bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1925: CK2 phosphorylates and inhibits tumor suppressor TAp73 function to promote cancer stem cell gene expression and phenotype in head and neck cancer
Authors: Lu Hai , Yan Carol H. , Bian Yansong , Chen Zhong , Waes Carter Van 
Published: May 2015

Abstract
Cancer development, cell survival, and therapeutic resistance have recently been linked to a small sub-population of cells expressing stem cell genes, and capable of reproducing the cancer cell population, called cancer stem cells (CSC). CK2 (formerly casein kinase II) has emerged as a key signal serine/threonine kinase that modulates diverse signal cascades that regulate cell fate and growth. We previously showed that CK2 is aberrantly expressed and activated in head and neck squamous cell carcinomas (HNSCC). Concomitant inactivation of tumor suppressor TAp73, along with mutation of related family member TP53, is also often observed, but the relationship between CK2, TAp73 inactivation, and CSC is unknown. Here, we observed that classical stem cell genes NANOG, SOX2, and OCT4, are overexpressed in HNSCC with inactivated TAp73 and mtTP53. Inhibition of CK2 by pharmacologic inhibitors or siRNA increased TAp73 mRNA and protein expression, while inhibiting CSC gene expression and the SP. Conversely, knockdown of TAp73 increased CSC gene expression and the SP. Bioinformatic analysis identified a single predicted CK2 threonine phosphorylation site (T27) within the N-terminal transactivation domain of TAp73. Nuclear CK2 and TAp73 interaction, confirmed by co-immunoprecipitation, was attenuated by CK2 inhibitor, or a T27A point-mutation of the predicted CK2 threonine phospho-acceptor site of TAp73. Furthermore, T27A mutation attenuated TAp73 phosphorylation, while enhancing its function in repressing CSC gene expression, and SP cells. Novel CK2 inhibitor CX-4945 inhibited CSC related SP cells, clonogenic survival, and spheroid formation, identifying CK2 modulation of tumor suppressor TAp73 as a potential target for inhibition of CSCs. Our study reveals a novel regulatory mechanism whereby aberrant CK2-mediated inactivation of TAp73 tumor suppressor function promotes key CSC genes and phenotype.
Supported by NIDCD intramural project ZIA-DC-00073
Citation Format: Hai Lu, Carol H. Yan, Yansong Bian, Zhong Chen, Carter Van Waes. CK2 phosphorylates and inhibits tumor suppressor TAp73 function to promote cancer stem cell gene expression and phenotype in head and neck cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1925. doi:10.1158/1538-7445.AM2014-1925
Abstract 193: Adipocytes, obesity and the multiple myeloma microenvironment
Authors: Henry Gervaise H. , Watson Nicholas J. , O'Neill Rebecca C. , Tabib Tracy , Bullwinkle Erika M. , DeCicco-Skinner Kathleen L. 
Published: May 2015

Abstract
Multiple myeloma (MM), a hematological malignancy characterized by monoclonal plasma cells in the bone marrow, affects nearly 23,000 Americans per year. Obesity contributes to the development and progression of multiple myeloma, yet the relationship between MM cells and adipocytes found in the tumor microenvironment has not been fully elucidated. To examine how adipocytes contribute to the growth and progression of MM, we co-cultured human myeloma cell lines with primary human adipocytes isolated from lipoaspirates. We found that MM cells directly co-cultured with adipocytes or exposed to their conditioned media had increased viability, angiogenic potential, invasion, colony formation, and production of inflammatory cytokines, when compared to MM cells alone. Moreover, adipocytes from obese individuals (BMI &gt; 30) further compounded this. Thus, we demonstrate an important role for adipocytes in promoting myeloma pathologies.
Citation Format: Gervaise H. Henry, Nicholas J. Watson, Rebecca C. O'Neill, Tracy Tabib, Erika M. Bullwinkle, Kathleen L. DeCicco-Skinner. Adipocytes, obesity and the multiple myeloma microenvironment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 193. doi:10.1158/1538-7445.AM2014-193
Abstract 1938: Inhibition of both physiological and aberrant Wnt/β-catenin signaling activities associated with stemness in nasopharyngeal carcinoma
Authors: Cheng Yue , Phoon Yee Peng , Lung Maria L. 
Published: May 2015

