bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2383: IL-6 and RANTES mediate the cross-talk between tumor cells and CAFs in the esophageal tumor microenvironment
Authors: Karakasheva Tatiana A. , Soni Monica , Waldron Todd , Rustgi Anil K. 
Published: August 2015

Abstract
Desmoplasia, or deposition of connective tissue proper in the stroma, is a key characteristic of esophageal squamous cell carcinoma (ESCC). The cellular component of connective tissue proper is comprised of fibroblasts, and cancer-associated fibroblasts (CAFs) are widely recognized as a major constituent of the tumor microenvironment (TME). The purpose of this study was to identify tumor-promoting factors that are secreted as a result of the crosstalk between CAFs and tumor cells in ESCC.
We have performed a comprehensive cytokine array and found that IL-6 and RANTES (also known as CCL5) are significantly overexpressed in conditioned media from co-culture of esophageal CAFs and ESCC cells, compared to mono-culture. Both proteins are known to play important roles in the development of multiple types of cancer, mostly via activation of the STAT3 signaling pathway. We have demonstrated that co-culture with fibroblasts prompts the ESCC cells to acquire a more mesenchymal phenotype and express potent mediators of cell migration and invasion, such as matricellular proteins (periostin, fibrillin, osteonectin) and hepatocellular growth factor (HGF). Furthermore, knockdown of IL-6 suppresses invasiveness and proliferation of human ESCC cells in our 3D organotypic culture model. We have also performed staining of tissue samples from ESCC patients and found that, compared to normal esophagus, expression of IL-6 and RANTES is enhanced in ESCC in both epithelial cells and fibroblasts.
In summary, our findings indicate that IL-6 and RANTES are responsible for migration and invasion of ESCC cells promoted by CAFs in the tumor microenvironment. This is the first report of such a dual induction of these specific cytokines in ESCC, and it provides a rationale for dual inhibition of IL-6 and RANTES as novel therapy for ESCC, and possibly other types of cancer.
Supported by NCI P01 CA098101.
Citation Format: Tatiana A. Karakasheva, Monica Soni, Todd Waldron, Anil K. Rustgi. IL-6 and RANTES mediate the cross-talk between tumor cells and CAFs in the esophageal tumor microenvironment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2383. doi:10.1158/1538-7445.AM2015-2383
Abstract 2392: Hyaluronan-dependent growth of human triple negative breast cancer MDA-MB-468 in mouse xenograft models
Authors: Zhao Chunmei , Marella Mathieu , Zimmerman Susan , Huang Lei , Shepard H. Michael , Huang Zhongdong 
Published: August 2015

Abstract
Hyaluronan (also known as hyaluronic acid or HA) is a nonsulfated glycosaminoglycan in the extracellular matrix. Elevated levels of HA in the tumor microenvironment have been associated with poor prognosis of several human cancers, including pancreatic, breast, colon and prostate. In many cases of breast cancer, HA is found to be associated with the stromal compartment. To understand the interaction between tumor cells and HA containing stromal compartment, we engineered a HA-high stromal cell line by overexpressing the human HAS3 gene in Balb/c 3T3 fibroblast cells. In vitro, the 3T3/HAS3 cells produced and secreted HA, which was shown to bind to the HA-low/CD44-high breast cancer cell line MDA-MB-468 at the cell surface. When co-grafted with MDA-MB-468 cells in mice, 3T3/HAS3 cells promoted the in vivo growth of MDA-MB-468 cells. Furthermore, depletion of HA with PEGPH20 (a pegylated form of the recombinant human PH20 protein) significantly inhibited the growth of MDA-MB-468 cells co-grafted with 3T3/HAS3 cells, suggesting that the HA provided by 3T3/HAS3 cells is critical for the growth of MDA-MB-468 cells in vivo. Immunohistochemical analysis of tumor xenograft samples showed that HA-low MDA-MB-468 cells were surrounded by HA-high stromal cells, resembling the tumor morphology observed in certain breast cancer patients. To model for breast cancers with tumor cell-associated HA, we overexpressed the human HAS3 gene directly in MDA-MB-468 cells. The in vivo growth of MDA-MB-468 was significantly enhanced by HAS3 overexpression. Depletion of HA by PEGPH20 synergized with Abraxane and improved its anti-cancer efficacy in the MDA-MB-468/HAS3 xenograft model compared to PEGPH20 and Abraxane alone. Taken together, we have developed tumor xenograft models that mimic HA-high breast cancers and can be used to test the pharmacological activity of anticancer agents. Further characterization of these models will provide insights into the understanding of the mechanisms by which increased levels of HA and the associated changes in the tumor microenvironment promote the disease progression in breast cancer and how depletion of HA can interfere with this process and synergize with chemotherapies to inhibit tumor progression.
Citation Format: Chunmei Zhao, Mathieu Marella, Susan Zimmerman, Lei Huang, H. Michael Shepard, Zhongdong Huang. Hyaluronan-dependent growth of human triple negative breast cancer MDA-MB-468 in mouse xenograft models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2392. doi:10.1158/1538-7445.AM2015-2392
Abstract 2393: PDAC cells release BAG3 that activates a paracrine loop with stromal macrophages
Authors: Rosati Alessandra , Basile Anna , D'Auria Raffaella , d'Avenia Morena , De Marco Margot , Falco Antonia , Festa Michelina , Guerriero Luana , Iorio Vittoria , Pascale Maria , Franco Renato , Arra Claudio , Barbieri Antonio , Rea Domenica , Menichini Giulio , Hahne Michael , Bijlsma Marteen , Barcaroli Daniela , Tuveson David A. , Todoric Jelena , Karin Michael , De Laurenzi Vincenzo , Turco Maria Caterina 
Published: August 2015

