bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4876: Characterization of malignant melanoma growth triggered by the brain microenvironment in experimental metastasis models
Authors: Nygaard Vigdis , Prasmickaite Lina , Vasiliauskaite Kotryna , Clancy Trevor , Hovig Eivind 
Published: May 2015

Abstract
The brain offers a unique microenvironment to which malignant melanoma frequently spreads leading to dismal prognosis for the patients. The molecular determinants that promote melanoma brain metastases however, remain largely unknown. Here, we show an experimental strategy utilizing two species of immune-compromised animals in a metastasis model to generate in vivo-cultivated metastatic tissues along with their corresponding host tissues in order to identify molecular events associated with brain metastases. The study was based on the melanoma cell lines, Melmet 1 and Melmet 5 with opposing phenotypes (invasive/proliferative, respectively) in the in vitro setting and distinct metastatic patterns in vivo, where Melmet 1 showed a preference to the brain. Transcriptional changes in the melanoma cells, as induced by the brain-microenvironment in both host species, revealed the opportunistic nature of melanoma in this context. We detected transitioning from the invasive phenotype to the proliferative phenotype, as the brain metastases passed from early to late growth phase. Of significance, we identified a brain-adaptive phenotype with synaptic characteristics and where glutamate signaling and Ca2+-dependent effectors played a central role. The brain-adaptive phenotype was more prominent in the earlier metastatic growth phases compared to a later phase. Analysis of host tissue uncovered a cooperative inflammatory microenvironment formed by activated host cells. Altogether, this suggests that acquisition of the brain-adaptive phenotype in a permissive environment might be critical for the establishment of metastatic growth in the brain microenvironment and further, targeting glutamate signaling may represent a therapeutic approach in brain metastasis. Global network modeling and functional annotation analysis revealed that several of the central molecular factors and pathways mediating melanoma brain metastasis in this study, are also central to other pathological diseases, in particular neurodegenerative diseases. The identification of essential molecular networks that operate to promote the brain-adaptive phenotype is of clinical relevance, as they represent leads to urgently needed therapeutic targets.
Citation Format: Vigdis Nygaard, Lina Prasmickaite, Kotryna Vasiliauskaite, Trevor Clancy, Eivind Hovig. Characterization of malignant melanoma growth triggered by the brain microenvironment in experimental metastasis models. [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 4876. doi:10.1158/1538-7445.AM2014-4876
Abstract 4883: CDK8: A new druggable mediator of NFκB activity
Authors: Chen Mengqian , McDermott Martina , Yang Zhengguan , Liang Jiaxin , Schools Gary P. , Lim Chang-uk , Lu Tao , George Stark R. , West Deborah K. , Porter Donald C. , Broude Eugenia V. , Roninson Igor B. 
Published: May 2015

Abstract
Cyclin-dependent kinase 8 (CDK8) is a transcription-regulating oncogenic serine kinase, which mediates several cancer-related transcriptional pathways such as beta-catenin, TP53, TGF-beta and HIF1A. We have recently discovered the first selective small-molecule inhibitors of CDK8 and its closely related isoform CDK19 and showed that these inhibitors block chemotherapy-induced tumor-promoting paracrine activities of both tumor and normal cells (Porter et al., PNAS 109, 13799, 2012). Since transcription factor NFκB plays a key role in damage-induced expression of tumor-promoting cytokines, we have tested the effects of a highly selective CDK8/19 inhibitor Senexin A on NFκB-induced transcription. Senexin A treatment or knockdown of CDK8 by shRNA inhibits transcriptional activation of NFκB-responsive promoters and of acutely responsive cytokine genes (such as CXCL1, CXCL2, IL8 and CCL20), by TNFα, a canonical NFκB activator, in several cell lines. CDK8 inhibition did not prevent nuclear translocation of active NFκB proteins. Chromatin immunoprecipitation (ChIP) analysis of HEK293 cells, untreated or treated with TNFα or Senexin A, singly or in combination, showed that CDK8 is recruited to NFκB early-responsive genes upon TNFα treatment, but the CDK8 inhibitor did not prevent the recruitment of NFκB, CDK8 or RNA Polymerase II (Pol II) to the target genes. However, CDK8 kinase activity was found to be required for C-terminal domain phosphorylation (both at S2 and S5 residues) of Pol II associated with the target genes, which is needed for the elongation of their NFκB-initiated transcription. In contrast, Pol II phosphorylation at constitutively expressed genes is not dependent on CDK8 kinase activity. These results suggest that CDK8 inhibitors may exert their effects against the activation of tumor-promoting and pro-inflammatory secreted factors in the tumor microenvironment by preventing transcriptional activation of NFκB-induced genes.
Citation Format: Mengqian Chen, Martina McDermott, Zhengguan Yang, Jiaxin Liang, Gary P. Schools, Chang-uk Lim, Tao Lu, Stark R. George, Deborah K. West, Donald C. Porter, Eugenia V. Broude, Igor B. Roninson. CDK8: A new druggable mediator of NFκB activity. [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 4883. doi:10.1158/1538-7445.AM2014-4883
Abstract 4888: The novel cytokine IL-17D at the intersection of cellular stress and tumor immunity
Authors: Saddawi-Konefka Robert , Bui Jack 
Published: May 2015

