bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C5: Epigenetic regulation of cancer stem cell marker CD133 by transforming growth factor-β
Authors: You Hanning , Rountree C. Bart 
Published: May 2012

Abstract
Background: Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. CD133, a trans-membrane glycoprotein, is an important cell surface marker for both stem cells and cancer stem cells in various tissues including liver. CD133 expression was recently linked to poor prognosis in HCC patients. CD133+ liver cancer cells are characterized by resistance to chemotherapy, self-renewal, multi-lineage potential, increased colony formation, and in-vivo cancer initiation at limited dilution. Recent studies demonstrate that CD133 expression is regulated by DNA methylation. In this paper, we explored the role of Transforming Growth Factor β (TGFβ), a multi-functional cytokine that plays a critical role in chronic liver injury, in the regulation of CD133 expression.
Materials and Methods: CD133- Huh7 cells were sorted from bulk cultured cells, CD133 expression was analyzed using flow cytometry, immuno-blots and real-time RT-PCR after the cells were treated with TGFβ1, DNA methyltransferase inhibitors and inhibitory Smads. Pyrosequencing was introduced to evaluate CD133 promoter-1 methylation status.
Results: TGFβ1 is capable of up-regulating CD133 expression specifically within the Huh7 HCC cell line in a time and dose-dependent manner. Furthermore, forced expression of inhibitory Smads, including Smad6 and Smad7, attenuated TGFβ1-induced CD133 expression. Within CD133-Huh7 cells, TGFβ1 stimulation inhibited the expression of DNA methyltransferases DNMT1 and DNMT3β, which are critical in the maintenance of regional DNA methylation; and global DNMT activity in CD133-Huh7 cells was inhibited by TGFβ1. DNMT3 inhibition by TGFβ1 was partially rescued with overexpression of inhibitory Smads. Lastly, TGFβ1 treatment led to significant demethylation in CD133 promoter-1 in CD133-Huh7 cells.
Conclusion: TGFβ1 is able to regulate CD133 expression through inhibition of DNMT1 and DNMT3 expression, and subsequent demethylation of promoter-1. The mechanism by which TGFβ induces CD133 expression is partially dependent on the Smads pathway.
Citation Information: Cancer Res 2009;69(23 Suppl):C5.
Abstract C57: The role of stromal cells in tumor metastases
Authors: Duyverman Annique , Duda Dan G. , Steller Ernst J.A. , Fukumura Dai , Jain Rakesh K. 
Published: May 2012

Abstract
Background: In 1889, Stephen Paget hypothesized that metastatic cells - the “seeds” - only grow in the secondary sites - the soil” - with a permissive microenvironment. Here, we show that the “seeds” can carry their own “soil” - activated fibroblasts from primary site of metastatic tumors. Moreover, we report that carryover of these non-malignant host-derived cells during metastatic cell colonization in the lungs can increase cancer's metastatic efficiency.
Materials and Methods: We use multiple animal models and two lung tumor cell lines (LLC1 and LA-P0297) to study the composition, origin and role of fragments shed by tumors in the metastatic process.
Results: We have shown that, in addition to single cells (81%), tumors shed fragments consisting of both tumor and host cells. We show that these fragments are more viable in the circulation compared to tumor cells alone (p&lt;0.05).When we selectively deplete the host cells in the tumor microenvironment the spontaneous formation of metastases is significantly reduced three weeks after primary tumor resection compared to control mice (p&lt;0.05). Next, survival was significantly increased when we deplete host-cells in mice with metastases after co-implantation of CAFs with LLC1, but had no effect in mice implanted with cancer cells alone (p&lt;0.01) Lastly, we have assessed the nature of these host stromal cells using immunohistochemistry and RT-PCR and identified them being of fibroblast origin.
Discussion: We found that tumor-associated stromal cells can escape primary tumors along with cancer cells, survive in blood circulation and in metastatic nodules. Pre-existence of a tissue-like structure in the form of heterotypic cell fragments may increase the viability of cancer cells in blood circulation and modulate metastasic efficiency. How this mechanism contributes to the organo-tropism of certain metastatic tumors is not known, but demonstration of the involvement of tumor “soil” in both the primary tumor as well as the metastatic site, has important conceptual and clinical implications for colonization during metastasis progression.
Citation Information: Cancer Res 2009;69(23 Suppl):C57.
Abstract C6: Barrett's esophagus and esophageal adenocarcinoma: A paradigm for the cancer stem cell model?
Authors: Grotenhuis Brechtje A. , Dinjens Winand N.M. , Sonneveld Petra , Sacchetti Andrea , Van Dekken Herman , Wijnhoven Bas P.L. , Van Lanschot Jan J.B. , Fodde Riccardo 
Published: May 2012