Abstract
Interactions between cancer cells and stromal cells are critically involved in tumor formation, progression and development of metastasis. Here we report for the first time that human pancreatic adenocarcinoma (PDAC) cells secrete BAG3 that binds and activates macrophages, inducing their activation and the secretion of pancreatic cancer- supporting factors. We also identify IFITM-2 as a BAG3 receptor, by its co-precipitation with BAG3 from macrophage cell membrane and by impairment of BAG3- induced activation in IFITM-2- silenced macrophages. Finally we show the importance of this pathway in vivo since in nu/nu mice carrying orthotopic xenografts of human PDAC (MIA PaCa-2) cells, BAG3 sequestration by an anti-BAG3 antibody results in reduced tumor growth and prevents metastastasis formation. In conclusion we have identified a novel paracrine loop involved in PDAC growth and metastatic spreading and shown that its pharmacological blockage with an anti-BAG3 antibody has therapeutic potential.
Citation Format: Alessandra Rosati, Anna Basile, Raffaella D'Auria, Morena d'Avenia, Margot De Marco, Antonia Falco, Michelina Festa, Luana Guerriero, Vittoria Iorio, Maria Pascale, Renato Franco, Claudio Arra, Antonio Barbieri, Domenica Rea, Giulio Menichini, Michael Hahne, Marteen Bijlsma, Daniela Barcaroli, David A. Tuveson, Jelena Todoric, Michael Karin, Vincenzo De Laurenzi, Maria Caterina Turco. PDAC cells release BAG3 that activates a paracrine loop with stromal macrophages. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2393. doi:10.1158/1538-7445.AM2015-2393
Abstract 24: The phosphorylation of p53 at serine 46 is essential to induce cell death through palmdelphin in response to DNA damage
Authors: Dashzeveg Nurmaa Khund , Yoshida Kiyotsugu 
Published: August 2015

