bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4273: DNA methyltransferase 3B mediates 5-aza-deoxycytidine hypersensitivity in cisplatin-sensitive and cisplatin-resistant pluripotent embryonal carcinoma cells
Authors: Beyrouthy Maroun J. , Garner Kristen , Hever Mary P. , Freemantle Sarah J. , Eastman Alan , Dmitrovsky Ethan , Spinella Michael J. 
Published: February 2011

Abstract
Testicular germ cell tumors (TGCTs) are the most common solid tumors of 15-35 year old men. TGCT patients are frequently cured with cytotoxic cisplatin-based therapy. However, TGCT patients refractory to cisplatin-based chemotherapy have a poor prognosis, as do those having a late relapse. Pluripotent embryonal carcinoma (EC) are the malignant counterparts to embryonic stem (ES) cells and are considered the stem cells of TGCTs. Here we show that human EC cells are highly sensitive to 5-aza-deoxycytidine (5-aza-CdR) as compared to a variety of somatic solid tumor cells. This is associated with markedly abundant expression of the pluripotency-associated DNA methyltransferase 3B, DNMT3B, as compared to somatic tumor cells. Knockdown of DNMT3B in EC cells resulted in substantial resistance to 5-aza-CdR, strongly implicating that 5-aza-CdR sensitivity is mechanistically linked to high levels of DNMT3B. Intriguingly, cisplatin resistant EC cells retain an exquisite sensitivity to low dose 5-aza-CdR treatment and pretreatment of 5-aza-CdR re-sensitizes these cells to cisplatin-mediated toxicity. These findings indicate that high expression of DNMT3B, a likely byproduct of their pluripotent and germ cell nature, sensitizes TGCT-derived EC cells to low dose 5-aza-CdR treatment. Decreased proliferation and survival with low nanomolar concentrations of 5-aza-CdR is associated with ATM activation, H2AX phosphorylation, increased expression of p21, and the induction of genes known to be methylated in TGCTs. Data pertaining to the mechanism of DNMT3B-dependent, 5-aza-CdR hypersensitivity in TGCTs will be presented. Efforts to extend this work to clinical samples are ongoing.
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 4273.
Abstract 4274: High aldehyde dehydrogenase activity identifies a chemotherapy-resistant population of ewing's sarcoma cells with a stem cell phenotype that retains sensitivity to EWS-FLI1 inhibition
Authors: Awad Ola , Yustein Jason T. , Shah Preeti , Gul Naheed , Rotenberg Julie B. , Toretsky Jeffrey , Loeb David 
Published: February 2011

Abstract
Ewing's sarcoma family tumors (ESFT) are the second most common bone tumors in children and young adults. Despite being quite responsive to chemotherapy, patients with localized disease have a 30% recurrence rate, and 80% of patients with metastatic disease die within 5 years of diagnosis. The expression of the EWS-FLI1 fusion protein as a result of chromosomal translocation (11; 22) (q24; q12) is crucial for initiation and maintenance of the tumor; however, the mechanism by which EWS-FLI1 mediates neoplastic transformation is poorly understood. RNA helicase A (RHA) physically interacts with EWS-FLI1, modulating its oncogenic activity. The cancer stem cell hypothesis proposes that tumors originate from and are maintained by a small subset of chemotherapy-resistant stem cells. Thus, identification of Ewing's sarcoma stem cells will lead to the development of targeted therapies that should improve the treatment of patients with this disease. We attempted to identify a population of Ewing's sarcoma cells with stem cell properties (self-renewal in vitro, clonogenic activity, and tumor initiating activity in immunodeficient mice) based on high aldehyde dehydrogenase (ALDHhigh) activity. The ALDHhigh population was enriched for stem cell activity (compared to the ALDHlow cells) as defined by these assays, and was resistant to standard chemotherapy drugs to treat sarcomas (doxorubicin and etoposide). Both populations expressed EWS-FLI1. We then investigated whether a novel small molecule, YK-4-279, which specifically targets the RHA/EWS-FLI1 interaction, is toxic to the chemotherapy-resistant ALDHhigh cells. We found that the ALDHhigh cells retain sensitivity YK-4-279. Our data demonstrate that ESFT cells that express high levels of ALDH have stem-like properties, and, combined with evidence that YK-4-279 inhibits the growth of ESFT xenografts in mice, provide support for a novel approach to ESFT therapy. This approach should improve the survival of patients with these tumors in the future.
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 4274.
Abstract 4282: The role of glycosphingolipids in the formation of cancer stem cells and drug resistance
Authors: Gupta Vineet , Patwardhan Gauri Anand , Gu Xin , Rowan Brian , Jazwinski Michal , Liu Yong Yu 
Published: February 2011