Abstract
Introduction: In recent years, accumulating experimental evidence has suggested that tumors have a hierarchical organisation where only a subset of parenchymal cells, the cancer stem cells (CSCs), has tumor-initiating properties. To date, several antibodies directed against surface antigens have been employed to prospectively isolate CSCs from a broad spectrum of malignancies, though not from esophageal adenocarcinoma. Here, we conducted a series of experiments to test whether Barrett's esophagus and esophageal adenocarcinoma may serve as a disease model for the cancer stem cell concept.
Methods: We employed a panel of previously established CSC markers (CD24, CD29, CD44, CD133, CD166, EpCAM) for immunohistochemistry (IHC) analysis and in vivo transplantation assays. Transplantation of serially diluted bulk cancer cells of human tumors into NOD-SCID mice was performed to investigate the presence of CSCs in esophageal adenocarcinoma. Analogous assays were carried out by injecting esophageal cancer cells sorted by FACS using the same panel of CSC markers as employed for IHC analysis.
Results: IHC revealed that the intensity of CD24 and CD29 staining tended to increase along the metaplasia — dysplasia — carcinoma sequence. Cells positive for CD24 or CD29 were mainly located in the basal compartment of the metaplastic and dysplastic epithelium. CD44 showed membranous staining mainly in adenocarcinomas, whereas CD166 revealed pronounced cytoplasmic staining in all stages.
Serial transplantation experiments with bulk tumor cells indicated that the frequency of tumor-initiating cells in the Lin- population of esophageal adenocarcinoma is approximately 1:50,000 cells. However, to date no tumor growth was observed when tumor cells of subpopulations expressing the above-described CSC markers were transplanted at lower multiplicities.
Conclusions: Tumor-initiating cells in esophageal adenocarcinoma are rare, reflecting a hierarchal organisation. However, surface-antigens that have been established as CSC markers in other malignancies do not seem to enrich for tumor initiating cells in esophageal adenocarcinoma.
Citation Information: Cancer Res 2009;69(23 Suppl):C6.
Abstract C60: The integrative genomics viewer
Authors: Robinson James , Thorvaldsdottir Helga , Nazaire Marc-Danie , Winckler Wendy , Reich Michael , Getz Gad , Mesirov Jill 
Published: May 2012

Abstract
Rapid improvements in next generation sequencing and array-based profiling methods have created a paradigm shift in how scientists approach the study of the cancer genome. Projects such as The Cancer Genome Atlas (TCGA) are harnessing these advances to probe the cancer genome at unprecedented resolution, generating comprehensively catalogs of the genetic alterations of hundreds of tumors.
Visualization plays an important role in assimilating the large, muti-modal datasets produced by TCGA and similar projects. To be maximally effective tools must flexibly integrate genomic, functional, and phenotypic data from a variety of platforms, and efficiently handle large datasets. To address these critical challenges we developed the Integrative Genomics Viewer (IGV), a flexible, scalable, high-performance tool for the concurrent visualization of multiple large scale datasets. The IGV supports integrated views of any data type that can be mapped to genomic coordinates, including, but not limited to, next generation sequence data, copy number, gene expression, RNAi, ChIP-seq, RNA-seq, and genome annotations. Data can be annotated, filtered, grouped, and sorted according to clinical and phenotypic attributes.
A particular strength of IGV is its ability to handle very large datasets, for example deep coverage sequence data from whole genome scans, or highresolution copy number data from thousands of samples, on standard desktop computers. IGV permits the user to move seamlessly across these datasets at any level of detail, and quickly zoom out to whole genome or drill down to base pair resolution. The ability to dynamically and flexibly integrate multiple data modalities and view them at any scale allows the user to elucidate complex biological relationships that would not otherwise be apparent.
The IGV is freely available without restriction. It is currently under active development and use in The Cancer Genome Atlas, 1000 Genomes Project, and other large genomic projects.
Citation Information: Cancer Res 2009;69(23 Suppl):C60.
Abstract C61: Reducing cancer incidence and mortality in African American, Arab American, and Chaldean communities in the Detroit metropolitan area utilizing a community-based participatory process
Authors: Dykes Vicky A. , Akhtar Adil , Berry Stanley , Jaiyesimi Ishmael , Douglas-Nikitin Vonda , Shetty Sugandh , Vicini Frank A. , Fakhouri Monty 
Published: May 2012

