bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3723: Tangeretin enhances sensitivity of human pancreatic cancer cells to gemcitabine through targeting the reprogramming of stemness.
Authors: Haque Inamul , Banerjee Sushanta K. , Banerjee Snigdha 
Published: August 2014

Abstract
Background: As a single agent, gemcitabine (2′,2′-difluorodeoxycytidine) has shown only a modest improvement in survival in patients with pancreatic ductal adenocarcinoma (PDAC). Our recent studies found CCN1 (a member of CCN family of growth factor) as an important factor in determining PDAC aggressiveness as it promotes epithelial to mesenchymal transition, tumor stemness, migration and tumorigenicity in xenograft model, possibly through the regulation of multiple miRNAs that are known to link with the progression of cancers and survival and the maintenance of cancer stem cells. Targeting CCN1 may lead to the development of novel therapeutic approaches for human cancers. Here, we examined the effects of tangeretin, a polymethoxylated flavonoid compound produced by citrus fruits in combination of gemcitabine on CCN1-sonic hedgehog (SHh) signaling in pancreatic cancer cells, and assessed the therapeutic potential of tangeretin with gemcitabine for the treatment and/or prevention of pancreatic cancer.
Methodology/Principal Findings: Cell viability and apoptosis were measured by crystal violet staining assay and annexinV/PI staining assay, respectively. Gene and protein expressions were measured by Western blot analysis, respectively. We found that tangeretin in combination with gemcitabine significantly decreased cell survival, clonogenicity, wound-healing capacity, sphere-forming capacity (pancreatospheres) in pancreatic cell lines. Tangeretin also decreased the expression of cancer stem cells (CSC) markers, CD44, Notch-1, Nanog, Oct-4, ABCG2, SHh and CCN1.
Conclusions: Collectively, these studies clearly suggest that tangeretin helps in sensitizing pancreatic cancer cells to gemcitabine by reprogramming the CSC-specific markers. Thus tangeretin could be useful for overcoming therapeutic resistance of pancreatic cancer cells.
Citation Format: Inamul Haque, Sushanta K. Banerjee, Snigdha Banerjee. Tangeretin enhances sensitivity of human pancreatic cancer cells to gemcitabine through targeting the reprogramming of stemness. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3723. doi:10.1158/1538-7445.AM2013-3723
Abstract 3740: Temozolomide-perillyl alcohol conjugate is cytotoxic for glioma cancer stem cells.
Authors: Jhaveri Niyati , Agasse Fabienne , Hofman Florence M. , Chen Thomas C. 
Published: August 2014

Abstract
Glioblastoma multiforme (GBM), the most malignant glioma, is a highly invasive tumor which is usually fatal within 2 years. The chemotherapeutic agent of choice is temozolomide (TMZ); however glioma patients inevitably become resistant to TMZ and tumors recur. Tumor recurrence has been associated with highly invasive, chemoresistant cancer stem cells (CSC) which is resistant to TMZ. We have constructed a new chemical entity by conjugating TMZ to perillyl alcohol (POH) via a carbamate bond. This compound, TMZ-POH, contains POH, a naturally occurring monoterpene that reduces tumor cell migration and has anti-tumor properties against gliomas as well as other cancers. In the studies presented here we demonstrate that TMZ-POH is cytotoxic to CSCs without affecting normal stem cells. The mechanism of TMZ-POH induced cytotoxicity is mediated in part through the DNA damage response pathway and apoptosis. Furthermore, the TMZ-POH conjugate is 5 to 10 fold more effective in inducing cell death compared to TMZ, POH or the mixture of these agents. Our data show that TMZ-POH is a promising novel compound directed against cancer stem cells and therefore important for the treatment of drug resistant, recurrent gliomas.
Citation Format: Niyati Jhaveri, Fabienne Agasse, Florence M. Hofman, Thomas C. Chen. Temozolomide-perillyl alcohol conjugate is cytotoxic for glioma cancer stem cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3740. doi:10.1158/1538-7445.AM2013-3740
Abstract 3742: Targeting the stem cell factor HMGA2 to improve outcomes in glioblastoma.
Authors: Kaur Harpreet , Hutt Marianne , Mao Xing-gang , Eberhart Charles G. , Raabe Eric H. 
Published: August 2014