Abstract
Tumorigenesis and malignant progression of cancers rely on a small subset of cells known as cancer stem cells (CSCs). In addition to forming primary tumors, metastasis and relapse, CSCs always display resistance to cytotoxins and this resistant feature protects CSCs during the course of chemotherapy. Glucosylceramide synthase (GCS) is a limited enzyme catalyzing the first glycosylation in glycosphingolipids synthesis. Glycosphingolipids are likely to play an essential role in maintaining the stemness of stem cells, since that deletion of GCS induces apoptosis of embryonic stem cell and stops embryo development in GCS knockout mice. The stage-specific embryonic antigens (SSEA-3, SSEA-4) are glycosphingolipids and serve as common pluripotent markers for human embryonic stem cells. In the present study, we have found that GCS modulates the formation and maintenance of breast cancer stem cells. GCS overexpression was interrelated to the increase of breast cancer stem cells (BCSCs) and drug resistance in human breast cancer MCF-7 cell lines after doxorubicin induction. In MCF-7/Dox (doxorubicin-resistant) cells, GCS protein was increased by 39-fold accompanied with enhanced enzyme activity, as compared to wild-type MCF-7 cell. Analyzed by using flow cytometry and immunostaining, the BCSCs with CD44+/CD24-/ESA+ phenotype were increased by 5-fold, and 3-fold in MCF-7/Dox and NCI-ADR/RES cell lines, as compared to MCF-7 cell lines, respectively. In BCSCs, GCS enzyme activity was 2-fold greater than other populations sorted from MCF-7/Dox. Silencing GCS by using mixed-backbone oligonucleotide (MBO-asGCS) significantly decreased the numbers of BCSCs in MCF-7/Dox cells. We observed tumorigenesis of NCI/ADR-RE/GCS (GCS overexpressed) and NCI/ADR-RE/asGCS (GCS silenced) in athymic nude mice. Aggressive tumors were found in all mice inoculated with NCI/ADR-RES and NCI/ADR-RE/GCS cells that were BCSC-enriched; however, no tumor or metastasis was observed in mice injected with NCI-ADR/asGCS cells. Furthermore, MBO-asGCS treatment (1 mg/kg) significantly decreased the numbers of BCSCs isolated from tumors of NCI-ADR/RES, as compared with control groups. Furthermore, BCSCs after MBO-asGCS treatment were more sensitive to doxorubicin. These results, for the first time, demonstrate that glycosphingolipid is involved in the regulation of cancer stem cell formation. Silencing GCS eliminates BCSCs, that can reverses drug resistance as well as prevent tumor relapse.
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 4282.
Abstract 4298: Identification of subpopulation with more defined characteristics of cancer stem cells in endometrial cancer
Authors: Nakamura Mitsuhiro , Kyo Satoru , Zhang Xiuzhi , Takakura Masahiro , Hashimoto Manabu , Mizumoto Yasunari , Mori Noriko , Sasagawa Toshiyuki , Inoue Masaki 
Published: February 2011