Abstract
Our laboratory has recently identified a novel role for the cytokine IL-17D as an important mediator of the antitumor immune response; and, the loss of IL-17D as a key component of tumor progression. Our data show for the first time that overexpression of the cytokine IL-17D is sufficient to induce tumor rejection or growth delay. Tumors expressing IL-17D displayed an increased infiltration of natural killer (NK) cells, which gave way to a commensurate increase of M1-type macrophages. While examining the regulation of IL-17D, we came across the surprising finding that IL-17D can be induced by oxidative stress signals via the transcription factor nrf2. Nrf2, responsible for regulating the expression of the anti-oxidant response element genes, is known as the primary cellular responder to oxidative stress. Although the role of nrf2 in cancer biology has been well studied, the role of nrf2 in the regulation of immune responses (particularly via IL-17D) has yet to be defined. We find that nrf2 is necessary to induce IL-17D expression in a variety of tumor and non-tumor cells, and that this regulation is active in tumor progression. These studies constitute an intriguing and novel connection between oxidative cellular stress and immune activation.
Citation Format: Robert Saddawi-Konefka, Jack Bui. The novel cytokine IL-17D at the intersection of cellular stress and tumor immunity. [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 4888. doi:10.1158/1538-7445.AM2014-4888
Abstract 489: Hypoxia-mediated ROS enhances HGF-induced cancer cell invasion and suppresses cell cycle progression
Authors: Lee Young H. , Bottaro Donald P. 
Published: May 2015

Abstract
The cellular response to hypoxia is a major influence on the aggressiveness of primary tumors, yet much of how this response mechanism influences other signaling pathways is unknown. The MET proto-oncogene, which encodes the tyrosine kinase receptor for hepatocyte growth factor (HGF), is often overexpressed in cancers and can drive cell proliferation, invasion, and metastasis. Prior studies demonstrated that the Met tyrosine-kinase receptor drives cell invasion and metastasis under hypoxic conditions, and this invasive phenotype is lost if MET expression is suppressed. Hypoxia also has been shown to sensitize HGF driven invasion through an as yet undefined molecular mechanism. The high mortality rate of metastatic cancer makes it crucial to understand the functional integration of these two prevalent drivers of metastasis, hypoxia and Met signaling, and to identify ways to selectively block cancer cell invasiveness. We show that hypoxia enhanced HGF-mediated invasion in the papillary renal cell (PRC) carcinoma cell lines ACHN and UOK112. Cells under hypoxic conditions accumulated high levels of ROS, which in turn sensitized the Erk pathway to enhance HGF-driven invasion. ROS accumulation was also associated with suppression of MAPK phosphatase DUSP2 mRNA. The other prevalent arm of Met mediated signaling, the PI3K/Akt pathway, normally drives cell survival and proliferation. In hypoxic conditions, however, Akt activation is suppressed by ROS mediated PP2a activation. This is accompanied by metabolic shift towards autophagy and decreased cell cycle progression. Thus hypoxia modifies HGF biologic program by enhancing invasion and suppressing proliferation. Identifying the specific effectors responsible for the integration these signaling pathways will improve our understanding of pro-metastatic invasiveness and potentially identify novels targets for its selective blockade.
Citation Format: Young H. Lee, Donald P. Bottaro. Hypoxia-mediated ROS enhances HGF-induced cancer cell invasion and suppresses cell cycle progression. [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 489. doi:10.1158/1538-7445.AM2014-489
Abstract 4890: Collagen 1 fibers are a key component in the establishment of distant pulmonary metastasis by breast cancer cells
Authors: Jacob Desmond , Kakkad Samata M. , Krishnamachary Balaji , Stasinopoulos Ioannis , Solaiyappan Meiyappan , Wildes Flonne , Glunde Kristine , Bhujwalla Zaver M. 
Published: May 2015