Abstract
Purpose: We reviewed the impact of a community based participatory process (CBPP) addressing cancer education, prevention, and screening in two ethnic/minority populations to determine their impact on personal health related decisions.
Materials and Methods: From 2005 – 2008, 2,281 community members participated in CBPP outreach efforts (cancer education, prevention and screening forums) conducted by the Beaumont Cancer Institute in cooperation with the Arab American and Chaldean Council, the National Cancer Institute and the American Cancer Society. The study population consisted of 1,067 (46.7%) individuals completing a post-cancer forum survey: 642 (60.2%) from the African American (AA) and 425 (39.8%) from the Arab American & Chaldean (AAC) communities. Data were collected on behavioral intent and knowledge including: (1) forum content, (2) participants' cancer screening history, (3) symposium logistics (4) educational materials and (5) participation in subsequent cancer screening tests.
Results: After attending at least one cancer education forum, 329 (30.8%) of the 1,067 participant respondents (14.4% of all attendees) underwent some type of cancer screening: 108 women (10.1%) underwent a screening mammogram, and 94 (8.8%) a pap smear. Thirty-eight men underwent (3.6%) a screening PSA, and 89 (8.3%) had other forms of cancer screenings (e.g. colonoscopy). Overall, 60.2% of AA versus 35% of ACC attendees completed a post-survey and 19.6% of AA versus 10% of AAC attendees underwent some type of cancer screening.
Conclusions: The results of this study suggest that CBPP's based around perceived and/or serious diseases negatively affecting a target population can positively impact their personal health related decisions.
Citation Information: Cancer Res 2009;69(23 Suppl):C61.
Abstract C63: Structure of the Skp1-Fbx4 complex reveals a new class of the SCF ubiquitin ligase
Authors: Li Yunfeng , Hao Bing 
Published: May 2012

Abstract
Ubiquitin-mediated proteolysis governs the levels of many cellular proteins via a triple-enzyme cascade, involving ubiquitin-activating (E1), conjugating (E2) and ligating (E3) activities. The E3 ligases recruit both E2 and specific substrates and catalyze the final step in ubiquitination reaction. SCF complexes are the largest family of E3 ubiquitin-protein ligases that consist of Cul1, Rbx1, Skp1 and a member of the F-box protein family. F-box proteins are the substrate-recognition components of SCF; they interact with Skp1 through the N-terminal ∼40-residue F box motif, to recruit substrates through their variable C-terminal protein-protein interaction domains, including WD40 repeats (Fbxw subfamily), leucine-rich repeats (LRRs; Fbxl subfamily) and other different or unknown domains (Fbxo subfamily).
Fbx4, which is the F-box protein responsible for the recognition of cell-cycle regulator cyclin D1 and telomeric DNA-binding protein Pin2, belongs to the Fbxo family that lack recognizable protein-protein interaction motif in their C-terminus. Reduced Fbx4 expression appears to be responsible, at least in part, for overexpression of cyclin D1 in human cancers. On the other hand, overexpression of Fbx4 in human cells promotes degradation of endogenous Pin2 and results in progressive telomere elongation. In order to define the fundamental structural properties of Fbx4, we have determined the crystal structure of the human Fbx4 protein in complex with Skp1 by single-wavelength anomalous dispersion method. The structure of the binary complex reveals that Skp1 and the F-box domain of Fbx4 retain the same overall fold as in other Fbxl and Fbxw structures determined, and that binding of the F box to Skp1 is very similar to that in other Skp1-F box complexes. Interestingly, the C-terminal domain of Fbx4 is projected away from Skp1 and F box, to adopt an α/β fold with a seven-stranded β sheet surrounded by seven α helices, which is distinct from LRR (in Fbxl) and WD40 (in Fbxw), reinforcing the notion that Fbx4 represents a new family of substrate-recognition subunits in SCF E3s. Moreover, mutagenesis experiments have revealed a potential substrate-binding site in Fbx4 C-terminal domain. Taken together, our structural and biochemical data provide a framework for understanding the molecular mechanism of substrate recognition by the SCFFbx4 ubiquitin ligase.
Citation Information: Cancer Res 2009;69(23 Suppl):C63.
Abstract C65: Mechanisms to maintain extra centrosomes in cancer cells
Authors: Godinho Susana A. , Kwon Mijung , Ganem Neil J. , Pellman David 
Published: May 2012