Abstract
Glioblastoma Multiforme (GBM) causes the majority of brain tumor-related deaths in the United States. The high invasiveness of GBM prevents complete surgical resection, allowing tumor recurrence. The lack of curative treatment highlights a dire need to develop specific targeted therapeutics. Identifying and targeting novel molecular markers in glioma stem-like cells (GSCs), one of the major causes of tumor invasion and recurrence, could lead to development of better therapies. HMGA2, a non-histone transcriptional modulator, is a regulator of normal and cancer stem cells. The significance of HMGA2 as a potential therapeutic target in GBM has not been investigated. To elucidate the role of HMGA2 in GBM, we have used a combination of in vitro and in vivo techniques in the present study. We found high expression of HMGA2 mRNA and protein in a subset of primary brain tumor samples from GBM patients, GBM cell lines and GBM stem-cell lines using quantitative real-time PCR and immunoblotting. Short hairpin RNA (shRNA)-mediated reduction of HMGA2 significantly inhibited invasion of GBM cell lines (U-87 MG and LN-229, 32 and 70% inhibition, respectively, with HMGA2 shRNA vs. control shRNA, P&lt;0.001) and GBM stem cell lines (040821, 62% inhibition with HMGA2 shRNA vs. control shRNA, P&lt;0.001) through Matrigel in vitro by transwell invasion assays. Conversely, overexpression of HMGA2 in GBM stem cell lines increased invasion (130% increase with HMGA2 overexpression vs. control vector, P&lt;0.0001) through Matrigel in vitro as demonstrated by transwell invasion assays. In addition, overexpression of HMGA2 increased clonogenicity of GBM stem cell lines in vitro in soft agar and methylcellulose clonogenic assays (40% increase with HMGA2 overexpression vs. control vector, P&lt;0.0001). Importantly, Kaplan-Meier analysis showed increased survival of mice injected with GBM stem cell lines transduced with HMGA2 shRNA compared to control shRNA (P&lt;0.05) in an in vivo, orthotopic, intracranial mouse xenograft model. Together, our results suggest the importance of HMGA2 in promoting tumorigenicity of GBM by increasing invasiveness and a stem-like state, thereby suggesting that HMGA2 is a potential therapeutic target in GBM. Future studies are aimed at elucidating the molecular mechanism by which HMGA2 regulates invasion and stemness in GBM.
Citation Format: Harpreet Kaur, Marianne Hutt, Xing-gang Mao, Charles G. Eberhart, Eric H. Raabe. Targeting the stem cell factor HMGA2 to improve outcomes in glioblastoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3742. doi:10.1158/1538-7445.AM2013-3742
Abstract 3744: G-CSF-dependent regulation of STAT3 in neuroblastoma cancer stem cell subpopulations.
Authors: Agarwal Saurabh , Chen Zaowen , Hsu Danielle , Kim Eugene , Shohet Jason M. 
Published: August 2014

Abstract
Neuroblastoma is a neural crest derived malignancy arising form peripheral sympathetic nervous system of infants and young children. We have recently defined a highly tumorigenic sub-population of neuroblastoma cells based on surface expression of CD114 (the G-CSF receptor, CSF3R). These cells meet the operational criteria for cancer stem cells based on their self-renewal, differentiation and lineage restricted tumorigenicity, and can be isolated directly from primary tumor biopsy specimens. As STAT3 activation is a canonical downstream event of G-CSF receptor ligation, is critical for neuronal specification, and is implicated in cancer stem cell maintenance, we hypothesized that inhibition of the STAT3 pathway may functionally inhibit the cancer stem cell-like neuroblastoma subpopulation. We used pathway-specific qPCR arrays to evaluate differential gene expression in CD114+ and CD114- tumor subpopulations. As predicted, STAT3 target genes were up-regulated in the CD114+ stem cell-like population. In addition, critical genes controlling early neural crest specification, cell cycle progression, self-renewal, and maintenance of pluripotency were up-regulated in CD114+ population while markers of mature mesenchymal neural crest were increased in CD114- population. Treatment of Neuroblastoma cell lines with G-CSF increased both CD114 expression and STAT3 transcriptional activation in a dose and time dependent manner. Phospho-flow analysis confirmed STAT3 phosphorylation (Y705) in response to exogenous G-CSF. The addition of a STAT3 inhibitor which prevents phosphorylation and dimerization of STAT3 (Stattic), specifically abrogated the effect of exogenous G-CSF treatment. Finally, we identified putative STAT3 binding sites within the 5’UTR of the CSF3R gene and confirmed binding of STAT3 and pSTAT3 using chromatin immunoprecipitation analysis (ChIP-qPCR). We demonstrate significant enrichment of binding in response to exogenous G-CSF within CD114 receptor positive subpopulation in contrast to CD114- population. These data support a model for a positive-feedback loop where G-CSF triggers STAT3 dependent up-regulation of the G-CSF receptor, further sensitizing these cells to exogenous ligand, promoting STAT3 transcriptional activation, and contributing to stem cell maintenance. Our data support further evaluation of the potential clinical role for specific STAT3 inhibitors as anti-cancer stem cell therapy in neuroblastoma.
Citation Format: Saurabh Agarwal, Zaowen Chen, Danielle Hsu, Eugene Kim, Jason M. Shohet. G-CSF-dependent regulation of STAT3 in neuroblastoma cancer stem cell subpopulations. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3744. doi:10.1158/1538-7445.AM2013-3744
Abstract 3746: Association with the sonic hedgehog pathway between gastric cancer stem cells.
Authors: Sung Jae Sook , Lee Jong Won , Jo Ukhyun , Kim Yeul Hong 
Published: August 2014

