bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1593: GSK3β mediated arsenite induction of spindle abnormalities
Authors: Lin Tz-Chi , Chen Ren-Meei , Kuo Hsiao-Hui , Yih Ling-Huei 
Published: May 2015

Abstract
Arsenite induces centrosome amplification and spindle abnormalities, leading to chromosome missegregation and consequently resulting in mitotic cell apoptosis or aneuploidy. However, the underlying mechanism of how arsenite disrupts mitotic spindles is not known. In this study, we showed that CGL2 cells treated with arsenic trioxide (ATO) were arrested at mitotic stage in company with the formation of substantial spindle abnormalities and significant reduction of acetylated- and detyrosinated-tubulin, characteristics of decreased MT stability. Immunofluorescence staining of EB1, a plus-end microtubule-binding protein, revealed discrete EB1 spots distributing along microtubule (MT) nucleated from the two spindle poles in untreated mitotic cells. However, it showed a disorganized pattern in ATO-arrested mitotic cells with the spot-like EB1 clusters splashing all over the cells. In addition, immunoblotting and immunofluorescence staining revealed that the mitosis-specific inhibitory phospho-GSK3 was diminished in ATO-arrested mitotic cells. Pharmacological inhibition of GSK3 could prevent ATO induction of spindle abnormalities, mitotic arrest, and cell death. Since GSK3β has been reported to reduce MT stability by phosphorylating several microtubule-associated proteins, our current results indicated that GSK3β may mediate ATO induction of spindle abnormalities.
Citation Format: Tz-Chi Lin, Ren-Meei Chen, Hsiao-Hui Kuo, Ling-Huei Yih. GSK3β mediated arsenite induction of spindle abnormalities. [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 1593. doi:10.1158/1538-7445.AM2014-1593
Abstract 1602: Clobetasol treatment of vulvar carcinoma cell lines influences growth rates
Authors: Lewis Jani E. , Mehta Mehek , Treichel Alison , Colligan Sean , Nguyen Vinh , Foster David C. 
Published: May 2015

Abstract
Vulvar cancer is an aggressive cancer often masked by diseases such as the vulvar rash known as lichen sclerosis (LS). Ultrapotent corticosteroids such as clobetasol are commonly used to treat LS but there is debate over the safety of long-term clobetasol use and development of vulvar cancer. Growing cells from LS biopsies has proven difficult so our objective was to decipher if clobetasol promotes changes in vulvar cancers in vitro that parallel the formation of more aggressive cancer types. Previously we have shown that clobetasol actually promotes transformation of one vulvar cancer cell line into a more aggressive phenotype. Our present studies used MTT assays to examine the effect that short-term (72 hours) and long-term (4 weeks) clobetasol treatment had on the growth rate of vulvar cancer cell lines. Our preliminary data indicates that the growth response varies between cell lines with at least two cell lines displaying increased cell growth after extended treatment with clobetasol when compared to controls.
Citation Format: Jani E. Lewis, Mehek Mehta, Alison Treichel, Sean Colligan, Vinh Nguyen, David C. Foster. Clobetasol treatment of vulvar carcinoma cell lines influences growth rates. [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 1602. doi:10.1158/1538-7445.AM2014-1602
Abstract 1616: Phosphoprotein enrichment pathway analysis tools for studying cancer signaling
Authors: Wiredja Danica , Liu Yu , Schlatzer Daniela , Gokulrangan Giridharan , Narla Goutham , Chance Mark 
Published: May 2015