Abstract
We previously demonstrated that basic or physiological levels of β-catenin signaling and tissue context play decisional roles in the regulation of self-renewal networks in nasopharyngeal carcinoma (NPC) HONE1 cells. Introduction of physiological levels of β-catenin signaling in HONE1 hybrid cells plays a central role in the control of other pathway activities, such as TGF-β, Activin, and pluripotency maintenance (LIFR and IL6ST), during the stemness transition process. These results revealed novel regulatory relationships among Wnt signaling, stemness, epithelial-mesenchymal transition (EMT), tumor suppressive pathways and expression of common cancer stem cell surface markers, such as CD44 and CD133, in human tumor cells. In current studies, we found that several NPC cell lines, including CNE1, HK1, HNE1, SUNE1, and C666-1, have aberrant and significant up-regulation of β-catenin expression, when compared to HONE1 cells that have low levels endogenous β-catenin expression. In these NPC cells with aberrant β-catenin signaling activities, the Wnt pathway (Axin2, APC, TCF1 and TCF3), stemness factors (Nanog, and Oct4) and pluripotency markers (IFITM1 and GRB7) are strongly overexpressed, compared to HONE1 cells. Our findings suggest that aberrant Wnt/β-catenin signaling activities may play a prominent role in promoting tumor progression in NPC cells. To further verify the role of aberrant β-catenin signaling in NPC, we utilize shRNA to knock down β-catenin expression in these cells, including CNE1 and HK1. As found in HONE1 hybrids, the diminished expression of core stem cell factors (Nanog, Oct4, Klf4, and Sox2) is also detected in both CNE1 and HK1 cell lines. Concomitantly, the gene expression of EMT markers (E-cadherin and Zeb1) is also inhibited when β-catenin is knocked down by shRNA β-catenin infection. These preliminary results suggest that β-catenin signaling plays a dominant role in regulating both physiological and aberrant Wnt/β-catenin signaling activities as well as EMT events in NPC development.
Citation Format: Yue Cheng, Yee Peng Phoon, Maria L. Lung. Inhibition of both physiological and aberrant Wnt/β-catenin signaling activities associated with stemness in nasopharyngeal carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1938. doi:10.1158/1538-7445.AM2014-1938
Abstract 194: E-selectin mediates targeted delivery of mesenchymal stem cells to tumor
Authors: Yang Cuixia , Li Danjuan , Wang Bo , Velazquez Omaida C. , Liu Zhao-Jun 
Published: May 2015

Abstract
Objectives. Tumor tissue produces abundant stromal cell-derived factor-1α (SDF-1α/CXCL12) that promotes recruitment of circulating stem/progenitor cells. We have recently found that SDF-1α induces elevated expression of CD162 and CD44, both are E-selectin ligands, on luminal endothelial cells lining capillaries. We thus postulate that highly expressed E-selectin ligands on tumor endothelium can serve as docking molecules to mediate specific homing of E-selectin-expressing circulating stem cells to tumor tissues. Here, we tested the role of E-selectin in mediating and facilitating homing of mesenchymal stem cells (MSC), which are modified to overexpress E-selectin, to SDF-1α−rich melanoma tissue.
Methods. MSC from C57 BL6 and E-selectin-/- mice were enriched by culturing bone marrow cells in MesenCultTM medium. MSC were genetically labeled with luciferase (Luc2) or GFP in vitro. MSC from C57 BL6 mice were engineered to stably overexpress E-selectin (E-selectin+). Human melanoma cells were engineered to overexpress SDF-1α. 2 x 10^6 SDF-1α+/melanoma cells were pre-engrafted into NSG mice via tail-vein or subcu to form lung metastatic foci or skin melanoma, respectively. After 7-10 days, 1 x 10^6 E-selectin+ or E-selectin-/- MSC were injected into tumor-bearing mice through tail-vein or subcu, respectively. Homing of injected MSC to melanoma was assessed at various time points by IVIS (for Luc2+/MSC) and flow cytometry (for GFP+/MSC), respectively.
Results. There were significantly increased numbers of engineered E-selectin-overexpressing MSC homing to melanoma tissues via systemic and local approaches, compared to control MSC or E-selectin-/-/MSC (p&lt;0.05).
Conclusions. E-selectin is an effective adhesion molecule in mediating tumor selective homing of MSC. Our study provides a useful method for targeted delivery of cells to tumor and may have therapeutic potential for developing stem cell-based cancer treatment.
Citation Format: Cuixia Yang, Danjuan Li, Bo Wang, Omaida C. Velazquez, Zhao-Jun Liu. E-selectin mediates targeted delivery of mesenchymal stem cells to tumor. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 194. doi:10.1158/1538-7445.AM2014-194
Abstract 1941: GSK3 signaling is critical to glioma stem cell growth and survival
Authors: Alvarez Angel , Ugolkov Andrey , Gaisina Irina , Kozikowski Alan P. , Joshi Kaushal , Kim Sunghak , Nakano Ichiro , Raizer Jeffrey J. , Mazar Andrew P. , Hu Bo , Cheng Shi-Yuan 
Published: May 2015