Abstract
We previously observed that silencing COX-2 significantly reduced the expression of degradative enzymes such as matrix metalloproteinase 1 (MMP1), and altered the expression of ECM components such as hyaluronan and lumican that play a role in intra-fibrillar collagen spacing [1]. We have also observed that primary human breast cancers that have metastasized have higher collagen 1 (Col1) fiber density and volume [2]. Here, for the first time, we have investigated Col1 fiber patterns in metastatic lung nodules established by metastatic MDA-MB-231 breast cancer cells and their subclone Clone 13 cells that express shRNA to significantly reduce, but not silence, COX-2 expression.
Second harmonic generation (SHG) microscopy studies were performed on H&E stained lung sections obtained from SCID mice five weeks post intravenous injection of MDA-MB-231 (five mice) and Clone 13 (three mice) human breast cancer cells. SHG images of 5-7 fields of view per mouse were acquired from the lung sections on an Olympus FV1000MPE multiphoton microscope, and analyzed for inter-fiber distance and percentage of fiber per metastatic area using in-house software [2]. Reducing COX-2 expression resulted in a significant reduction of metastatic lung burden in mice. Analysis of the Col1 fiber structures of similar sized metastatic nodules revealed significantly fewer fibers and larger inter fiber distance in lung nodules of mice injected with Clone 13 cells compared to parental MDA-MB-231 cells.
Reducing COX-2 resulted in the establishment of significantly fewer metastatic lung nodules with significantly sparser Col1 fibers. These data suggest that the ability to lay down Col1 fibers is a key requirement for the successful establishment of metastatic lesions. Reducing COX-2 expression in MDA-MB-231 breast cancer cells affects the ability of these cancer cells to lay down a Col1 fiber scaffold suitable for cancer cell growth in the lungs. These data identify new aspects of the role of Col1 fibers and COX-2 in the establishment of metastatic lesions.
References: [1] I. Stasinopoulos et al., Neoplasia (2008); [2] S. Kakkad et al., J Biomed Opt (2012).
This work was supported by NIH R01CA82337 and P50CA103175.
Citation Format: Desmond Jacob, Samata M. Kakkad, Balaji Krishnamachary, Ioannis Stasinopoulos, Meiyappan Solaiyappan, Flonne Wildes, Kristine Glunde, Zaver M. Bhujwalla. Collagen 1 fibers are a key component in the establishment of distant pulmonary metastasis by 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 4890. doi:10.1158/1538-7445.AM2014-4890
Abstract 4894: The HSP90 inhibitor ganetespib potentiates effect of ionizing radiation in human non-small cell lung cancer
Authors: Casal Roberto Gomez , Bhattacharya Chitralekha , Epperly Michael , Socinski Mark , Levina Vera 
Published: May 2015