Abstract
Cancer development and progression is driven by dysregulated signaling transduction, which is predominantly regulated by serine, threonine, and tyrosine phosphorylation. Consequently, MS-based phosphoproteomics, which can identify and quantitate thousands of phosphopeptides, provides a powerful quantitative tool to detect and comprehensively catalog alterations in cancer signaling cascades that cannot be captured by analysis of DNA or RNA alone. Unfortunately, the complexity of the datasets generated by these advanced proteomic methodologies are still not matched with well-established or fully tested bioinformatics tools to extract critical pathways from these high-dimensional phosphoprotein data.
Here, we present two approaches for identifying pathways with altered phosphorylation patterns: Protein Set Enrichment Analysis (PSEA) and Protein Interaction Enrichment Network Analysis (PIENA). Development of these tools was inspired by two published methods utilizing gene expression datasets to identify disrupted gene sets: Gene Set Enrichment Analysis (GSEA) and Gene Interaction Enrichment Network Analysis (GIENA), respectively. PSEA, through pathway scoring, extracts pathways that show a uniform directional phosphorylation change through all protein members of that set. As in the traditional GSEA method, an enrichment score is calculated for each pathway based on intensity values from all detected phosphopeptides. The second method, PIENA, looks for notable differences in phosphorylation between phosphopeptide pairs. Ultimately, this approach identifies pathways enriched with altered phosphoprotein interactions.
Both methods have been used to identify changes in signaling states for two lung adenocarcinoma cell lines, A549 and H358, treated with either control or a novel phosphatase activator with anti-cancer properties. Both PSEA and PIENA identify pathways classically implicated in cancer, including p53, mitosis and cell cycle progression, insulin secretion, immune regulation, and RAS signaling cascades. Furthermore, the ERK pathway is consistently found to be significantly disrupted in both A549 and H358. This corroborates biological findings that this novel drug has activity against KRAS mutated cell lines. Although future cellular experiments will help to confirm the detailed mechanism of this drug's effects, our current results demonstrate the advantage of these new pathway identification tools in providing unbiased and global identification of key drivers of signaling.
Citation Format: Danica Wiredja, Yu Liu, Daniela Schlatzer, Giridharan Gokulrangan, Goutham Narla, Mark Chance. Phosphoprotein enrichment pathway analysis tools for studying cancer signaling. [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 1616. doi:10.1158/1538-7445.AM2014-1616
Abstract 1628: Direct anti-cancer effects of zoledronic acid on human cancer cell
Authors: Jiang Pengfei , Mukthavavam Rajesh , Nomura Natsuko , Pingle Sandeep C. , Kesari Santosh 
Published: May 2015

Abstract
Zoledronic Acid (ZA) is a potent nitrogen-containing bisphosphonates (NBP) has been extensively used to limit bone turnover in a various diseases including tumors. Recently, clinical trails of Zoledronic Acid demonstrated direct anti-cancer effects as well as the known skeletal-related events. We investigated the effect of 4 NBPs on human tumor cells proliferation and found ZA is most potent for GBM cell, breast cell and GBM patients' stem-cell-like cells. ZA also effectively inhibited GBM tumor growth in mouse model. ZA stimulated strong autophagy but not apoptotic signals in all tested cells. One intermediate product of cholesterols synthesis pathway—-geranylgeranyl diphosphate (GGPP) rescued cell from the cytotoxicity of ZA. Knock-down RABGGTA, which encoded a subunit of the Rab geranylgeranyltransferase proteins, induced a similar effect as Zoledronic Acid in cancer cell lines. These data suggested great potential for Zoledronic Acid against human cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Pengfei Jiang, Rajesh Mukthavavam, Natsuko Nomura, Sandeep C. Pingle, Santosh Kesari. Direct anti-cancer effects of zoledronic acid on human cancer cell. [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 1628. doi:10.1158/1538-7445.AM2014-1628
Abstract 163: Identification of a bone marrow-derived MDSC subset that promotes the growth of colon carcinoma liver metastases
Authors: Ham Boram 
Published: May 2015

