bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 425: BIRD0796, p38δ inhibitor, inhibits cholangiocarcinoma cell EGI-1 migration in a p53-dependent manner
Authors: Dachuan Huang , Chii Wong Jing , Huimin Bernice Wong , Kiat Ong Choon , Aikseng Ooi , Tean Teh Bin 
Published: February 2011

Abstract
Cholangiocarcinoma (CC) is a devastating cancer, which affects any area of the bile ducts. The new cases of CC have increased in the Western countries. Besides, CC is also an endemic in several Southeast Asia countries such as Thailand and Myanmar. CC is notoriously challenging to diagnose and treat. Currently, only surgical resection is associated with improvement of 5-year survival rate. However, distant metastases, extensive regional lymph node metastasis and vascular encasement or invasion preclude surgical resection. Our previous report showed that the p38δ gene expression was up-regulated in CC tumor sample as well as in CC cell lines. In this study, we further found that inhibition of p38δ by BIRD0796, a p38 δ inhibitor impaired migration ability in CC cell line EGI-1 in vitro (p = 0.006232). The result was further confirmed with p38δ siRNA knowdown (p = 0.0005) and plasmid over-expression experiments (p = 0.003). Interestingly, BIRD0796 did not exhibit similar inhibition effect on migration in TGB cells (p &gt; 0.05). Analysis of p53 gene sequences revealed that there is a frame shift mutation (c.525 526insGCGC) in TGB cells but not any of functional mutation in EGI-1 cells. It indicates that the migration inhibition effect of BIRD0796 in CC metastasis may dependent on p53. Our results suggest that BIRD0796 may be a potential chemotherapeutic compound for CC.
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 425.
Abstract 4251: Murine hepatocellular carcinoma stem cells express pluri-potency-associated transcription factors and are sensitive to immune-mediated apoptosis
Authors: de Kluyver Rachel L. , Stauffer Jim , Brooks Alan , Shanker Anil , Sayers Tom 
Published: February 2011

Abstract
Worldwide the incidence of hepatocellular carcinoma (HCC) resulting from hepatitis C infection and chronic inflammation is increasing. Poor prognosis HCC is characterized by over-expression of Ep-CAM and alpha-fetoprotein (AFP) which define a population of tumor-initiating cells with stem/progenitor features. Current evidence supports the view that cancer stem cells (CSCs) constitute the primary pathogenic component of both metastases and minimal residual disease, and that elimination of CSCs is required for cure. Typically cell surface markers have been used to identify CSCs, however cell surface phenotype alone does not identify CSC in all tumors from the same tissue or in all patients. Therefore there is a need to define and test more reliable markers of CSCs. Oct-4, Sox-2 and Nanog transcription factors are key regulatory factors in maintenance of pluripotency and have been demonstrated to be robust intracellular biomarkers for tissue and cancer stem cells. A GFP-based reporter driven by a promoter responsive to Nanog or Oct-4 was used to mark pluripotent tumor cells from in vitro cultured, cancer cell lines (breast cancer- 4T1.2), and from autochthonous hepatocellular carcinoma induced by hydrodynamics-based gene transfer of constituitively active Akt and β-Catenin. This tumorigenesis model allows tumor initiation by delivery of clinically relevant oncogenes whose sporadic distribution reflects spontaneous cancer. The molecular profile of primary Akt/β-Cat-induced murine HCC recapitulates that observed in poor prognosis Ep-CAM+/AFP+ human HCC. Further, in vitro functional analyses suggest that Ep-CAM and CD133 (surface markers) and Nanog and Oct-4 (transcription factors required for maintenance and regulation of pluripotency in undifferentiated cells) are CSC markers in this model of HCC. Directly ex vivo, murine HCC stem cells express abundant CD1d and MHC class II in addition to TNF-R2, lymphotoxin-β receptor (LTβR) and DR5. The functional significance of CD1d, MHC class II, TNF-R2, LTβR and DR5 expression will be assessed in future studies using in vitro apoptosis and cytotoxicity assays and transplantation at orthotypic sites prior to adoptive transfer of tumor-specific T cells. Studies of freshly isolated CSCs have demonstrated that a variety of mechanisms combine to render CSC resistant to conventional chemo- and radiotherapies. This study has combined in vitro and in vivo approaches to address whether CSC can be rendered sensitive to T cell-mediated apoptosis, and will provide valuable proof-of-principle data to the merits of CSCs as targets for curative anti-cancer therapies.
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 4251.
Abstract 4252: Mechanistic and clinical implications of epigenetic modulation in liver cancer stem cells
Authors: Marquardt Jens U. , Raggi Chiara , Andersen Jesper B. , Seo Deakwan , Avital Itzhak , Holczbauer Agnes , Factor Valentina M. , Thorgeirsson Snorri S. 
Published: February 2011