Abstract
Cancer stem cells (CSCs) have been hypothesized to drive the growth, metastasis and chemoresistance capacity. Activation of sonic hedgehog (SHH) signaling has been implicated in progression of variety of tumors. In this study, we investigated potentiality that activation of the SHH pathway maintained the characteristics of gastric CSCs. First, we establish spheres culture system from 5 human gastric cancer cells and identified spheres from 3 gastric CSCs (MKN45, SNU638, SNU601). Compared with parent cells, spheres had more self-renewing capacity and multipotent capacity. Gastric cancer spheres shown that increased expression of stem cell markers (Oct4 and Nanog) and decreased epithelial maker (Cytokeratin 18). However, expressions of CSCs markers (CD44, CD24, CD54 and CD133) were not significantly. Spheres showed more CSCs characteristics, such as more colony formation and more resistance to conventional chemotherapeutic drugs (5-FU, cisplatin and paclitaxel) compared to parent cells. Next, western blot showed that the expression levels of SHH related pathway (Ptch, Smo and Gli1) were significantly higher in spheres than in parent cells. Further analysis, we found that SHH pathway blocked by cyclopamine enhanced the efficacy of chemotherapeutic drugs in spheres. In the further study, we will confirm SHH dependence and in vivo xenograft study. In conclusion, our data suggest that sonic hedgehog blockade could improve the antitumor efficacy of chemotherapy of human gastric cancer. [This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. A010250)]
Citation Format: Jae Sook Sung, Jong Won Lee, Ukhyun Jo, Yeul Hong Kim. Association with the sonic hedgehog pathway between gastric cancer stem cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3746. doi:10.1158/1538-7445.AM2013-3746
Abstract 3754: Methionine adenosyltransferase IIα regulates histone methyltransferase G9a expression in colorectal cancer stem cells.
Authors: Li Kai-Chun , Cha Shih-Ting , Chu Chia-Yu , Kuo Min-Liang 
Published: August 2014