Abstract
GSK3 is an attractive therapeutic target in cancer, known for its role in regulating proliferation, differentiation, metabolism, and apoptosis. Previous studies demonstrate the effectiveness of GSK3 inhibition on established glioma cell lines and patient-derived glioma stem cell lines in vitro and in vivo. In glioma cell lines, GSK3 inhibition induces apoptosis through c-MYC activation, mitochondrial destabilization, and reduction of NF-κB activity. We have characterized a novel set of GSK3 inhibitors for their ability to inhibit glycogen synthase phosphorylation, reduce levels of XIAP, and induce cell death in cancer cells. However, it is uncertain if this mechanism is functional with respect to cancer stem cells and glioma tumor subtype. The need to investigate the mechanistic effects of GSK3 in cancer stem cells is important given their malignancy, innate resistance to therapy, and tumorigenicity. Moreover, the intracellular signaling and transcription networks may differ in glioma stem cells, particularly among cells with different subtypes. We have recently demonstrated that cancer stem cells isolated from glioma patients can be segregated into either a proneural or mesenchymal subtype based on their gene expression pattern. The oncogenic activity of genes like c-MYC in glioma stem cells and differences between glioma stem cell subtypes, such as NF-κB activation, raises questions as to whether GSK3 inhibition will be effective against both subtypes and if their effects utilize distinct mechanisms of inhibition. In this study, we examine the effects of two established and two novel GSK3 inhibitors on glioma stem cells with respect to tumor subtype and investigate their mechanisms of action. Our in vitro data shows that GSK3 inhibition significantly reduces growth and causes cell death in both proneural and mesenchymal glioma stem cells. Using a glioma stem cell xenograft model, we test the effectiveness of GSK3 inhibition as a single agent and in conjunction with clinically-approved chemotherapeutic agents. The characterization of cancer stem cell inhibitors and their effectiveness in different tumor subtypes has significant clinical implications. Our work supports the therapeutic potential of novel GSK3 inhibitors for the treatment of malignant gliomas.
Note: This abstract was not presented at the meeting.
Citation Format: Angel Alvarez, Andrey Ugolkov, Irina Gaisina, Alan P. Kozikowski, Kaushal Joshi, Sunghak Kim, Ichiro Nakano, Jeffrey J. Raizer, Andrew P. Mazar, Bo Hu, Shi-Yuan Cheng. GSK3 signaling is critical to glioma stem cell growth and survival. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1941. doi:10.1158/1538-7445.AM2014-1941
Abstract 1942: Lgl1 loss promotes stemness and invasion in EGFRvIII-driven gliomas
Authors: Gomez-Lopez Sandra , Lerner Robin G. , Petritsch Claudia 
Published: May 2015

Abstract
Stem and progenitor cells may divide asymmetrically to self-renew and produce differentiating progeny in a single division. Usually, during an asymmetric cell division (ACD), determinants of self-renewal and differentiation segregate to opposite daughter cells during mitosis and thereby specify distinct cell fates.
Disruption of ACD is seen in many cancers with a stem or progenitor cell component, including malignant gliomas (Sugiarto et al., 2011, Cancer Cell 20:328-40). Yet, it is not clear whether this is a contributing factor or a consequence of neoplastic transformation. Lethal giant larvae 1 (Lgl1), a gene that was initially identified as a tumor suppressor in Drosophila, has been implicated in the asymmetric localization of cell fate determinants in neural progenitor cells (Klezovitch et al., 2004, Genes Dev 18:559-571). Here, we investigated the effects of Lgl1 depletion on distinct hallmarks of glioma.
In murine neural progenitor cells carrying conditional null alleles of Lgl1 (Klezovitch et al., 2004, Genes Dev 18:559-571), depletion of Lgl1 resulted in reduced rates of ACD, increased expression of progenitor markers and impaired differentiation. In an orthotopic model of glioma, driven by expression of EGFRvIII, a frequent and constitutively active mutant form of epidermal growth factor receptor (EGFR), Lgl1 inactivation led to increased tumor invasiveness.
Our data suggest that disruption of ACD in glioma precursor cells promotes maintenance of progenitor features and hampers differentiation. At later stages of gliomagenesis, loss of ACD and cell polarity controls may contribute to tumor invasiveness.
Citation Format: Sandra Gomez-Lopez, Robin G. Lerner, Claudia Petritsch. Lgl1 loss promotes stemness and invasion in EGFRvIII-driven gliomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1942. doi:10.1158/1538-7445.AM2014-1942
Abstract 1966: A unique cross-talk between HER2 and sonic hedgehog signaling promotes anoikis resistance in breast cancer cells
Authors: Gupta Parul , Srivastava Sanjay K. 
Published: May 2015