Abstract
Epigenetic mechanisms play critical roles in both stem cell and cancer biology. Epigenetic modulation directs stem cells towards pluripotency and promotes differentiation of more mature derivatives. We hypothesized, that if similar mechanisms are relevant to the cancer stem cell (CSC) model, then epigenetic modulation might enrich the CSC population, thereby facilitating CSCs isolation and rigorous evaluation.
Five hepatoma cell lines were treated with Zebularine (ZEB), an effective DNMT1-inhibitor. Putative CSC were isolated using the “side population” (SP) approach. FACS-sorted SP and non-SP fractions were examined for tumorigenic capacity and differences in gene expression. SP-derived signatures were integrated with HCC microarray database and tested for a prognostic value.
ZEB-treatment significantly reduced the SP size while remarkably increasing the proportion of cells with CSC properties as judged by a superior tumor-initiation capacity relative to the untreated SP cells. This was further confirmed in serial transplantation as well as direct cell tracking experiments using genetically labeled SP and non-SP cells. Furthermore, integrative transcriptome analysis of the ZEB-enriched CSC populations identified common stemness traits although various oncogenic pathways (e.g. EGFR, SRC and MYC) were activated in individual hepatoma cell lines. Moreover, each individual as well as the common CSC signatures were associated with poorly differentiated tumors, high recurrence rate and poor survival in liver as well as lung cancers.
In conclusion, we demonstrate that modulation of the liver cancer epigenome is a useful tool to increase the representation of highly tumorigenic cells with CSC properties within the SP fraction. The integrative analysis of the CSC transcriptome revealed a pernicious interaction of common CSC stemness genes with variety of known oncogenic pathways in liver cancer. The significance of CSC- enriched gene signature for the prognosis of liver and other cancers provides a rationale for therapeutic targeting of CSCs.
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 4252.
Abstract 4258: Role of β2SP in asymmetric division and differentiation of intestine epithelial cells
Authors: Li Ying , Jogunoori Wilma , Yao Wenguo , Cao Hong , Mishra Bibhuti , Mishra Lopa 
Published: February 2011

Abstract
The adult intestinal epithelium of the gastrointestinal tract has a well-defined organizational structure. The epithelium can be divided into two regions, a functional region that houses differentiated cells (villi) and a proliferative region (crypts of Lieberkühn) that represents the epithelial stem cell niche. In the small intestine, finger-like projections protrude from the floor of the intestine, forming villi. Multiple proliferative crypts surround each villus base. All epithelial cells that populate the villus originate from these crypts. Multipotent epithelial stem cells reside in the crypts and give rise to four principal epithelial lineages: absorptive enterocytes, mucin secreting-goblet cells, peptide hormone secreting enteroendocrine cells, and Paneth cells. Three of these cell lineages differentiate as they migrate up and out of the crypts onto the adjacent villus. The fourth lineage, Paneth cells, differentiates with a downward migration to reside at the base of the crypt. It is believed that these different cell types are generated by asymmetric cell divisions of stem/progenitor cells. However, the molecular mechanisms of how stem cells differentiate into four different cell types are only partially understood. Aim: in the current study, we evaluated the role of β2SP (β2 spectrin) in the differentiation and asymmetric division of stem/progenitor cells in normal intestine epithelium. Results: Our preliminary data showed that the number of secreting-goblet cells and peptide hormone secreting enteroendocrine cells was reduced in β2SP+/− mice compared to the wt mice. The number of cells undergo asymmetric division was also 3 folds lower in β2SP+/− mice than in wt mice. In in vitro studies, polarization of Par3 and PKCζ was impaired in β2SP−/− MEF cells. The coimmunoprecipitation assay demonstrated that β2SP directly bound to Par3 and actin in normal intestine epithelial cells, indicating that β2SP was involved in the spindle orientation and positioning during the asymmetric division of intestine epithelial cells. Conclusion: β2SP interacts with Par3 and regulates spindle orientation and polarization in the process of cell division, thereby contributing to the differentiation and asymmetric division of intestinal stem/progenitor cells.
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 4258.
Abstract 4260: Activation of cancer stem cells in hepatic Pten deficient mice requires liver injury
Authors: Galicia Vivian A. , Kanel Gary , He Lina , Vendryes Christopher , Stiles Bangyan L. 
Published: February 2011