Abstract
Background: Ionizing irradiation (IR) is used to treat NSCLC however; radiotherapy remains largely palliative due to radioresistance.
Recently, we reported that IR-resistant residual cells in NSCLC expresses a complex phenotype combining cancer stem cell (CSC) and the epithelial to mesenchymal transition (EMT) traits. The tyrosine kinase receptors (RTK) receptors, such as PDGFRa, EGFR FGFR and VEGFR, are expressed in nonrelated cells and IR-resistant residual cells. Moreover, PDGFRb is dramatically upregulated in IR resistant cells. Since all of these RTK receptors, as well as other oncogenic proteins are client proteins of the molecular chaperone HSP90a, NSCLC cells and specifically IR-resistant residual cells could be highly dependent on HSP90 and sensitive to HSP90 inhibition.
We hypothesize that inhibition of HSP90 will eliminate IR-resistant residual cells and sensitize NSCLC cells to IR treatment.
Methods/Results: HSP90 inhibitor Ganetespib, kindly provided by SYNTA Pharmaceuticals, was used in this study. A549 cells, primary human adenocarcinoma cells and primary normal human airway epithelial (HSAEC), were utilized. Using MTT and clonogenic assays we have demonstrated that ganetespib does not affect primary normal HSAEC cells, but suppresses the proliferation of NSCLC cells and potentiates the effect of IR treatment. Ganetespib inhibits the growth of lung tumor spheres. Using a wound healing assay we have determined that ganetespib inhibits motility of NSCLC cells and IR-resistant residual cells. We also have investigated the effect of ganetespib on cells cycle, apoptosis and DNA repair machinery in irradiated cells. Using a SCID mice model, we have demonstrated that ganetespib applied as monotherapy inhibits the growth of T2821 primary adenocarcinoma cells in vivo and significantly sensitizes T2821 tumors to IR-treatment.
Conclusion: The HSP90 inhibitor ganetespib potentiates the effect of IR in NSCLC and eliminates IR-resistant residual cells.
Note: This abstract was not presented at the meeting.
Citation Format: Roberto Gomez Casal, Chitralekha Bhattacharya, Michael Epperly, Mark Socinski, Vera Levina. The HSP90 inhibitor ganetespib potentiates effect of ionizing radiation in human non-small cell lung 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 4894. doi:10.1158/1538-7445.AM2014-4894
Abstract 49: Zinc finger protein 185 is a key molecule of liver metastasis in colon cancer
Authors: Furukawa Daisuke , Chijiwa Tsuyoshi , Matsuyama Masahiro , Mukai Masaya , Matsuo Ei-ichi , Nishimura Osamu , Kawai Kenji , Suemizu Hiroshi , Hiraoka Nobuyoshi , Nakagohri Toshio , Yasuda Seiei , Nakamura Masato 
Published: May 2015

Abstract
Colorectal cancer is among the three leading causes of cancer-related deaths worldwide. Nearly 50% of patients with colon cancer develop liver metastases. Mortality associated with the advanced stage of colon cancer has principally been attributed to the development of liver metastases. Therefore, clarifying the biological mechanisms underlying liver metastasis from colon cancer and accelerating the development of new treatment strategies are needed. We isolated Zinc finger protein 185 (ZNF185) as a metastasis-related protein by global quantitative proteome analysis of the in vivo liver metastasis model of super immunodeficient NOG mice with the highly liver-metastatic subline SW48-LM2 (Matsuo E, et al. AACR, #3947, 2008). LIM domain proteins have many fundamental biological processes including cell lineage specification, cytoskeleton organization, and organ development. ZNF185 is one of the LIM domain proteins and is considered to be involved in regulating cellular differentiation and/or proliferation. However, the functions and properties of ZNF185 in the multi-step process of cancer biology have not yet been elucidated in detail. In the present study, we analyzed the relationships between ZNF185 and the clinicopathological features of colon cancer (age, gender, histological type, lymphatic involvement, venous involvement, T and N statuses, liver metastasis, and stage). The expression of the ZNF185 protein was immunohistochemically analyzed. The expression of ZNF185 was detected in the cancer cells of 78 of 87 colon cancer patients. A correlation was observed between ZNF185 and the histological type (p=0.010, G-test). The expression of ZNF185 was also correlated with liver metastasis (p=0.030, G-test). Multivariate analysis using the Cox proportional hazards model was performed among the cause-specific survival rate, ZNF185 expression, and clinicopathological features. The histological type, liver metastasis, and ZNF185 expression were found to be independent prognostic indicators (p= 0.028, p&lt;0.0001, p=0.036, respectively). ZNF185 expression was found to be an independent indicator of liver metastasis and prognosis in colon cancer.
Citation Format: Daisuke Furukawa, Tsuyoshi Chijiwa, Masahiro Matsuyama, Masaya Mukai, Ei-ichi Matsuo, Osamu Nishimura, Kenji Kawai, Hiroshi Suemizu, Nobuyoshi Hiraoka, Toshio Nakagohri, Seiei Yasuda, Masato Nakamura. Zinc finger protein 185 is a key molecule of liver metastasis in colon 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 49. doi:10.1158/1538-7445.AM2014-49
Abstract 490: Investigation of telomere shortening caused by dyskeratosis congenita-associated heterozygous TIN2 mutations
Authors: Tran Duy C. , Frank Amanda K. , Xu Lifeng 
Published: May 2015