Abstract
Metastatic cancer cells possess a unique capacity to survive without appropriate signaling from the extracellular matrix (ECM). The epithelial cells surrounded by proper ECM within tissues are designed to grow and differentiate whereas epithelial cells lacking suitable EMC are destined to anoikis, a form of apoptosis. The metastatic cancer cells resist anoikis to survive under the absence of ECM. Current study identifies a novel interplay between HER2 and sonic hedgehog signaling in promoting anoikis resistance. MDA-MB-231 cells exhibited an up-regulation of HER2 expression in cells cultured under anchorage- independent conditions as compared to adherent cells. Similar phenomenon was also observed in 4T-1 cells. The survival of MDA-MB-231 cells with stable HER2 overexpression (HH) was significantly enhanced when cultured under anchorage-independent conditions. However, the enhanced survival of MDA-MB-231 (HH) was reduced when HER2 was silenced using shRNA. These observations indicate the obligatory role of HER2 in anoikis resistance. Furthermore cells grown under anchorage-independent conditions induced the expression of sonic hedgehog (SHH). Increase in SHH was accompanied with enhanced expressions of PTCH2 and GLI2, the receptor and subsequent transcription factors of the sonic hedgehog signaling. Our results further showed that the induction of SHH was significantly higher in MDA-MB-231 (HH) cells relative to parent cells when cultured under anchorage-independent conditions, suggesting a correlation between HER2 and SHH signaling. Treatment of MDA-MB-231 and 4T-1 cells with cyclopamine (SHH signaling inhibitor) reduced the survival of cells under anchorage-independent conditions. Interestingly, cyclopamine treatment also inhibited the induction of HER2 during anchorage-independent culture conditions. Taken together, our study suggests a SHH-mediated induction of HER2 to promote anoikis resistance in breast cancer cells. Further mechanistic and in vivo studies are under progress. [Supported in part by R01 grant CA129038 (to S.K.S) awarded by the National Cancer Institute].
Citation Format: Parul Gupta, Sanjay K. Srivastava. A unique cross-talk between HER2 and sonic hedgehog signaling promotes anoikis resistance in breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1966. doi:10.1158/1538-7445.AM2014-1966
Abstract 1970: Co-culture of 3D tumor spheroids with fibroblasts as an in vitro model for drug resistance study
Authors: Kim Sun-Ah , Kuh Hyo-Jeong 
Published: May 2015

Abstract
Purpose. Chemotherapeutic failure of human solid tumor is attributed to tumor microenvironmental (TME) factors associated with drug resistance. Three dimensional (3D) tumor spheroid (TS) model is known to be in vivo mimic and has demonstrated its clinical relevancy. Fibroblasts in TME have been shown to play a significant role in drug resistance. The present study was to develop and characterize a co-culture of 3D TS with fibroblasts for human colorectal tumor model.
Methods. TS of human colorectal cancer cells (HT-29) was prepared by using liquid overlay method and co-cultured in collagen-coated 24-well plates with colon fibroblasts (CCD-18co) grown in Transwell® inserts. Differentail expression of extracellular matrix (ECM), growth signaling molecules, and microRNAs was analyzed using IHC, ELISA, western blot and qRT-PCR. For miRNA transfection study, changes in motility and drug sensitivity were measured by wound healing assays and APH or MTS assay, respectively.
Results. Significant resistance to 5-FU was shown in TS either with or without fibroblasts compared to monolayers. Compared to single culture of TS, co-culture with fibroblast showed 1.3-fold increased outgrowth on collagen gel, indicating increased motility. Cell-to-cell adhesion structures, expression of ECM and active form TGFβ1 were higher in TS-fibroblast co-culture. Expression of several growth- and TME-related factors, such as fibronectin, EGFR, β-catenin and CTGF, was higher in fibroblast co-culture up to the level of HT-29 xenograft tissues. Among miRNAs showing differential expressions, miR-96 showed down-regulation in TS. HT-29 cells transfected with miR-96 showed increase in cell motility, proliferation, and sensitivity to 5-FU, suggesting its potential role in regulation of genes associated with 5-FU resistance.
Conclusions. Co-culture of 3D TS-fibroblasts was successfully established and demonstrated in vivo mimic characteristics with respect to presence of adhesion microstructures, expression of ECM and growth signaling molecules, and resistance to 5-FU. MiR-96 showed its potential role in 3D drug resistance which warrants further studies.
Citation Format: Sun-Ah Kim, Hyo-Jeong Kuh. Co-culture of 3D tumor spheroids with fibroblasts as an in vitro model for drug resistance study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1970. doi:10.1158/1538-7445.AM2014-1970
Abstract 1975: Real-time FUCCI imaging demonstrates targeting dormant cancer cells
Authors: Yano Shuya , Zhao Ming , Tazawa Hiroshi , Hoffman Robert M. , Fujiwara Toshiyoshi 
Published: May 2015