Abstract
Cancer stem cells have been identified in solid and aqueous tumors and are defined as “altered” stem cells with the capacity to form tumors. We used the liver specific Pten (phosphatase and tensin homologue deleted on chromosome ten) deletion murine model to investigate the role of hepatic cancer stem cells in vivo. Proliferation of hepatic progenitor cells in other rodent models has been observed as a consequence of chronic liver injury. Pten-null mice demonstrate escalating levels of hepatic injury markers from 6-12M of age. In addition, TUNEL analysis revealed that hepatocytes from mutant mice are undergoing extensive apoptosis relative to control mice. We hypothesize that hepatocyte cell death induced by lipotoxicity promotes progenitor cell proliferation to replace liver parenchyma. We show here that activation of hepatic progenitor cells (oval cells) in this model occurs progressively. In mutant mice hepatic injury is followed by elevated expression of hepatic progenitor cell markers Cytokeratin 19 (CK 19), Epithelial cell adhesion molecule (EpCAM), α-fetoprotein (AFP) as well as activation of the Wnt/β-Catenin signaling pathway. Furthermore, we report that liver specific Pten-null mice develop both cholangiocellular carcinoma (CC) and hepatocellular carcinoma (HCC) by 12-15 months of age. Collectively these results suggest that liver tumors in this model arise from hepatic progenitor cells. Our studies also demonstrate that when hepatic injury is attenuated tumor onset is significantly delayed, highlighting the relevance of hepatic injury to progenitor cell induced carcinogenesis. In addition, we show that reactive oxygen species (ROS) is the likely molecular mediator for hepatocyte cell death. This study presents in vivo evidence for the contribution of hepatic injury to progenitor cell mediated liver tumorigenesis.
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 4260.
Abstract 4262: Characterization and regulation of a CXCR4-expressing subpopulation in head and neck cancer stem cells
Authors: Kiang Alan , Abhold Eric L. , Blair Katherine J. , Yu Michael A. , Haas Martin , Brumund Kevin , Weisman Robert A. , Ongkeko Weg M. 
Published: February 2011