Abstract
Multiple centrosomes in tumor cells create the potential for multipolar divisions that can lead to aneuploidy and cell death. Nevertheless, many cancer cells successfully divide because of mechanisms that suppress multipolar mitoses. Using a genome-wide RNAi screen in Drosophila S2 cells, we defined several mechanisms that suppress multipolar mitoses. We also found that HSET, a normally non-essential kinesin motor was essential for the viability of cancer cells containing extra centrosomes. Interestingly, using fibronectin micropatterns, we found that interphase cell shape and adhesion pattern can determine the success of the subsequent mitosis in cells with extra centrosomes. Thus, cell adhesion is an important morphological feature that contributes to centrosome clustering. Importantly, during tumor progression, changes in cell architecture and adhesion patterns, such as loss of E-cadherin and acquisition of an elongated cell shape, are often observed. This is referred to as the epithelial-to-mesenchymal transition (EMT). The presence of extra centrosomes is often correlated with more malignant tumors, which lost their epithelial phenotype most likely through EMT. Thus, we hypothesized that the ability of cells to cluster extra centrosomes varies between epithelial cells and non-epithelial cells. To test this idea we used a panel of non-transformed mammalian epithelial and non-epithelial cell lines and quantified their ability to cluster extra centrosomes. We treated cells with DCB to generate tetraploid cells containing extra centrosomes and followed them by live-cell imaging. We found that non-epithelial cells cluster their extra centrosomes much more efficiently than epithelial cells. This finding suggests that loss of cell-cell adhesion might facilitate centrosome clustering. Consistent with this idea, our preliminary data indicate that induction of EMT in the epithelial cell lines MCF10A and MDCK increases the number of tetraploid cells that undergo a bipolar mitosis. We propose that changes that take place during tumor progression, such as loss of cell-cell adhesion, might facilitate centrosome clustering and therefore increase the ability of cancer cells to maintain extra centrosomes. We are currently investigating the nature of the changes that occur during EMT that facilitate centrosome clustering.
Citation Information: Cancer Res 2009;69(23 Suppl):C65.
Abstract C67: Hypoxia-inducible factor-2α regulates macrophage functions in both acute and tumor inflammation
Authors: Imtiyaz Hongxia Zhang , Williams Emily P. , Hickey Michele M. , Patel Shetal A. , Durham Amy C. , Yuan Li-Jun , Keith Brian , Simon M. Celeste 
Published: May 2012