Abstract
Tumor suppressor p53 plays a pivotal role in cell cycle arrest, DNA repair, and apoptosis in response to DNA damage. Promoter selectivity of p53 depends mainly on post-translational modification. Notably, the apoptotic function of p53 is related to its phosphorylation at serine-46 (ser46) to promote pro-apoptotic genes. However, little is known about the pro-apoptotic genes induced by Ser46 phosphorylation. Our research achieved to investigate the pro-apoptotic genes induced by p53 in a phospho-ser46-specific manner using microarray and ChIP sequencing in human cancer cell lines. As a result, palmdelphin (PALMD), an isoform of paralemmin protein, was strongly elicited from the phosphorylation of ser46. The mRNA and protein expression of PALMD increased only in wild type p53 transfected cells, but not in ser46-mutated cells. Importantly, PALMD moved to the nucleus in response to DNA damage and the apoptotic function of PALMD was tightly exerted with localization into nucleus. Interestingly, down-regulation of PALMD by siRNA resulted in necroptosis-like cell death through ATP depletion. Moreover, we found vimentin as a PALMD interacting protein and the depletion of vimentin increased PALMD level to accelerate apoptosis. These results demonstrate that p53 regulates cell death fate (apoptosis or necroptosis-like cell death) through promoting PALMD expression in a phospho-ser46-specific manner in response to DNA damage.
Citation Format: Nurmaa Khund Dashzeveg, Kiyotsugu Yoshida. The phosphorylation of p53 at serine 46 is essential to induce cell death through palmdelphin in response to DNA damage. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 24. doi:10.1158/1538-7445.AM2015-24
Abstract 2418: A comparison of NVP-AUY-922 (AUY) and Geldenamycin (G) in human tumor primary culture microspheroids
Authors: Nagourney Robert Alan , Bernard Paula J. , Francisco Federico , Cule Meghan , Wexler Ryan , Evans Steven S. 
Published: August 2015

Abstract
Introduction: Molecular chaperone heat shock protein 90 (HSP 90) maintains the stability and function of client proteins essential for malignant transformation. The ansamycin Geldenamycin (G) and its derivative 17-AAG are potent HSP90 inhibitors with activity observed in human tumors. The resorcinol-based HSP90 inhibitor AUY offers advantages with regard to solubility & DT-diaphorase independence. To evaluate and compare the activity of AUY & G we conducted ex vivo analysis of programmed cell death (EVA/PCD™) on microspheroids isolated from fresh human tumor specimens. Methods: The EVA/PCD™ method as previously reported (Nagourney, RA Anticancer Res. 2012) isolates microspheroids of desired size by mechanical & enzymatic disaggregation followed by precise density centrifugation. Drug activity is measured by delayed loss of membrane integrity & ATP content (luciferase). Lethal concentration (LC50) values are interpolated from 5-point dose response curves and compared by modified Z-Score. Concentrations ranges for AUY were 6.25-100 uM and for G 1.25-20 uM. Results: AUY and G activity compared in 22 parallel analyses by Pearson Moment revealed a correlation coefficient R = 0.59 (p &lt;0.005). Activities for AUY & G by disease were generally similar favoring Heme &gt;Sarcoma &gt;Melanoma &gt;Ovary&gt;NSCLC&gt;Breast. ERBB2 (+) breast appeared more sensitive as did several EGFr mutation (+) NSCLC specimens. Metachronous assays conducted in 3 EGFr (+) NSCLC pts revealed activity for G following Erlotinib failure. Additional studies with AUY alone and in combination are underway. Conclusions: i) HSP-90 inhibitors are active in human tumor primary cultures ii) AUY and G activity correlate iii) HSP90 inhibitor activities reveal disease & patient-specific profiles iv) EVA/PCD™ analyses could facilitate the development of clinical strategies for the use of HSP90 inhibitors. Supported by The Vanguard Cancer Foundation & The Nagourney Institute. NVP-AUY-922 was the kind gift of Novartis AG.
Citation Format: Robert Alan Nagourney, Paula J. Bernard, Federico Francisco, Meghan Cule, Ryan Wexler, Steven S. Evans. A comparison of NVP-AUY-922 (AUY) and Geldenamycin (G) in human tumor primary culture microspheroids. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2418. doi:10.1158/1538-7445.AM2015-2418
Abstract 2422: Pan-pim kinases inhibitor, AZD1208 suppresses tumor growth and synergistically interacts with an AKT inhibitor in gastric cancer cells
Authors: Lee Miso , Lee Kyung-Hun , Min Ahrum , Kim Jungeun , Im Seock-Ah , Kim Seon-Gyeong , Jang Hyemin , Yang Yae-Won , Kim Tae-Yong , Han Sae-Won , Oh Do-Youn , Kim Tae-You , Bang Yung-Jue 
Published: August 2015