Abstract
The cancer stem cell (CSC) hypothesis proposes that only the CSCs within a tumor possess the ability to self-renew and to generate new tumors. Under this model, CSCs are presumed responsible for cellular invasion and metastasis, as well as the recurrence of cancers following chemotherapy. In head and neck squamous cell carcinoma (HNSCC), cells which are CD44 positive and lineage negative (CD44+/Lin-) have been shown to possess properties of CSCs. These cells form tumors in NOD/SCID mice at a much greater efficiency compared to CD44-/Lin- cells, and express the proto-oncogene BMI-1. More recently, it has been shown in pancreatic cancer that a distinct subpopulation of CSCs expressing the chemokine receptor CXCR4 is essential for tumor metastasis. Here we demonstrate the existence of a highly invasive CXCR4+ subpopulation in HNSCC cancer stem cells and elucidate the pathways through which this subpopulation could be regulated.
For this study putative CSC cultures derived from primary HNSCC tissue were used from which CXCR4-expressing subpopulations were isolated. A matrigel invasion assay revealed that the CXCR4+ fraction of CSCs was significantly more invasive compared to the CXCR4- fraction. We also surveyed the mRNA expression of these two fractions by qRT-PCR, and found that expression of the proteinases MMP2 and MMP9 was markedly higher in CXCR4+ cells. Interestingly, treatment with nicotine increased the expression of CXCR4 and its ligand SDF-1 in the parental CSC culture, suggesting a possible mechanism by which CXCR4 could be regulated within the CSC population. Nicotine, a major component of tobacco, is known to have proliferative, anti-apoptotic, and angiogenic effects, and has been shown to promote epithelial-to-mesenchymal transition in a variety of human cancers.
Mortality from HNSCC remains high due primarily to cancer invasion of vital structures and development of distant metastases. Our findings shed light on the mechanisms by which CXCR4 confers an invasive and metastatic CSC phenotype. In addition, the observed effects of nicotine could provide novel insights towards the regulation of the CXCR4/SDF-1 axis in HNSCC, for which tobacco use has been identified as the leading risk factor. Continued efforts in mapping the molecular mechanisms surrounding CXCR4-mediated invasion and metastasis of CSCs could lead to new and effective treatment strategies for HNSCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4262.
Abstract 4263: Epithelial-mesenchymal transition mediator, S100A4, in maintenance of head and neck cancer initiating cells
Authors: Yu Cheng-Chia , Chiou Shih-Hwa , Yu Yau-Hua , Lo Jeng-Fan 
Published: February 2011

Abstract
Background: Cancer initiating cells (CICs) represent a rare subpopulation of cells, which are responsible for tumor growth. Previously, we have identified and characterized the CICs from head and neck squamous cell carcinomas (HNSCCs), termed head and neck cancer initiating cells (HN-CICs). HN-CICs possess both the hallmarks of stem cells and malignant tumor cells. Herein, we determined the critical role of S100A4, a common mediator of epithelial-mesenchymal transition (EMT), in maintenance of stemness properties and cancerous phenotypes in HN-CICs.
Methods: Affymetrix microarray analysis was performed to identify S100A4 as a putative candidate on mediating the stemness properties of HN-CICs. Consequently, we elucidated the stemness properties and tumorigenicity of HN-CICs with S100A4 down-regulation or overexpression, respectively. Finally, immunohistochemical staining of S100A4 on HNSCC tumor tissues was examined.
Results: S100A4 transcripts and protein level were found significantly up regulated in the enriched HN-CICs. Down-regulation of S100A4 significantly reduced the self-renewal ability and stemness properties in HNSCCs. In addition, knockdown of S100A4 lessened tumorigenicity of HNSCCs both in vitro and in vivo. Conversely, over-expression of S100A4 enhanced the CSC properties in HNSCCs. Furthermore, expression of S100A4 was positively correlated with clinical grading, and survivals and recurrence, respectively (p&lt;0.001, 0.05 and 0.01) according to the immunohistochemical staining. Finally, depletion of endogenous S100A4 resulted in down-regulation of Notch2 and PI3K/pAKT and up-regulation of PTEN in HNSCCs.
Conclusion: Our study reveals the crucial role of S100A4 signaling pathways in the maintenance of stemness properties and tumorigenicity of HN-CICs, and S100A4 might be a potential therapeutic target for HNSCC by eliminating HN-CICs.
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 4263.
Abstract 4266: Potential role of reactive oxygen species in affecting tumorigenicity of glioblastoma stem cells
Authors: Wang Feng , Hammodi Naima , Yuan Shuqiang , Chen Gang , Feng Li , Kim Sangbae , Colman Howard , Lee Ju-Seog , Xu Ruihua , Huang Peng 
Published: February 2011