Abstract
Histone modification is critical for regulation of chromatin structure and gene transcription in cells and recent evidences have characterized that histone methylation may contribute to tumorigenesis and cancer malignancies. In general, the methyl donor for methylation is synthesized from S-adenosylmethionine (SAM), in a reaction catalyzed from methionine by methionine adenosyltransferase (MAT). Our previous studies have demonstrated the expression of histone methyltransferase G9a, which is responsible for histone H3 lysine 9 methylation, not only correlates to tumor aggressiveness but also plays a crucial role in regulation of colorectal cancer stem cells (CSCs), which endow high tumorigenecity, drive metastasis and therapy-resistance. We discover that G9a is enriched in CSCs and knockdown of its expression will promote differentiation, inhibit drug-resistance and metastatic ability of CSCs. Here, we further report that MATIIα expression is specifically elevated in the nucleus and interacts with G9a in CSCs. Overexpression of MATIIα in non-CSCs will increase G9a expression, self-renewal ability and stemness marker expression. In contrast, knockdown of MATIIα decreases G9a expression, it reveals that the self-renewal ability will be blocked in CSCs. Furthermore, inhibition of MATIIα expression by its inhibitor, SAM, can also decrease G9a expression and stem-cell like characteristics. Taken together, we first demonstrate that the expression and the function of G9a are both maintained by MATIIα in colorectal CSCs. These findings provide a new insight into understanding of the link between the metabolic enzyme and epigenetic regulator in CSCs, which may be a therapeutic target in the future.
Citation Format: Kai-Chun Li, Shih-Ting Cha, Chia-Yu Chu, Min-Liang Kuo. Methionine adenosyltransferase IIα regulates histone methyltransferase G9a expression in colorectal cancer stem cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3754. doi:10.1158/1538-7445.AM2013-3754
Abstract 3756: MiR-203 inhibits the proliferation and self-renewals of esophageal cancer stem-like cells by suppression stem renewal factor Bmi-1.
Authors: Yu Xiying , Jiang Xingran , Li Hongxia , Guo Liping , Jiang Wei , Lu Shih-Hsin 
Published: August 2014

Abstract
Recent reports have shown that cancer stem-like cells exist in many malignancies and several stem cell-related gene products and miRNAs, such as Bmi-1 and miR-203, were identified as cancer stem-like cell regulators using gene microarray or sequencing analysis. Bmi-1 is essential for the self-renewal capacity of several types of normal stem cells and cancer stem-like cells while miR-203 is involved in stem cell self-renewal regulation. Previously, we used side population (SP) sorting to enrich cancer stem-like cells from esophageal squamous cell carcinoma (ESCC) cell line EC9706. Our results demonstrated that EC9706 SP cells have the same common features of cancer stem-like cells, such as the ability of self renewal, highly proliferation and tumorigenesis. In this study, we examined expression regulation of Bmi-1 and miR-203 in ESCC SP and none-SP (NSP) cells. Our results showed that, when compared with NSP cells, Bmi-1 was up-regulated and miR-203 was down-regulated in SP cells. During the differentiation from SP to NSP cells, the expression levels of Bmi-1 were gradually decreased, suggesting that Bmi-1 might be required for maintaining the ESCC SP cells. As sequence analysis revealed that the mRNA 3’UTR of Bmi-1 has a highly conserved binding site of miR-203, we overexpressed miR-203 in EC9706 cells using lentivirus mediated gene transduction. Overexpression of miR-203 (lenti-miR-203) resulted in a significant reduction of endogenous Bmi-1 protein levels in EC9706 cells. SP and NSP analyses revealed that the SP cell fraction markedly decreased in lenti-miR-203 cells. Lenti-miR-203 cells also showed significantly reductions of the colony formation, resistant to chemotherapeutic drug treatment and tumorigenicity in nude mice. Rescue experiments demonstrated that ectopic expression of Bmi-1 in lenti-miR-203 cells increased the SP fraction and restored cell proliferation. Taken together, these results indicated that stem renewal factor Bmi-1 is a direct target of miR-203. Regulation of Bmi-1 by miR-203 may play an important role in controlling cell proliferation and self-renewals of esophageal cancer stem-like cells.
Citation Format: Xiying Yu, Xingran Jiang, Hongxia Li, Liping Guo, Wei Jiang, Shih-Hsin Lu. MiR-203 inhibits the proliferation and self-renewals of esophageal cancer stem-like cells by suppression stem renewal factor Bmi-1. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3756. doi:10.1158/1538-7445.AM2013-3756
Abstract 3767: Nicotine promotes acquisition of stem cell and epithelial-to-mesenchymal properties in head and neck squamous cell carcinoma.
Authors: Yu Michael A. , Kiang Alan , Wang-Rodriguez Jessica , Rahimy Elham , Haas Martin , Yu Vicky , Ellies Lesley G. , Fan Jian-Bing , Brumund Kevin T. , Weisman Robert A. , Ongkeko Weg M. 
Published: August 2014