Abstract
The ends of eukaryotic chromosomes are composed of repetitive telomere sequences bound by the shelterin protein complex. Telomerase, a reverse transcriptase complex, is known to express in highly proliferative tissues and cells in humans to maintain a constant telomere length and to sustain their proliferative potential. Heterozygous missense mutations within one of the shelterin proteins, TIN2, have been identified in patients with Dyskeratosis Congenita (DC), a multiple stem-cell failure syndrome characterized by extremely short telomeres in affected patients. Our study aims to elucidate the mechanism by which TIN2 mutations shorten telomeres in human cells.
TIN2 is an essential protein that tethers the shelterin complex together. We generated HCT 116 colorectal cancer cell lines containing heterozygous TIN2 R282H mutation, one of the most common DC-related TIN2 mutations, by zinc-finger-nuclease facilitated gene editing. Clones with heterozygous TIN2 mutation showed progressive telomere shortening, while the wild-type (WT) clones showed no change in telomere length over extended cell proliferation. The progressive telomere shortening phenotype in TIN2 mutants can be rescued by exogenous expression of WT TIN2. However, TIN2 mutant clones do not contain elevated levels of deprotected telomeres, suggesting that the TIN2 mutation does not lead to overall telomere deprotection. We are currently investigating whether the DC-related TIN2 mutation induces telomere shortening by inhibiting telomerase or by accelerating telomere attrition through telomerase-independent mechanisms.
Citation Format: Duy C. Tran, Amanda K. Frank, Lifeng Xu. Investigation of telomere shortening caused by dyskeratosis congenita-associated heterozygous TIN2 mutations. [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 490. doi:10.1158/1538-7445.AM2014-490
Abstract 4903: Luteolin's role as a radiosensitizer by promoting cell death and ROS modulation
Authors: Ahn Kwang-Chul , Choi Jae Yeon , Hwang Sang-Gu , Um Hong-Duck , Park Jong Kuk 
Published: May 2015

Abstract
Radiotherapy is one of major cancer treatment, but radiation treatment could evoke resistance or side effects such as fibrosis. To overcome these obstacles against radiation treatment, many researchers are developing effective radiosensitizer. To develop a new radiosensitizer, we test whether luteolin has functions as a radiosensitizer candidate because previous studies already demonstrated luteolin could promote cancer cell death by reactive oxygen species (ROS) induction, and this phenomenon is one of main effects of radiation-induced cell death. Luteolin is 3′,4′,5,7-tetrahydroxyflavone, which could induce cell death of various cancer cells. We observed luteolin treatment could induce cell death of non-small cell lung cancer cells with independent manner of p53 and PTEN status, and combination treatment of radiation and luteolin enhance more cell death than those of radiation only or luteolin only treatment condition. Dose enhancement ratios of luteolin and radiation combination are 1.54 and 1.31 in NCI-H460 and NCI-H1299, respectively. Combined treatment with luteolin and radiation down-regulate Bcl-2 level and induce the phosphorylation of JNK and activation of caspase-3/9. ROS accumulation also was induced in combined condition of luteolin and radiations. In a xenograft assay, the combined luteolin and radiation group showed 27.2 days of growth delay versus the control in terms of tumor growth. The enhancement factor of this combined treatment was determined to be 3.2. Taken together, we conclude that luteolin contain role of radiosensitizer via promotion of cell death and ROS accumulation.
Citation Format: Kwang-Chul Ahn, Jae Yeon Choi, Sang-Gu Hwang, Hong-Duck Um, Jong Kuk Park. Luteolin's role as a radiosensitizer by promoting cell death and ROS modulation. [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 4903. doi:10.1158/1538-7445.AM2014-4903