Abstract
Glioblastoma multiforme (GBM) is a common and highly aggressive primary brain tumor with poor prognosis due in part to drug resistance and high incidence of tumor recurrence. The drug resistant and cancer recurrence phenotype may be ascribed to the presence of cancer stem cells, which seem to reside in special stem-cell niches in vivo and require special culture conditions including certain growth factors and serum-free medium to maintain their stemness in vitro. In this study, we used two lines of stem-like cancer cells (GSC11 and GSC23) derived from the tumor tissues of two GBM patients by classical neurosphere culture system, and showed that addition of serum (FBS) to the medium induced an increase of ROS, leading to aberrant differentiation and eventual cell death. Although both GBM stem-like cell lines showed high percentage of CD133-positive cells (20% in GSC11 and 70% in GSC23), exposure to serum only caused a moderate decrease of CD133 expression at later time points. Several methods were used to further test the role of ROS in affecting the stemness of the GSC cells and their self-renewal capacity. Addition of 5% FBS or removal of the antioxidant supplements (B27) from the culture medium caused the spheroid GSC cells to attach to the culture surface, exhibit differentiation morphology, decrease expression of certain stem-cell markers, and eventually die within two weeks. Serum exposure also resulted in a decrease of the GSC ability to form colonies in soft agar assay and to grow tumors in a mouse xenograft model. Although an increase of general cellular ROS could be detected when GSC cells were exposed to FBS, the mitochondrial superoxide appeared to be prominent and likely to be a primary event, which led to a compensatory increase of the mitochondrial SOD2 expression and upregulation of glutathione synthesis. Interestingly, addition of the antioxidant N-Acetylcysteine to the FBS-containing medium partially blocked the FBS-induced aberrant differentiation and improved cell viability and self-renewal capacity, suggesting that ROS may play an important role in affecting stemness and differentiation status of the cancer stem cells. We postulate that during tumor development, only the progeny cells that acquire the ability to counteract the impact of ROS increase induced by serum may eventually proliferate and grow as the tumor bulk, and that proper redox-modulation may be a potential novel strategy to block tumor formation and possibly kill the stem-like cancer cells.
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 4266.
Abstract 4268: Breast cancer stem cells play a role in trastuzumab resistance in mouse xenograph models
Authors: Hasan Korkaya , Paulson Amanda K. , Zen Qin , Smithkort Hayley J. , Quraishi Ahmet A. , Patel Shivani , Liu Suling , Heath Amber , Clouthier Shawn G. , Wicha Max S. 
Published: February 2011

Abstract
One of the most significant advances in breast cancer therapeutics has been the development of HER2 targeted therapies for treatment of HER2 overexpressing breast cancer. The use of HER2 inhibitors such as trastuzumab have improved patient outcome in both the adjuvant and advanced setting. However, one-third of HER2-positive tumors do not respond to HER2 targeted agents and resistance may develop in patients with chronic exposure. Nearly 50% of patients who respond to HER2 targeted agents relapse within a year. The mechanism of resistance to HER2 targeted agents is not entirely clear. However, increasing evidence indicates that this resistance may be associated with loss of PTEN (phosphotase and tensin homolog), the gain of function of somatic mutations of PI3KA or truncation of the extracellular domain of HER2. We have recently demonstrated that trastuzumab reduces the cancer stem cell (CSC) population in trastuzumab sensitive but not trastuzumab resistant cell lines. In order to elucidate the mechanisms of trastuzumab resistance we engineered MCF7 cells to overexpress HER2, knockdown PTEN or both. HER2 overexpression or PTEN knockdown increased the proportion of CSC's as assessed by the Aldefluor assay and tumor initiation in NOD/SCID mice. Cell lines with both HER2 overexpression and PTEN knockdown contained a significantly higher proportion of Aldefluor positive (3.2 %) compared to either alteration alone (1.7%, 1.9% respectively and 0.5 % in parental cells). In addition, cells with both PTEN deletion and HER2 overexpression showed several fold increase in their invasive properties in vitro as compared cells with either alteration alone. Furthermore, cells with the combined alterations but not those with either alone were highly metastatic in NOD/SCID mice consistent with the demonstrated role of CSC's in mediating tumor metastasis. Trastuzumab treatment significantly reduced the Aldefluor positive population in HER2 overexpressing cells. In contrasts trastuzumab had no effect on the Aldefluor positive population in cells with both HER2 overexpression and PTEN knockdown. These studies suggest that PTEN deletion renders Her 2 overexpressing MCF7 breast cancers resistant to trastuzumab by regulating the CSC population. Strategies aimed at blocking downstream signaling through PI3K or Akt inhibition may effectively target this important cell population in trastuzumab resistant tumors.
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 4268.