bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3874: Loss of DDB2 enhances the tumorigenicity of ovarian cancer cells through expanding cancer stem-like cell population
Authors: Han Chunhua , Zhao Ran , Liu Xingluo , Srivastava Amit Kumar , Gong Li , Mao Hsiaoyin , Qu Meihua , Zhao Weiqiang , Yu Jianhua , Wang Qi-En 
Published: May 2015

Abstract
Ovarian cancer is an extremely aggressive disease associated with a high percentage of recurrence and chemotherapy resistance. DNA damage binding protein 2 (DDB2) is a 48-kDa protein originally identified as a component of the damage-specific DNA-binding heterodimeric complex DDB. Besides the known ability of DDB2 protein to bind ultraviolet (UV)-damaged DNA and serving as the initial damage recognition factor during nucleotide excision repair (NER), DDB2 was also reported to be involved in the promotion of apoptosis to reduce cisplatin resistance of ovarian cancer cells, control of cell migration, invasiveness and breast tumor progression, as well as suppression of metastasis of colon cancer through a transcriptional regulatory mechanism. Here we show that DDB2 is downregulated in human ovarian serous adenocarcinomas. DDB2 overexpression in human ovarian cancer cell line CP70 suppressed its capability to recapitulate tumors in athymic nude mice, as well as the growth of these cells cultured in semisolid media. Flow cytometry analyses indicate that DDB2 overexpression in CP70 cells reduced the abundance of ALDH+ cells, which are believed to be cancer stem-like cells (CSCs) in ovarian cancer. In contrast, downregulation of DDB2 in ovarian cancer cell line A2780 increased the percentage of ALDH+ cells. In addition, we analyzed the expression level of DDB2 in the putative CSCs isolated from various ovarian cancer cell lines, and demonstrated that DDB2 expression is downregulated in all tested CSCs in comparison with their parental bulk tumor cells. Overexpression of DDB2 in the ovarian CSCs reduced the expression of CSC marker Nanog, as well as inhibited the self-renewal of these CSCs. In addition, overexpression of DDB2 in CSCs isolated from ovarian cancer cell line SKOV-3 also decreased the tumorigenicity of these cells in NOD/SCID mice. Further analysis of publicly available gene expression array datasets revealed that low DDB2 expression correlates with poor outcomes among ovarian cancer patients, suggesting that loss of DDB2 may promote ovarian tumor relapse through expanding CSC population. Given that the DDB2 protein level is downregulated in ovarian tumor cells, targeting DDB2 expression could be a promising strategy to eradicate CSCs, and helps to halt ovarian cancer relapse. (Supported by NIH R01 grant CA151248 to QEW)
Citation Format: Chunhua Han, Ran Zhao, Xingluo Liu, Amit Kumar Srivastava, Li Gong, Hsiaoyin Mao, Meihua Qu, Weiqiang Zhao, Jianhua Yu, Qi-En Wang. Loss of DDB2 enhances the tumorigenicity of ovarian cancer cells through expanding cancer stem-like cell population. [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 3874. doi:10.1158/1538-7445.AM2014-3874
Abstract 3877: Evolution of cancer stem cells in glioma to promote their therapy-resistant phenotype
Authors: Nakano Ichiro 
Published: May 2015