Abstract
[Background] Cancer stem cells (CSCs) have been known to be the major source of tumor propagation and might be an attractive therapeutic target. Our previous study showed that CD133+ Ishikawa and MFE 280 endometrial cancer cells have the ability of tumorigenicity, self-renewal and differentiation capacity in vitro and in vivo, while CD133- cells did not. Furthermore, CD133+ cells showed more resistance to cisplatin- or paclitaxel-induced cytotoxicity than CD133- cells. These results indicate that CD133 is the CSC maker in endometrial cancer cells. In the present study, we sought to identify the subpopulation with more defined CSC characteristics in endometrial cancer.
[Methods] We examined the expression of CD133, CD44 and Hoechst 33342 side population (SP) marker by flow cytometry (FACS) in endometrial canecr cells. MIcroarray analysis was performed to investigate the molecules essential for the CSCs characteristics by 3D-Gene chip (TORAY).
[Results] FACS analysis demonstrated that in the CD133+ Ishikawa and MFE280 cells, about 50% cells showed CD44 expression, whereas about 20% cells expressed it in CD133- cells. Isolated CD44+/CD133+ cells showed more extensive proliferation and tumorigenicity, compared with CD44+/CD133-, CD44-/CD133+ and CD44-/CD133- cells, indicating that the CD44+/CD133+ endometrial cancer cells have the potential of more defined CSCs. On the other hand, the ratio of SP fraction was similar in CD133+ and CD133- cells. Microarray analysis showed elevated expression of MT1-MMP and VEGF in CSCs, compared to non-CSCs. Invasion assay revealed that CSCs have more invasive property than non-CSCs. The inhibition of MT1-MMP gene by siRNA significantly reduced the invasive ability of CSCs. These results suggest that MT1-MMP is one of the critical molecules that generate biological features of CSC and may be a potential therapeutic target in endometrial cancer.
[Conclusions] We demonstrated that CD44+/CD133+ cells might be more defined CSCs in endometrial cancer and identified important molecules essential for characterizing endometrial CSCs that might be a therapeutic target of this tumor type.
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 4298.
Abstract 43: Role of Ets-1 in the regulation of energy metabolism in cancer cells
Authors: Verschoor Meghan L. , Verschoor Chris P. , Singh Gurmit 
Published: February 2011

Abstract
Cancer cells predominantly utilize glycolysis for ATP production even in the presence of abundant oxygen, an environment that would normally result in energy production through oxidative phosphorylation. Although the molecular mechanism for this metabolic switch to aerobic glycolysis has not been fully elucidated, it is likely that mitochondrial damage to the electron transport chain and the resulting increased production of reactive oxygen species (ROS) are significant driving forces. In this study, we have investigated the role of the transcription factor Ets-1 in the regulation of mitochondrial function and metabolism. Microarray analysis of the effects of Ets-1 over-expression in 2008 ovarian cancer cells was conducted using the Affymetrix GeneChip® Human Gene 1.0ST Array. Our findings show that Ets-1 up-regulates key enzymes involved in glycolysis and associated feeder pathways, fatty acid metabolism, and antioxidant defense. Additionally, Ets-1 down-regulates genes involved in the citric acid cycle, electron transport chain, and mitochondrial proteins. These results were validated using real-time qRT-PCR. The mitochondrial activity of both ovarian cancer Ets-1 over-expressing and breast cancer Ets-1 down-regulating cells was evaluated by examining oxygen consumption using various electron transport chain inhibitors (Oxygraph 2k), growth in the absence of glucose, and sensitivity to the glycolytic inhibitor 2-DG. We have found that Ets-1 expression is directly correlated with cellular oxygen consumption whereby increased expression causes decreased oxygen consumption. Ets-1 over-expression also caused increased sensitivity to glycolytic inhibitors, as well as pronounced growth inhibition in a glucose-depleted culture environment. In the context of ROS production, Ets-1 up-regulation induces a significant reduction in H2O2 production, likely due to Ets-1-mediated up-regulation of antioxidants. Collectively, our findings show that Ets-1 is involved in the regulation of cellular metabolism and response to oxidative stress in cancer cells. (This work was supported by operating grants to GS provided by the Canadian Institutes of Health Research)
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 43.
Abstract 430: Serpin-A1 and A3 as potential pharmacodynamic biomarkers for NOV-002, a redox-modulating anti-cancer agent
Authors: Grek Christina L. , Townsend Danyelle M. , Uys Joachim D. , Pazoles Christopher J. , Tew Kenneth D. 
Published: February 2011