Abstract
Hypoxia and inflammation in the tumor microenvironment profoundly influence carcinogenesis and tumor progression. In order to connect hypoxic signaling to inflammatory responses and their roles in oncogenesis, we investigated how one of the master regulators of hypoxic hypoxia-inducible factor (HIF)-2α, adaptations, regulates macrophage functions in both acute inflammatory diseases and cancer (a disease involving various inflammatory components). Myeloid-specific deletion of HIF-2α results in defective expression of a panel of proinflammatory cytokines in macrophages responding to innate stimuli. Also, mice lacking myeloid HIF-2α are resistant to lipopolysaccharide-induced endotoxemia and display a marked inability to mount inflammation in response to several other acute irritants, revealing that this transcription factor is essential for macrophage inflammatory responses. Tumor-associated macrophages (TAMs) represent the major inflammatory cell type within tumors and HIF-2α is robustly expressed in these cells. Clinically, increased TAM HIF-2α level correlates with high tumor grade and poor prognosis in breast and uterine cervical cancer, respectively. To characterize roles of HIF-2α in TAMs, we induced hepatocellular carcinoma (HCC) and colitis-associated cancer (CAC), two established inflammation-associated tumor models, in mice lacking myeloid HIF-2α expression. Interestingly, we found that HIF-2α -deficient TAMs migrate less efficiently into tumors, leading to reduced tumor cell proliferation and decreased malignancy in mutant mice. Further studies revealed that the deficient macrophages were attributable to compromised migration capacity of HIF-2α to insufficient expression of M-CSF receptor, CXCR4 and extracellular fibronectin-1. Therefore, our study demonstrated HIF-2α as an important regulator in both acute inflammation and cancer, suggesting that the myeloid HIF-2α pathway could be exploited as therapeutic targets for treating these diseases.
Citation Information: Cancer Res 2009;69(23 Suppl):C67.
Abstract C68: Using a chemical genetic approach to define the role of CDK2 in normal and transformed cell lines
Authors: Huskey Noelle E. , Horiuchi Dai , Kusdra Leonard , Zhang Chao , Shokat Kevan , Goga Andrei 
Published: May 2012

Abstract
Cyclin dependent kinases (CDKs) drive progression through the eukaryotic cell cycle, making them an attractive target for cancer therapeutics. In particular, CDK2 is thought to regulate mammalian S-phase entry and progression, and frequently shows increased activity in a variety of tumors. Surprisingly, recent studies using conventional genetic approaches suggest that CDK2 is dispensable for cellular proliferation, both during normal development and in malignant cell lines. Here we use an alternative chemical genetic approach to determine whether acute ablation of CDK2 activity has the same affect as genetic deletion. We have replaced the endogenous CDK2 allele in mouse embryonic fibroblasts (MEFs) with a mutant analogue sensitive CDK2 allele, allowing us to selectively inactivate CDK2 using bulky ATP analogs. In contrast to genetically deleting CDK2, the acute inhibition of CDK2 resulted in severe defects in proliferation of non-transformed MEFs, as well as MEFs that were transformed using various oncogenes. These findings reveal a requirement for CDK2 in mammalian cell proliferation and suggest its potential as a therapeutic target in tumor cells.
Citation Information: Cancer Res 2009;69(23 Suppl):C68.
Abstract C69: Elastic properties of highly metastatic cells using nano-capillary wrinkling
Authors: Hurth Cedric , Pratap Divya , Yang Jianing , Zenhausern Frederic 
Published: May 2012

Abstract
We have adapted an existing emerging method to characterize elastic properties of thin (30–150 nm) polystyrene (PS) films based on the observation of the wrinkling patterns of the film (J. Huang et al, Science 2007, 317, 650–653). Our goal is to evaluate the stiffness of cell layers cultured on top of such polystyrene films when they enter metastasis as compared to healthy epithelial cells. Recent reports using atomic force microscopy (AFM) suggest differences in cell stiffness at the local single cell level (J.K. Gimzewski et al, Nature Nanotechnology 2007, 2, 780–783). We plan to measure similar properties when cells are arranged in a sheet and compare them to AFM measurements. A relevant system is the melanoma cell lines such as A 375 and SK-Mel28, for instance. We characterized the wrinkling patterns obtained using a stereomicroscope to provide a first straightforward assessment of the elastic properties by counting the number of wrinkles and measuring their average lengths. By comparing the wrinkling pattern when either healthy or melanoma cells are grown on top of the thin PS films to that obtained when bare thin PS film floats on water and developing a theoretical model based on 2 films of different but close Young moduli associated in parallel, one can extract quantities of interest to characterize the elastic properties of normal vs. cancer cells. In addition, we propose to use digital holographic microscopy (DHM) to improve the observation of the wrinkling patterns and allow access to other relevant viscoelastic information such as relaxation of the films. Because we propose an innovative technique coupled with an emerging form of microscopy yet unexplored for cancer research, i.e. DHM, to study the mechanical elastic forces within an interconnected assembly of metastatic cells with the goal of complementing current methods of clinical diagnostic, we hope to answer the current need for new ways of studying the mechanisms of cancer.
Citation Information: Cancer Res 2009;69(23 Suppl):C69.