Abstract
High grade glioma (HGG) is a life-threatening brain tumor. Among heterogeneous tumor cells, glioma stem cells (GSCs) are defined as a subpopulation resistant to chemo- and radiotherapy with prominent tumorigenic ability. Identification of novel therapeutics designed to target the GSC population in HGGs is a challenge. The recent genome-wide transcriptome analysis identified 3 subtypes, proneural (PN), proliferative, and mesenchymal (MES), in HGGs. These HGG subtypes harbor distinct gene signatures and altered signaling pathways with some clinical relevance. During malignant transformation, HGGs appear to gain therapy resistance, at least in part, through their phenotypic drift into mesenchymal tumors. In addition, some of the current therapies, if not all, appear to induce mesenchymal transformation of HGGs resulting in more therapy-resistant tumors. Nonetheless, identification of subtype-specific GSCs remains elusive.
My lab recently identified clinical HGG sample-derived two mutually-exclusive GSCs: PN and MES GSCs with striking phenotypic differences with clinical relevance (Mao et al., PNAS 2013). Transcritpome microarray analysis, miRNA profiling, and subsequent functional analysis demonstrated that distinct signaling pathways regulate tumorigenesis and propagation of the individual GSC subtypes. For example, PN GSCs are dependent on the oncogenic transcription factor c-Myb (Miyazaki et al., Clinical Cancer Res. 2012) and MES GSCs are dependent on the oncogene/mitotic kinase MELK and Survivin (Guvenc et al., Clinical Cancer Res. 2012; Gu et al., Stem Cells 2013; Joshi et al., Stem Cells 2013). Intriguingly, upon radiation treatment, PN GSCs gain the phenotypes of MES GSCs (PN-to-MES transformation; PMT), which are much more aggressive and radioresistant than original PN GSCs. Of note, targeting the MES-specific pathways partially blocks PMT of GSCs. These results may patially explain the molecular mechanisms underlying mesenchymal transformation of HGGs to promote therapy resistance. Here I summarize our latest data to elucidate the molecular mechanisms that drive GSC evolution to promote their therapy resistant phenotype.
Citation Format: Ichiro Nakano. Evolution of cancer stem cells in glioma to promote their therapy-resistant phenotype. [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 3877. doi:10.1158/1538-7445.AM2014-3877
Abstract 3880: Targeting the root of cancer: a data-driven approach for identification of lung cancer stem cell biomarkers
Authors: Fan-Minogue Hua , Butte Atul 
Published: May 2015

Abstract
Cancer stem cells (CSCs) are a small group of cancer cells with stem cell-like properties and have been revealed to be the drive force of tumorigenesis, metastasis and drug resistance in many cancers. Current CSC surface biomarkers, such as CD133, CD44 and CD166, have been used to isolate CSC population. However, they are often not specific and unassociated with tumor outcome. Here, we applied a data-driven approach to identify new and functional biomarkers of CSC. We systematically screened for genes whose expressions are statistically correlated with CSC surface biomarkers. Normalized DNA microarray data of 160 cases of squamous carcinoma and 33 cases of adenocarcinoma and 8 cases of normal lung were analyzed for association with CD133, CD44 and CD166 respectively. Multiple hypothesis testing was corrected with the false discovery rate (FDR) less than 1%. We find CD133, CD44 and CD166 each has a different set of statistically associated genes in either adeno or squamous subtypes. Moreover, correlated genes with each of the surface marker are different between adeno and squamous subtypes. Among the highly correlated receptor genes with CD133 in squamous subtype is a hormone receptor of the reproduction regulator oxytocin (OXTR, r=0.4276, p=1.699e-8). We experimentally validated the correlation between OXTR and CD133 in human lung cancer tissues and cell lines. Further with functional assays, we discovered a new role of OXTR in promoting the self-renewal and differentiation of lung CSC. Our study suggests highly heterogeneous molecular features of CSC in different lung cancer types and demonstrates that association studies of CSC surface markers can be applied to identify new CSC biomarkers, which can be potentially used for development of probes for CSC imaging and targeting.
Citation Format: Hua Fan-Minogue, Atul Butte. Targeting the root of cancer: a data-driven approach for identification of lung cancer stem cell biomarkers. [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 3880. doi:10.1158/1538-7445.AM2014-3880
Abstract 3896: The Hippo coactivator YAP1 upregulates SOX9 and endows cancer stem cell properties in non-transformed cells and esophageal cancer cells
Authors: Song Shumei , Ajani Jaffer A. , Honjo Soichiro , Maru Dipen M. , Chen Qiongrong , Jin Jiankang , Scott Ailing W. , Heallen Todd R. , Xiao Lianchun , Hofstetter Wayne L. , Weston Brian , Lee Jeffrey H. , Wadhwa Roopma , Sudo Kazuki , Martin James F. , Stroehlein John R. , Hung Mien-Chie , Johnson Randy L. 
Published: May 2015