Abstract
NOV-002 is a formulation of disodium glutathione disulfide (GSSG) that is in Phase III clinical trials for the treatment of advanced non-small cell lung cancer and other oncology indications in combination with standard chemotherapeutic regimens. In addition to increased efficacy compared to chemotherapy alone (survival, tumor growth), NOV-002 has been shown to mitigate chemotherapy-induced hematological suppression. In animal studies it was found that, when administered after chemotherapy, NOV-002 stimulated proliferation of bone marrow progenitor cells and normalized peripheral blood levels of leukocytes and platelets. NOV-002's pharmacokinetic properties demonstrate first order absorption / elimination with a plasma half-life of ∼13 mins. The redox regulation of protein thiols persist in plasma for ∼4 hours. Using mass spectrometry, we identified that Serpin-A1 and -A3 were S-glutathionylated following NOV-002 administration to mice. Serpin-A1 and -A3 were also glutathionylated in a dose- and time- dependent S-glutathionylation following NOV-002 treatment of mouse or human plasma in vitro. There is evidence that members of the Serpin protein family can influence myeloproliferation and hematopoetic progenitor cell mobilization (Winkler et al., 2005; van Pel et al., 2006). Specifically, down regulation of serpins has been demonstrated in bone marrow during progenitor cell mobilization (van Pel et al., 2006), and this influences the marrow microenvironment and migratory behavior of hematopoetic precursor cells. Furthermore, glutathionylation of Serpins has been shown to inhibit their activity (Taygi et al., 1991 and 1992). Since our data shows that Serpins A1 and A3 are S-glutathionylated in plasma following NOV-002 treatment, there may be a mechanistic link between this effect and its in vivo myeloproliferative actions. Moreover, liberation of serpins into the peripheral circulation may also provide an indication that proteolytic pathways have been activated. Since the plasma half-life of S-glutathionylated proteins is ∼4 hours (Townsend et al., 2006), it may be possible to identify and develop these post-translationally modified blood proteins as pharmacodynamic biomarkers.
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 430.
Abstract 4300: Constitutive activation of Stat3 increases hair follicle progenitor population at the expense of bulge region keratinocyte stem cells
Authors: Rao Dharanija , Carbajal Steve , Kiguchi Kaoru , DiGiovanni John 
Published: February 2011

Abstract
Mouse skin epidermis is maintained throughout life by a highly proliferative compartment located in the outer root sheath called the hair follicle bulge. Stem cells located in the mouse hair follicle bulge region have self-renewing, slow cycling and quiescent characteristics and maintain hair and epidermal growth. In the present study, we examined the impact of Stat3 activation on the number and proliferative capacity of bulge region keratinocyte stem cells (KSCs). K5. Stat3C transgenic mice express a constitutively active/dimerized form of Stat3 called Stat3C via the bovine keratin 5 (K5) promoter. The K5 promoter targets expression of Stat3C in the basal layer of the epidermis as well as in the bulge region KSCs. We analyzed the number of KSCs using the bulge specific stem cell markers CD34 and α6 integrin. The number of CD34+ve/α6 +ve cells was significantly reduced in Stat3C mice as compared to the non-transgenic littermates. Sca-1 positive cells reside in the infundibulum region of the hair follicle. We analyzed the Sca-1 expressing population in the total hair follicle cells and found that the number of Sca-1 expressing cells was increased in the Stat3C mice. Activation of Stat3, in bulge region KSCs appeared to cause epidermal stem cells to exit the stem cell compartment. To understand how Stat3 exerts these effects we studied the expression of Stat3 target genes like Myc and cyclin D1. Both Myc and cyclin D1 were found to be upregulated in total hair follicle cells in the transgenic mice. In addition, the levels of both α6 and β1 integrin were reduced in total hair follicle cells of the Stat3C mice supporting the hypothesis that activation of Stat3 causes stem cell to exit from the bulge region. Overall, these studies suggest that Stat3 is critical for the behavior, growth properties and quiescent characteristics of bulge region KSCs. Supported by NIH Grant CA76520.
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 4300.
Abstract 4301: Isolation and expansion of human gastric cancer-initiating cells for drug development
Authors: Liu Yan , Lv Junjie , Ning Jinying 
Published: February 2011