Abstract
The hepatic microenvironment can play an important role in promoting liver metastasis. We and others have shown that when metastatic carcinoma cells enter the liver, a rapid inflammatory response mediated by TNF-α is triggered, enabling tumor transendothelial migration and metastasis. TNF-α binds to the cell surface through two receptors; the p55/p60 TNFR1 and the p75/p80 TNFR2. To elucidate the roles of these receptors in the inflammatory cascade and in liver colonization by tumor cells, we used mice with tnfr1, tnfr2 and combined tnfr1/tnfr2 gene deficiencies and investigated parameters of the host response and the outcome of metastasis in these mice using the highly metastatic mouse colon carcinoma MC-38 and lung carcinoma H-59 cells. We found that experimental liver metastasis following intrasplenic/portal inoculation of the tumor cells was markedly reduced in TNFR2-/- and even further in TNFR1-/-/TNFR2-/- female mice as compared to wild-type controls but no reduction was observed in TNFR1-/- mice. To identify the underlying mechanism(s), we investigated changes in the liver microenvironment following tumor inoculation using a combination of immunohistochemistry, confocal microscopy, qRT-PCR, and cytokine/chemokines profiling. We found that while in wild-type and TNFR1-/- mice, VCAM-1 expression on the sinusoidal endothelium was significantly upregulated within 16 hr post tumor injection, it was unchanged in TNFR2-/- and double negative female mice. In addition, qRT-PCR analysis revealed that the production of the neutrophil chemokine CXCL1, while upregulated in control mice, was suppressed in TNFR2-/- mice. These changes were associated with a parallel decrease in Ly6G+ neutrophil recruitment into extravascular, pro-metastatic niches 16-48 hr post tumor inoculation. Interestingly, these reductions were not observed in male TNFR2-/- mice and correspondingly, their metastatic burden was not reduced relative to control mice. Taken together, the results suggest that TNFR2 plays a critical and gender-specific role in Ly6G+ cell recruitment into the tumor-microenvironment by regulating sinusoidal endothelial VCAM-1 expression and chemokine production. In turn, the recruitment of these cells into extravascular pro-metastatic niches appears to promote liver metastasis.
Citation Format: Boram Ham. Identification of a bone marrow-derived MDSC subset that promotes the growth of colon carcinoma liver metastases. [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 163. doi:10.1158/1538-7445.AM2014-163
Abstract 1640: A novel small molecule inhibitor of lysophosphatidic acid acyltransferase-beta inhibits pancreatic cancer cell proliferation and mTOR signaling
Authors: Blaskovich Michelle A. , Luo Yunting , Ge Yiyu , Sebti Saïd M. , Lawrence Harshani R. , Lawrence Nicholas J. , Springett Gregory M. 
Published: May 2015

Abstract
Lysophosphatidic acid acyltransferase (LPAAT-β), a phosphatidic acid (PA)-generating enzyme, plays an essential role in triglyceride synthesis. A less familiar role for LPAAT-β is that of a regulator of cell growth and differentiation by means of the function of its product, PA, which plays a vital role in the activation of key signal transduction proteins including Raf, PKC-ζ and mTOR. It is in this role that LPAAT-β presents as a potential therapeutic target in cancer. Accordingly, we developed a library of small molecule inhibitors of LPAAT-β with nanomolar activity against LPAAT-β enzyme activity in vitro (2012 Annual Meeting, Abstract #2470). We have now performed additional SAR and lead optimization to produce a potent small molecule that inhibits proliferation, mTOR signaling pathways, and total cellular PA levels at low micromolar concentrations. The lead compound also inhibits anchorage-independent growth of pancreatic cancer cell lines at nanomolar concentrations. This compound demonstrates effects on cellular signaling that are similar to the effects of LPAAT-β siRNA.
Citation Format: Michelle A. Blaskovich, Yunting Luo, Yiyu Ge, Saïd M. Sebti, Harshani R. Lawrence, Nicholas J. Lawrence, Gregory M. Springett. A novel small molecule inhibitor of lysophosphatidic acid acyltransferase-beta inhibits pancreatic cancer cell proliferation and mTOR signaling. [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 1640. doi:10.1158/1538-7445.AM2014-1640
Abstract 1658: Enhanced shedding of extracellular vesicles from amoeboid prostate cancer cells: Potential effects on the tumor microenvironment
Authors: Kim Jayoung , Morley Samantha , Le Minh , Bedoret Denis , Umetsu Dale , Vizio Dolores D. , Freeman Michael 
Published: May 2015