Abstract
Cancer stem cells are proposed to initiate and maintain tumor growth. Dysregulation of normal stem cell signaling may lead to the generation of cancer stem cells (CSCs), however, the molecular determinants of this process remain poorly understood. Here we show that the transcriptional co-activator YAP1 through direct regulation of SOX9 promotes the generation of CSCs and that the inhibition of YAP1 and SOX9 attenuates CSC formation. SOX9 transcripts and expression are upregulated upon YAP1 activation and several lines of evidence indicate that SOX9 is a direct target of YAP1. The Chromatin Immunoprecipitation analysis and luciferase assays demonstrate direct binding of YAP1 to the SOX9 promoter through a conserved TEAD binding site. Mutation of this site abrogates transcriptional regulation of SOX9 by YAP1 and Tead2. Functional studies demonstrate that YAP1 regulation of SOX9 is necessary and sufficient to confer CSC properties and tumorigenesis in vitro and in vivo. The small molecule inhibitor of YAP1, Verteporfin (VP) significantly blocks CSC self-renewal properties in cells with high YAP1 and a high proportion of the CSC marker aldehyde dehydrogenase 1 (ALDH1) indicating that VP targets the CSC population. These data identify YAP1 as a driver of esophageal cancer (EC) stem cells, in part, by regulation of SOX9 and suggest that pharmacological inhibition of YAP1 may be an effective means of specifically targeting EC stem cells.
Citation Format: Shumei Song, Jaffer A. Ajani, Soichiro Honjo, Dipen M. Maru, Qiongrong Chen, Jiankang Jin, Ailing W. Scott, Todd R. Heallen, Lianchun Xiao, Wayne L. Hofstetter, Brian Weston, Jeffrey H. Lee, Roopma Wadhwa, Kazuki Sudo, James F. Martin, John R. Stroehlein, Mien-Chie Hung, Randy L. Johnson. The Hippo coactivator YAP1 upregulates SOX9 and endows cancer stem cell properties in non-transformed cells and esophageal 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 3896. doi:10.1158/1538-7445.AM2014-3896
Abstract 3909: Cisplatin resistant head and neck cancer cells are susceptible to growth inhibition by CDF curcumin
Authors: Basak Saroj K. , Zinabadi Alborz , Venkatesan Natarajan , Duarte Victor M. , Dalgard Clifton L. , Srivastava Meera , Wang Marilene B. , Sarkar Fazlul H. , Srivatsan Eri S. 
Published: May 2015

Abstract
Head and neck (H&N) cancer is the sixth most common type of cancer, with about 650,000 new cases in the world every year. Platinum-based agents (cisplatin/carboplatin) are the most common chemotherapeutic agents for H&N cancer; however the five year survival rate is only 50% and development of drug resistance is one of the major challenges for effective therapy. Thus, development of new strategies to overcome drug resistance will help in H&N cancer treatment. Our studies using H&N cancer cisplatin resistant cell lines in vitro have indicated that Cancer Stem cell (CSC) specific markers such as CD44 and cytokines (IL-8, IL-10) are up-regulated during the development of drug resistance. Furthermore, our in vitro studies indicated that the treatment of drug resistant cell lines with a novel synthetic curcumin analog known as CDF in liposomal encapsulation (liposomal CDF) resulted in statistically significant growth inhibition (p&lt;0.05). Similarly, our studies in a nude mouse xenograft drug resistant H&N cancer tumor model showed that treatment with liposomal CDF (1 mg/100 µl in saline, i.v. injection 5 days a week for 3 weeks) resulted in greater than 50% tumor growth inhibition. The CDF treated cell lines and xenograft tumors showed a statistically significant reduction in the expression of CD44 (p&lt;0.05), indicating an inhibitory effect of CDF on cancer stem cells, which is consistent with previously published data on other tumor models. These results demonstrate that CDF can be useful for the treatment of drug resistant H&N cancer.
Citation Format: Saroj K. Basak, Alborz Zinabadi, Natarajan Venkatesan, Victor M. Duarte, Clifton L. Dalgard, Meera Srivastava, Marilene B. Wang, Fazlul H. Sarkar, Eri S. Srivatsan. Cisplatin resistant head and neck cancer cells are susceptible to growth inhibition by CDF curcumin. [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 3909. doi:10.1158/1538-7445.AM2014-3909
Abstract 3920: Understanding the molecular nature of cancer cell lines
Authors: Volpe Lysa A. , Bal Anupreet , Foulke John , Jackson Michael , Chen Luping , Tian Fang 
Published: May 2015

