abstract 3349: Transformation of mammary epithelial cells by inactivation of p53 and PTEN generates cancer stem cells driven by an IL-6/TGF-beta inflammatory loop
Authors: Hasan Korkaya , Kim Gwangil , Malik Fayaz , Davis April , Paulson Amanda K. , Quraishi Ahmet A. , D'Angelo Rosemarie C. , Tawakkol Nader , Liu Suling , Hassan Khaled , Clouthier Shawn G. , Wicha Max S. 
Published: August 2012

Abstract
The PTEN and p53 tumor suppressor genes, frequently inactivated in human breast cancers have been shown to be regulators of normal and malignant breast stem cell self-renewal. In addition, inactivation of tumor suppressors in preneoplastic lesions are implicated in tumor progression from ductal situ in carcinoma (DCIS) to invasive ductal carcinoma. To determine the relationship between stem cell self-renewal and carcinogenesis, we examined the effects of PTEN and p53 knockdown on normal mammary epithelial cells obtained from reduction mammoplasties, as well as in the non-transformed mammary cell line MCF10A. Simultaneous knockdown of PTEN and p53 in normal mammary epithelial cells generated hyperplastic and DCIS-like lesions when these cells were transplanted into the humanized mammary fat pads of NOD/SCID mice. In MCF10A cells knockdown of PTEN and p53 synergized to expand the stem cell compartment transforming these cells and generating highly metastatic tumors in NOD/SCID mice. Stem cell expansion was driven by activation of an inflammatory loop involving both IL-6 and TGF-b. This inflammatory loop was mediated by both AKT/b-Catenin and Stat3/NF-kB pathways. Conversely collective inhibition of these pathways including TGF-b, IL-6 and Wnt/b-Catenin and Stat3/NF-kB was necessary to revert back this stem cell phenotype. This may suggest that synergistic activity of these pathways may contribute to the expansion and transformation of mammary stem cells. The expanded cancer stem cells were highly metastatic and invasive and displayed properties of EMT. The IL6-R antibody tocilizumab blocked this loop resulting in a reduction of CSCs and thus inhibiting tumor growth in mouse xenografts. These studies suggest that loss of PTEN and p53 transforms mammary epithelial cells by activating an inflammatory loop mediated by IL-6 and TGF-b, generating CSCs with an EMT phenotype. Since CSCs drive tumor growth and metastasis, targeting the self-renewal by interfering with this CSC, inflammatory loop represents a rational strategy for breast cancer prevention and therapy.
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 3349. doi:1538-7445.AM2012-3349
Abstract 335: Human neuroblastoma cells undergo TGF-beta mediated mesenchymal change in the transition to drug resistance
Authors: Naiditch Jessica A. , Clark Sandra , Lautz Timothy B. , Jie Chunfa , Madonna Mary Beth , Chu Fei 
Published: August 2012

Abstract
Background: Hypoxia inducible factor 1-alpha (HIF1-alpha) is overexpressed in doxorubicin-resistant neuroblastoma cell lines relative to drug sensitive parental cells lines, and has been implicated in inducing epithelial to mesenchymal transition (EMT). We hypothesized that the transition of human neuroblastoma cells from a drug-sensitive to drug-resistant phenotype involves mesenchymal change. Methods: A doxorubicin resistant (DoxR) human neuroblastoma cell line was generated by incubating parental wild type (WT) SK-N-Be(2)C cells in stepwise concentrations of doxorubicin. Cells were deemed resistant after surviving in a concentration of drug approximately 2 Log above the wild type IC50, confirmed by MTT colorimetric survival assay. Cell migration and capacity for invasion were assayed using the scratch test and Matrigel invasion culture system. EMT pathway related genes differentially expressed in the DoxR cells relative to the parental (WT) lines were analyzed using the Ilumina Human HT-12 v4 Expression Beadchip. Genes of interest with a fold change in expression &gt;1.5 and an adjusted p &lt; 0.1 are reported. Quantitative RT-PCR and western blot analysis were used to confirm the results. Results: Western blot confirmed that HIF1-alpha was up-regulated in BE(2)C/DoxR cells relative to WT. DoxR cells also demonstrated increased migration and invasion typical of mesenchymal cells. Up-regulation of TGF-beta dependent induction pathways of EMT via RhoA, PI3K, and ILK and via SMADs was seen on microarray pathway analysis in BE(2)C DoxR cells when compared to WT cells. Genes involved in these EMT pathways that were up-regulated in DoxR cells included TGFBRII, the gene encoding TGF beta-receptor II, TGFB3, the gene for TGF beta 3, as well as other genes implicated in TGF-beta signaling, including PAK1, LEF1, SMAD3, ZEB2, and NET1. EMT markers including vimentin (VIM), and slug (SNAI2) were also up-regulated. Interestingly, CDH2, the gene for N-cadherin, and TWIST1 were down regulated in DoxR cells. CDH1, the gene for E-cadherin, and SNAI1, the gene for Snail-1, were not differentially expressed. Conclusions: As SK-BE(2)C human neuroblastoma cell lines acquire drug-resistance, they undergo mesenchymal change via TGF-beta mediated pathways, displaying increased invasion and migration.
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 335. doi:1538-7445.AM2012-335
Abstract 3351: Cord blood stem cells inhibit epidermal growth factor receptor translocation to mitochondria in glioblastoma
Authors: Dasari Venkata Ramesh , Velpula Kiran Kumar , Alapati Kiranmai , Gujrati Meena , Tsung Andrew J. 
Published: August 2012

Abstract
Overexpression of EGFR is one of the most frequently diagnosed genetic aberrations of glioblastoma multiforme (GBM). EGFR signaling is involved in diverse cellular functions and is dependent on the type of preferred receptor complexes. EGFR translocation to mitochondria has been reported recently in different cancer types. However, mechanistic aspects of EGFR translocation to mitochondria in GBM have not been evaluated to date. In the present study, we analyzed the expression of EGFR in GBM-patient derived specimens using immunohistochemistry, reverse-transcription based PCR and Western blotting techniques. In clinical samples, EGFR co-localizes with FAK in mitochondria. We evaluated this previous observation in standard glioma cell lines and in vivo mice xenografts. We further analyzed the effect of human umbilical cord blood stem cells (hUCBSC) on the inhibition of EGFR expression and EGFR signaling in glioma cells and xenografts. Treatment with hUCBSC inhibited the expression of EGFR and its co-localization with FAK in glioma cells. Also, hUCBSC inhibited the co-localization of activated forms of EGFR, FAK and c-Src in mitochondria of glioma cells and xenografts. In addition, hUCBSC also inhibited EGFR signaling mechanisms in glioma cells both in vitro and in vivo. We have shown that hUCBSC treatments inhibit phosphorylation of EGFR, FAK and c-Src forms. Our findings associate EGFR expression and its localization to mitochondria with specific biological functions in GBM cells and provide relevant preclinical information that can be used for the development of effective hUCBSC-based therapies.
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 3351. doi:1538-7445.AM2012-3351