Abstract
The gene encoding the cytoskeletal regulator DIAPH3 is lost at high frequency in metastatic prostate cancer, and silencing of DIAPH3 evokes a transition to an amoeboid phenotype in multiple tumor cell backgrounds. This amoeboid transformation is accompanied by increases in plasma membrane deformations (blebbing), cell migration, invasion, and metastasis. DIAPH3 silencing also promotes the shedding of atypically large (&gt;1μm) extracellular vesicles (EV) containing bioactive cargo. Whether loss of DIAPH3 also stimulates the release of bioactive nano-sized EV (exosomes) is not established. Here we examined the mechanism of release and potential biological functions of EV shed from DIAPH3-silenced and other prostate cancer cells. We observed that stimulation of LNCaP cells with the prostate stroma-derived growth factor heparin-binding EGF-like growth factor (HB-EGF), combined with p38MAPK inhibition caused exosome shedding, a process mediated by ERK1/2 hyperactivation. DIAPH3 silencing in DU145 cells also increased rates of exosome production. EV isolated from DIAPH3-silenced cells activated AKT1 and androgen signaling, increased proliferation of recipient tumor cells, and suppressed proliferation of human macrophages and peripheral blood mononuclear cells (PBMC). DU145-derived EV contained miR-125a, which suppressed AKT1 expression and proliferation in recipient human peripheral blood mononuclear cells and macrophages. Our findings suggest that EV across a wide size range (∼70nm to &gt;1um) are produced by amoeboid prostate cancer cells as a result of DIAPH3 loss and/or growth factor stimulation. These EV may condition the tumor microenvironment through multiple mechanisms, including promoting the growth of cancer cells and suppression of tumor-infiltrating immune cells.
Citation Format: Jayoung Kim, Samantha Morley, Minh Le, Denis Bedoret, Dale Umetsu, Dolores Di Vizio, Michael Freeman. Enhanced shedding of extracellular vesicles from amoeboid prostate cancer cells: Potential effects on the tumor microenvironment. [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 1658. doi:10.1158/1538-7445.AM2014-1658
Abstract 167: Roles of adipocytes and M2-macrophages in high-fat diet-stimulated lymph node metastasis of B16F10 melanoma
Authors: Cho Han Jin , Jung Jae I. , Jung Yoo Jin , Lee Ki Won , Sung Mi-Kyung , Park Jung Han Yoon 
Published: May 2015

Abstract
The tumor microenvironment consists of a number of distinct cell types including tumor cells, fibroblasts, endothelial cells, immune cells, and adipocytes, and produces a wide variety of factors, which contribute to tumor progression. We previously observed that high-fat diet (HFD) feeding stimulates solid tumor growth and lymph node (LN) metastasis in mice subcutaneously injected with B16F10 melanoma cells. We also observed that HFD feeding increases the number of lipid vacuoles and M2-macrophage (M2-Mϕ)s as well as the expression of various cytokines/growth factors in tumor tissues. In the present study, we noted that HFD increased the expression of CCR7 in the tumor. The concentrations of CCL19 and CCL21, the CCR7 ligands, were significantly higher in the LN than those in tumor, and HFD feeding increased the concentrations of these ligands in the LN with negligible changes in the tumor tissue creating higher concentration gradients of these two ligands between the LN and tumor. In order to explore the interactions between tumor cells, adipocytes, lymphatic endothelial cell (LEC)s, and/or M2-Mϕs, we established in vitro co-culture models involving 3 distinct cell types. The mRNA levels of cytokines and growth factors were increased in B16F10 cells and M2-Mϕs when B16F10 cells, M2-Mϕs, and/or mature adipocyte (MA)s were co-cultured in a transwell system. Among these cytokines/growth factors, the mRNA levels of MCP-1 were synergistically increased in B16F10 cells when co-cultured with M2-Mϕs and MAs. The migration of monocytes was tremendously elevated when media conditioned by B16F10 cells/M2-Mϕs/MAs co-cultures was used as a chemoattractant. Furthermore, MAs increased the expression of CCR7 mRNA in B16F10 cells and the expression of CCL19 and CCL21 mRNAs in LECs. These results indicate that in HFD-fed mice, adipocytes induce MCP-1 expression and monocyte infiltration which play important roles in solid tumor growth and LN metastasis. Additionally, adipocyte-stimulated activation of CCL19, CCL21/CCR7 axis in lymphatic endothelial cells and tumor cells helps tumor cells to enter the lymphatic vessels and increased ligand concentration gradients between the LN and tumor facilitate tumor cell migration to the LN.
Citation Format: Han Jin Cho, Jae In Jung, Yoo Jin Jung, Ki Won Lee, Mi-Kyung Sung, Jung Han Yoon Park. Roles of adipocytes and M2-macrophages in high-fat diet-stimulated lymph node metastasis of B16F10 melanoma. [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 167. doi:10.1158/1538-7445.AM2014-167
Abstract 168: Understanding the role of the carcinoid associated fibroblasts in the neuroendocrine tumor microenvironment
Authors: Bowden Michaela , Sicinska Ewa , Kulke Matthew , Loda Massimo 
Published: May 2015