Abstract
Large-scale cancer genome programs have generated rich data of genetic abnormalities observed in thousands of clinical patient tumors, which provides a major opportunity to develop a landscape of molecular aberrations across tumor types and propose new therapeutic targets. Although human tumor cell lines have been important tools for the cancer researcher for decades, there is a lack of bio-functional validation of genetic alterations and systematic molecular characterization across commonly used cell lines in this genomic age. To meet the need of applying cancer genome knowledge to facilitate basic and translational cancer research, an updated and accurate knowledge of the cell lines in use, particularly from a molecular viewpoint, is critical for in vitro studies. Here, we show systematic molecular characterization and clustering of 90 authenticated human tumor cell lines, which represent the most common human cancer types found in the clinic, such as lung, breast, colon, pancreatic, skin cancer and so on. By next generation sequencing and molecular profiling, those tumor cell lines were fully analyzed to capture the driver gene mutations, DNA copy number variations, gene expressions, protein expressions and relevant cell signaling pathway activations. In addition to driver mutations such as BRAF V600, KRAS G12, PI3K E545 and EGFR T790, the gene copy number amplifications of AKT, FGFR, MET, ERBB2 and deletion of PTEN are presented in this work. Moreover, correlating with the verified genetic alternations, the endogenous basal levels of protein expression and signaling pathway activations within the cells were analyzed by western blot and immunofluorescence staining. A set of 6 wild type control cell lines that were derived from either normal tissues or tumors were characterized in parallel. Furthermore, live cell growth kinetics was continually monitored by label-free cell based assay. Finally, the cell lines are clustered into 10 genetic alteration panels according to driver genes, critical protein kinases, or key components of signaling pathways. Cell lines are essential models for progressing our understanding of the cancer genome, as they allow for the functional and biological validation of the genetic alterations proposed by NGS data. The genetic alteration tumor cell panels and their molecular signature profiles provide powerful tools to accelerate the discoveries in basic cancer research, compound screening, biomarker selection, pathway analysis, and targeted therapeutic development.
Citation Format: Lysa A. Volpe, Anupreet Bal, John Foulke, Michael Jackson, Luping Chen, Fang Tian. Understanding the molecular nature of cancer cell lines. [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 3920. doi:10.1158/1538-7445.AM2014-3920
Abstract 3921: Generation of a T-cell lymphoma mouse model based on chronic LPS challenge and TGF-β signaling disruption
Authors: Muñoz Nina M. , Katz Lior H. , Gagea Mihai I. , Rashid Asif , Mishra Lopa 
Published: May 2015

Abstract
Background: It has been demonstrated that elevated alcohol intake affects the permeability of the gut allowing endotoxins such as LPS to enter into the portal circulation and to promote liver ethanol toxicity. It has also been shown that increased ethanol intake and LPS challenge impairs liver function and affects liver tumor formation. Hence, with the aim of generating a mouse model of alcoholic liver disease that would rapidly develop steatosis, inflammation and fibrosis, we formulated a regimen that combined chronic injections of low dose LPS with ethanol feeding to mice with impaired TGF-β signaling through constitutive disruption of β2-spectrin (Sptbn1+/-) , Smad3 (Smad3+/-) or both. Methods: Wild type, Sptbn1+/-, Smad3+/- and Sptbn1+/-;Smad3+/- female mice between 8-10 weeks of age were fed orally with a Lieber-DeCarli-based diet containing 6.7% ethanol, and 2-4 weeks later they were injected with 2mg/kg LPS via i.p. 3 times/week for up to 20 weeks or death, whichever occurred first. Survival analysis was done using the Gehan-Breslow-Wilcoxon test. Results: Unexpectedly, the mice treated with chronic low dose LPS and fed the alcohol-containing diet only developed a mild liver phenotype, i.e. steatosis but not hepatitis or fibrosis. Instead, these mice developed very aggressive T-cell lymphomas with massive abdominal and thoracic hemorrhages to which the TGF-β mutant mice succumbed more rapidly than the wild type mice. The median survival of the mutants oscillated between 39 to 42 weeks vs. undefined of the wild type mice. We found statistically significant decreased survival of the mutant mice vs. the wild type (p-values between 0.0015 and 0.028). Conclusions: To our knowledge, this is the first report of a mouse model of aggressive T-cell lymphoma based on chronic challenge with low dose LPS and alcohol feeding. We are currently assessing the cross-talk of the LPS/TLR4 and TGF-β pathways in T-cells from these mice to understand the molecular mechanism underlying the accelerated rate of lymphoma development in these mice.
Citation Format: Nina M. Muñoz, Lior H. Katz, Mihai I. Gagea, Asif Rashid, Lopa Mishra. Generation of a T-cell lymphoma mouse model based on chronic LPS challenge and TGF-β signaling disruption. [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 3921. doi:10.1158/1538-7445.AM2014-3921
Abstract 3923: Molecular characterization of an animal model for neuroendocrine thyroid cancer
Authors: Pozo Karine , Hillmann Antje , Augustyn Alexander , Singh Tanvir , Plattner Florian , Minna John , Chen Herbert , Cote Gilbert J. , Bibb James A. , Nwariaku Fiemu E. 
Published: May 2015