Abstract
Introduction: Pim kinases are highly conserved serine/threonine kinases that control proliferation and survival pathways in cancer cells. Different expression patterns of each isoforms (Pim-1, Pim-2, and Pim-3) have been observed in various types of human cancer including gastric cancer. AZD1208 is a potent and selective inhibitor that affects all three isoforms of Pim. We investigated the effect of AZD1208 as a single agent or in combination with an Akt inhibitor on the growth and cell death in gastric cancer cells.
Materials and Methods: The antitumor activity of AZD1208 with/without an Akt inhibitor was evaluated in a large panel of gastric cancer cell lines through growth inhibition assay. The underlying mechanism was also examined by western blotting, immunofluorescence assay (IFA), and cell cycle analysis.
Results: Direct substrates of Pim kinases were downregulated by the treatment with AZD1208, but we could not find any reduction of cell viability in short-term cell cultures. In contrast, cell viability decreased significantly in long-term cultures. Light chain 3B (LC3B), a marker for autophagy, increased in sensitive cells in dose dependent manner with AZD1208 treatment, which suggest that the growth inhibition effect of AZD1208 was achieved through autophagy, but not through apoptosis. Moreover, we found that ATM and Chk2, two critical components of the DNA repair pathway, were activated in an AZD1208-resistant cell line. We also confirmed that the combination of an Akt inhibitor with AZD1208 produced a highly synergistic effect in gastric cancer cell lines.
Conclusion: AZD1208 induced cell death through autophagy in gastric cancer cells. Additionally, the combination of AZD1208 with an Akt inhibitor shows synergistic antitumor effects.
Citation Format: Miso Lee, Kyung-Hun Lee, Ahrum Min, Jungeun Kim, Seock-Ah Im, Seon-Gyeong Kim, Hyemin Jang, Yae-Won Yang, Tae-Yong Kim, Sae-Won Han, Do-Youn Oh, Tae-You Kim, Yung-Jue Bang. Pan-pim kinases inhibitor, AZD1208 suppresses tumor growth and synergistically interacts with an AKT inhibitor in gastric cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2422. doi:10.1158/1538-7445.AM2015-2422
Abstract 2444: Directed evolution strategy for generating of novel zinc finger peptides with affinity for gapped DNA
Authors: Plaskon Dylan , Guerra Rachel M. , McGuckin Connor P. , Lopez Ruiz Vania , Sheehan Colin T. , Weeks Ryan A. , Cincotta Dylan , Rice Kevin P. 
Published: August 2015

Abstract
A significant fraction of oncologists’ chemotherapeutic arsenal consists of agents that cause DNA damage. Repair proteins that recognize aberrant DNA structural features mitigate this damage and thus the efficacy of such anticancer drugs. DNA damage recognition is also crucial for genomic stability, and thus avoidance of carcinogenesis, in healthy cells. The DNA repair enzymes poly(ADP-ribose) polymerase (PARP) and DNA ligase III use similar zinc finger motifs to facilitate this sequence-independent DNA recognition. Reported here is a strategy to model these protein-DNA interactions using small proteins. Proteins with high affinity for gapped DNA are selected from highly diverse libraries of proteins, based on PARP-like zinc finger domains, using phage display. These populations were engineered at the DNA level, using two parallel approaches, with built-in randomization then cloned into viral chromosomes. The de novo approach involved synthetic oligonucleotides with specific random codons. In addition, the gene encoding the second PARP zinc finger was cloned from human cells and subjected to 30 cycles of error-prone PCR with a mutation rate of 0.02 per nucleotide. From each approach, a library of approximately 10 billion distinct phage-displayed variants is exposed to immobilized DNA molecules featuring a gapped DNA construct. Selected molecules are either identified by DNA sequencing or subjected to further selection after amplification in bacterial culture. A preliminary selection against nicked DNA yielded a single, truncated peptide after four rounds of selection. In subsequent experiments, Illumina sequencing will identify consensus sequences that will be cloned into plasmids appropriate for expression in bacteria. Molecules discovered by this strategy will help illuminate the structure-function relationships of proteins that recognize distinct DNA structures and may lead to new anticancer approaches.
Citation Format: Dylan Plaskon, Rachel M. Guerra, Connor P. McGuckin, Vania Lopez Ruiz, Colin T. Sheehan, Ryan A. Weeks, Dylan Cincotta, Kevin P. Rice. Directed evolution strategy for generating of novel zinc finger peptides with affinity for gapped DNA. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2444. doi:10.1158/1538-7445.AM2015-2444
Abstract 2445: DNA recognition by XR5944, a novel bis-intercalator and potent anticancer drug
Authors: Lin Clement , Mathad Raveendra I. , Sidell Neil , Yang Danzhou 
Published: August 2015