Abstract
The ability of nicotine to enhance the malignancy of cancer cells is known; however, the possibility that nicotine could regulate a cancer stem cell phenotype remains to be well-established. In this study we sought to determine whether long-term exposure to nicotine could promote cancer stem cell-like properties in two head and neck squamous cell carcinoma cell lines, UMSCC-10B and HN-1. Nicotine treatment induced epithelial-to-mesenchymal transition (EMT) in both cell lines by repressing E-cadherin expression, and led to the induction of stem cell markers Oct-4, Nanog, CD44 and BMI-1, which was reversed upon ectopic re-expression of E-cadherin. Nicotine-treated cells formed spheres at a higher efficiency than non-treated cells, formed larger tumors when injected into mice, and formed tumors with 4-fold greater efficiency compared to control cells when injected at limiting doses. Consistent with previous literature, nicotine-treated cells demonstrated a greater capacity for survival and also a higher tendency to invade. Comparison of microRNA profiles between nicotine and control cells revealed the upregulation of miR-9, a repressor of E-cadherin, and the downregulation of miR-101, a repressor of EZH2. Taken together, these results suggest that nicotine may play a critical role in the development of tobacco-induced cancers by regulating cancer stem cell characteristics, and that these effects are likely mediated through EMT-promoting, microRNA-mediated pathways. Further characterization of such pathways remains a promising avenue for the understanding and treatment of tobacco-related cancers.
Citation Format: Michael A. Yu, Alan Kiang, Jessica Wang-Rodriguez, Elham Rahimy, Martin Haas, Vicky Yu, Lesley G. Ellies, Jian-Bing Fan, Kevin T. Brumund, Robert A. Weisman, Weg M. Ongkeko. Nicotine promotes acquisition of stem cell and epithelial-to-mesenchymal properties in head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3767. doi:10.1158/1538-7445.AM2013-3767
Abstract 3770: ER-α36-mediated non-genomic estrogen signaling positively regulates ER-positive breast cancer stem/progenitor cells .
Authors: Deng Hao , Zhang Xintian , Wang Molin , Guo Mingxi , Liu Lijiang , Wang Zhaoyi 
Published: August 2014

Abstract
Accumulating experimental and clinical evidence indicated that breast cancer may arise from mammary stem/progenitor cells that posses the features like the ability of self-renewal and tumor generation from very few cells, slow cell division, differentiation into different lineages, selective resistance to radio- and chemo-therapy, constitutive activation of anti-apoptotic pathways and induction of angiogenesis, the ability to migrate and spread in metastasis. Many signaling pathways involved in regulation of normal mammary stem cells including Hedgehog, Bmi-1, Wnt, NOTCH, HER-2, p53 and PTEN/Akt/β-catenin pathways have been identified to play roles in breast cancer stem/progenitor cells. However, the involvement of estrogen signaling, a major signaling pathway in breast cancer development, in regulation of breast cancer stem/progenitor cells has not been well established, mainly because expression of estrogen receptor-α (ER-α) in breast cancer stem/progenitor cells remains controversial. Previously, we have identified and cloned a novel variant of ER-α, ER-α36, that is mainly expressed near the plasma membrane and in the cytoplasm, and mediates non-genomic estrogen signaling such as activation of the MAPK/ERK and PI3K/AKT signaling pathways. In this study, we ivestigated the function of ER-α36 in regulation of breast cancer stem/progenitor cells. We found that ER-α36 was highly expressed on the plasma membrane of the breast cancer stem/progenitor cells while the original ER-α was expressed outside of the cell nuclei. We also found that the genomic estrogen signaling was down-regulated in ER-positive breast cancer stem/progenitor cells. ER-positive breast cancer cells with forced expression of recombinant ER-α36 exhibited increased populations of stem/progenitor cells and high tumor seeding efficiency. Estrogen treatment significantly increased the population of breast cancer stem/progenitor cells while failed to do so in ER-positive breast cancer cells with knocked-down expression levels of ER-α36. We further found that estrogen positively regulates breast cancer stem/progenitor cells through ER-α36-mediated non-genomic estrogen signaling pathways such as activation of the PI3K/AKT pathway. Thus, our results demonstrated that the novel variant of ER-α, ER-α36 plays an important role in estrogen regulation of ER-positive breast cancer stem/progenitor cells.
Citation Format: Hao Deng, Xintian Zhang, Molin Wang, Mingxi Guo, Lijiang Liu, Zhaoyi Wang. ER-α36-mediated non-genomic estrogen signaling positively regulates ER-positive breast cancer stem/progenitor cells . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3770. doi:10.1158/1538-7445.AM2013-3770