Abstract
Screening for agents that specifically kill quiescent cancer cells has not been possible due to the inability to readily identify these cells. Using cancer cells expressing a fluorescent ubiquitination-based cell cycle indicator (FUCCI), we describe here an approach to screening for agents against dormant tumor spheres consisting of cancer stem-like cells expressing CD133. In the FUCCI system, cycling cells have green fluorescent nuclei and quiescent cells contain nuclei which fluoresce red. FUCCI-expressing cancer cells in tumor spheres had predominantly red nuclei after more than 7 days without cell division. Conventional anticancer agents did not kill these quiescent cells. In contrast, the genetically-engineered oncolytic adenovirus OBP301 and Salmonella typhimurium A1-R induced quiescent cancer cells to cycle and become sensitive to DNA-damaging chemotherapy. This imaging technology provides a novel platform for visualizing trafficking candidate therapeutic agents that could decoy dormant cancer cells to cycle and become chemosensitive.
Citation Format: Shuya Yano, Ming Zhao, Hiroshi Tazawa, Robert M. Hoffman, Toshiyoshi Fujiwara. Real-time FUCCI imaging demonstrates targeting dormant cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1975. doi:10.1158/1538-7445.AM2014-1975
Abstract 1982: Invading cancer cells are mostly in G0/G1 and resist chemotherapy demonstrated by real-time FUCCI imaging of cell-cycle kinetics in Gelfoam® histoculture
Authors: Yano Shuya , Miwa Shinji , Mii Sumiyuki , Hiroshima Yukihiko , Uehara Fuminari , Kishimoto Hiroyuki , Tazawa Hiroshi , Zhao Ming , Bouvet Michael , Fujiwara Toshiyoshi , Hoffman Robert M. 
Published: May 2015

Abstract
Invasive cancer cells are a critical target for chemotherapy in order to prevent metastasis. In the present report, we demonstrate real-time visualization of cell-cycle kinetics of invading cancer in three-dimensional (3D) Gelfoam® histoculture. A fluorescence ubiquitination cell cycle indicator (FUCCI) was used whereby G1/G0 cells express a red fluorescent protein and S/G2/M cells express a green fluorescent protein. With FUCCI imaging, we observed that cancer cells in G0/G1 phase in Gelfoam® histoculture migrated more rapidly and further than the cancer cells in S/G2/M phase. Cancer cells ceased migrating when they entered S/G2/M phases and restarted migrating after division and re-entry into G1/G0. Migrating cancer cells also were resistant to chemotherapy since they were preponderantly in G1/G2 and cytotoxic chemotherapy targets cells in S/G2/M phase. The results of the present report suggest that novel therapy targeting G1/G2 cancer cells is necessary to prevent metastasis.
Citation Format: Shuya Yano, Shinji Miwa, Sumiyuki Mii, Yukihiko Hiroshima, Fuminari Uehara, Hiroyuki Kishimoto, Hiroshi Tazawa, Ming Zhao, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman. Invading cancer cells are mostly in G0/G1 and resist chemotherapy demonstrated by real-time FUCCI imaging of cell-cycle kinetics in Gelfoam® histoculture. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1982. doi:10.1158/1538-7445.AM2014-1982