Abstract
Gastric carcinoma is the second most common cause of death from cancer in the world. The isolation and characterization of tumorigenic gastric cancer cells may help to develop novel diagnostic and therapeutic methods. Although there is increasing evidence that cancer stem cell, which is responsible for tumor formation and maintenance, exists in a wide variety of solid tumors, this has not been extensively explored in gastric cancer. We report here the isolation and in vitro propagation of gastric cancer-initiating cells from human primary tumor xenografts. The isolated tumor cells can form spheroid colonies in defined serum free medium. Subcutaneous injection of as few as 100 sphere-forming cells readily reproduced the original tumor in immunodeficient mice. Such tumors were serially transplanted for several generations and the cultured cells grew exponentially for more than 40 passages in vitro as undifferentiated tumor spheres. Interestingly, CD44, recently reported as a gastric cancer stem cell surface marker, was positive in both cultured cells and in engrafted tumor tissues. In vitro and in vivo drug sensitivity assays on these sphere-forming cells are currently ongoing.
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 4301.
Abstract 4308: Dynamic regulation of CD24 and the invasive, CD44posCD24neg phenotype in breast cancer cell lines
Authors: Meyer Matthew J. , Fleming Jodie M. , Ali Mustapha A. , Pesesky Mitchell W. , Ginsburg Erika , Vonderhaar Barbara K. 
Published: February 2011

Abstract
Introduction
The invasive, mesenchymal phenotype of CD44posCD24neg breast cancer cells has made them a promising target for eliminating the metastatic capacity of primary tumors. It has been previously demonstrated that CD44neg/lowCD24pos breast cancer cells lack the ability to give rise to their invasive CD44posCD24neg counterpart. Here we demonstrate that noninvasive, epithelial-like CD44posCD24pos cells readily give rise to invasive, mesenchymal CD44posCD24neg progeny in vivo and in vitro. This interconversion was found to be dependent upon Activin/Nodal signaling.
Methods
Breast cancer cell lines were sorted into CD44posCD24pos and CD44posCD24neg populations to evaluate their progeny for the expression of CD44, CD24, and markers of a mesenchymal phenotype. The FACS sorted populations were injected into immunocompromised mice to evaluate their tumorigenicity and invasiveness of the resulting xenografts.
Results
CD24 expression was dynamically regulated in vitro in all evaluated breast cancer cell lines. Furthermore, a single noninvasive, epithelial-like CD44posCD24pos cell had the ability to give rise to invasive, mesenchymal CD44posCD24neg progeny. Importantly, this interconversion occurred in vivo as CD44posCD24pos cells gave rise to xenografts with locally invasive borders as seen in xenografts initiated with CD44posCD24neg cells. Lastly, the ability of CD44posCD24pos cells to give rise to mesenchymal progeny, and vice versa, was blocked upon ablation of Activin/Nodal signaling.
Conclusions
Our data demonstrate that the invasive, mesenchymal CD44posCD24neg phenotype is under dynamic control in breast cancer cell lines both in vivo and in vitro. Furthermore, our observations suggest that targeted therapy against CD44posCD24neg tumor cells may have limited success in preventing primary tumor metastasis unless Activin/Nodal signaling is arrested.
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 4308.