Abstract
DNA is a major target for drugs used in cancer therapy. However, DNA interactive chemotherapeutics are limited by adverse effects due to their poor selectivity. The bis-phenazine compound XR5944 is a DNA bis-intercalator and potent anticancer drug which reached phase I clinical trials. The DNA binding mode and mechanism of XR5944 are unique, allowing it to recognize and bind the estrogen response element (ERE) sequence to inhibit ERα activity and making it highly effective against ER-positive breast cancer in vitro. Understanding XR5944's novel mechanism of DNA recognition may allow the further development of anti-cancer agents capable of overcoming drug resistance to current anti-estrogen treatments by directly targeting transcriptional control, bypassing the hormone-receptor complex currently targeted by anti-estrogen treatments. In this study, we used nuclear magnetic resonance (NMR) spectroscopy to determine the structure of XR5944 in complex with its preferred DNA duplex sequence identified its binding mode. The structure of the 2:1 complex of XR5944 with the naturally occurring TFF1-ERE exhibits several unexpected features. Our NMR structure shows the two phenazine moieties are well stacked and the carboxamide amino linker lies in the major groove of DNA. At both binding sites in the 2:1 complex, XR5944 intercalates strongly at one site but weakly at the other. The binding sites within a native promoter sequence appear to be context- and sequence- dependent. Taken together, our results highlight that the DNA binding of a bis-intercalator is different from the simple addition of two single intercalation sites. Our study suggests that improved XR5944 derivatives targeting EREs may be designed through optimization of aminoalkyl linker and intercalation moieties.
Citation Format: Clement Lin, Raveendra I. Mathad, Neil Sidell, Danzhou Yang. DNA recognition by XR5944, a novel bis-intercalator and potent anticancer drug. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2445. doi:10.1158/1538-7445.AM2015-2445
Abstract 2452: Deorphanizing TLX: Implications for treatment of glioblastomas
Authors: Benod Cindy C. , Villagomez Rosa , Webb Paul 
Published: August 2015

Abstract
Nuclear receptors (NRs) are important ligand-dependent transcriptional factors. Presently, no natural or synthetic ligand has been identified for a large group of so- called “orphan” NRs. The orphan NR tailless (TLX, NR2E1), a transcriptional repressor, is a major player in neurogenesis and emerging evidence indicates that it is an excellent target to treat Neural Stem Cell (NSC) derived brain tumors and glioblastomas. Indeed, several groups hypothesized that small molecules de-repressing TLX activity in glioblastoma cells should slow tumor progression and invasiveness by inducing the cyclin-dependent kinase inhibitor p21 and the tumor suppressor pten. Until recently, no chemical probes to modulate TLX activity to test this hypothesis were available, and it was not clear whether TLX was druggable. Our homology models of the TLX ligand binding domain (LBD) suggest that TLX belongs to an emerging class of NRs that lack two LBD helices and fold into an auto-repressed conformation. While our models suggests that TLX could harbor a ligand binding pocket, the consequences of its unusual organization for small molecule development were unknown. We used a medium throughput screening strategy to assess TLX ligand binding capacity. We investigated direct binding of 20,000 compounds to purified human TLX protein and verified interactions with a secondary (orthogonal) assay. We then assessed effects of verified binders on TLX activity. As a result, we reported three compounds that bind to TLX with affinities in the high nanomolar to low micromolar range and enhance TLX transcriptional repressive activity. Based on this study, we could conclude that TLX is druggable. We are now investigating how to de-repress TLX transcriptional activity using derivatives of these small molecules. We are imaging the mode of binding of the three identified ligands and discovering surfaces which bind coregulators of TLX in glioblastomas. This knowledge will allow us to devise strategies to chemically modify novel TLX ligands to disrupt coregulator interactions and to obtain the desirable biological activities. A first generation of novel analogues is currently being tested. In this presentation we will describe ongoing Structure-Activity Relationship studies to identify new specific TLX ligands able to de-repress TLX transcriptional activity.
Citation Format: Cindy C. Benod, Rosa Villagomez, Paul Webb. Deorphanizing TLX: Implications for treatment of glioblastomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2452. doi:10.1158/1538-7445.AM2015-2452