Abstract
Neuroendocrine tumors are rare forms of cancers originating from hormone-producing cells that are scattered throughout the body. Medullary thyroid carcinoma (MTC) develops from calcitonin-secreting, C cells, in the thyroid gland. Surgical removal of the thyroid is the best treatment currently available for early stage cancer patients but advanced forms of MTC are often incurable and fatal. Thus, better therapies are needed. A lack of relevant animal models for this disease has slowed the development of new treatments. We have recently reported a novel conditional mouse model for MTC. In these mice, overexpression of the cyclin-dependent kinase 5 (Cdk 5), activator, p25 in C cells induces MTC tumors. Furthermore, interruption of p25 overexpression results in growth arrest of these tumors. Here we take advantage of our conditional mouse model to investigate the molecular pathways underlying MTC tumorigenesis. We used Illumina Mouse WG-6 v2.0 Expression BeadChip to compare the gene expression profile of proliferating versus arrested mouse MTC tumors. We found that a total of 920 genes encoding transcription factors, cell cycle proteins, motor proteins and angiogenesis factors were differentially regulated in growing versus arrested tumors. Particularly the genes encoding cell cycle proteins that are involved in the regulation of Rb pathway were significantly up-regulated in the proliferating tumors. Selected genes with higher degrees of change were evaluated by quantitative PCR and immunoblotting analyses. Taken together these findings suggests that the Rb signaling pathways is involved in MTC tumorigenesis and that Cdk5 may act as a critical regulator of the Rb signaling pathway in this cancer. Thus, targeting Cdk5 and/or the Rb pathway may be a valid strategy to stop the progression of neuroendocrine thyroid cancer.
Citation Format: Karine Pozo, Antje Hillmann, Alexander Augustyn, Tanvir Singh, Florian Plattner, John Minna, Herbert Chen, Gilbert J. Cote, James A. Bibb, Fiemu E. Nwariaku. Molecular characterization of an animal model for neuroendocrine thyroid 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 3923. doi:10.1158/1538-7445.AM2014-3923
Abstract 394: TET1, which act as an tumor suppressor gene, is suppressed by DNA hypermethylation in gastric cancer
Authors: Park Jong-Lyul , Kwon Oh-Hyung , Song Kyu Sang , Kim Seon-Young , Kim Yong Sung 
Published: May 2015

Abstract
5-hydromethylcytosine (5hmC) is a hydroxmethylated form of DNA cytosine catalyzed by TET proteins. Recently, it was reported that aberrant regulation of 5hmC is associated with many cancers such as breast cancer, glioma, leukemia and melanoma. In this study, we examined the status of 5hmC and the role of TET1, which converts 5mC to 5hmC, in gastric cancer. Dot blot and ELISA assay results revealed global loss of 5hmC level in gastric cancer, and that decreased TET1 expression was associated with decreased 5hmC levels. Importantly, in gastric cancer patients, TET1-low group had advanced metastasis and poor survival compared with TET1-high group. To understand the mechanisms of TET1 suppression in gastric cancer, we performed pyrosequencing in 80 paired normal and tumors samples from gastric cancer patients, and found that the promoter region of TET1 was hypermethylated in tumors than adjacent normal tissues. Treating AGS cells with 5-Aza-2′deoxycytidine (Aza-dC) restored the expression of TET1. Transient transfection of in vitro transcribed TET1 mRNA into AGS cells significantly reduced the growth of AGS cells. In summary, our results showed that DNA methylation is responsible for the suppression of TET1 which has a tumor suppressor role in gastric cancer
Citation Format: Jong-Lyul Park, Oh-Hyung Kwon, Kyu Sang Song, Seon-Young Kim, Yong Sung Kim. TET1, which act as an tumor suppressor gene, is suppressed by DNA hypermethylation in gastric 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 394. doi:10.1158/1538-7445.AM2014-394