Abstract
A lack of cell lines and animal models has been an obstacle in developing novel therapeutic agents for advanced carcinoid tumors. In the past two years we have developed a collection of short-term carcinoid cell lines. Carcinoid cells in culture grow slowly and are importantly attached to, much faster, growing stromal fibroblasts, referred to as CAF's (Carcinoid Associated Fibroblasts). This phenotype is conserved in vivo and closely mimics the status of these tumors in humans. CAF's are known to have pro-tumorigenic effects; are attractive targets for cancer therapy; as well as valuable clinical biomarkers of prognosis. With the availability of an in-house panel of primary cell lines and control cultured fibroblasts, teasing apart the tumor-fibroblast relationship is feasible through collection of cell culture supernatants and in vitro screening of secreted proteins. We present here our initial screening studies using three cell culture environments, namely normal human fibroblasts, carcinoid-associated fibroblasts (CAF's) and the tumor microenvironment co-culture of stromal cells and CAF's.
We screened 55 secreted proteins with known carcinogenic associations by multiplexed bead-based (BioPlex, BioRad) analysis. We have identified a potential 5-marker CAF signature encompassing elevated secretion of IL-6 and MCP-1; and the suppression of IL-8 and FGF basic, coupled with VEGF expression. As part of the next phase we plan to utilize our collection of banked whole blood, serum, and plasma specimens comprising over 1000 cases of patients with neuroendocrine tumors, to validate our secreted protein signature in early diagnosis and / or assessing progression and prognosis in patients with neuroendocrine tumors based on stage and tumor subtype.
Citation Format: Michaela Bowden, Ewa Sicinska, Matthew Kulke, Massimo Loda. Understanding the role of the carcinoid associated fibroblasts in the neuroendocrine tumor microenvironment. [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 168. doi:10.1158/1538-7445.AM2014-168
Abstract 1686: Synergistic combination of Trabectedin and Olaparib in breast cancer tumor cell lines
Authors: Avila Sonia , Martínez Marta , Moneo Victoria , Martínez-Leal Juan F. , Cuevas Carmen , Garcia-Fernández Luis F. , Galamarini Carlos M. 
Published: May 2015

Abstract
Trabectedin (Yondelis, ET-743) is a marine-derived antitumor agent that is currently used for the treatment of sarcoma and, in combination with pegylated-liposomal doxorubicin, of platinum-sensitive ovarian cancer patients. After binding to the DNA minor groove, trabectedin induces a potent transcription inhibition on tumor cells and tumor-associated macrophages. The resolution of functional DNA adducts generated by the drug is known to occur through the coordinated action of multiple DNA repair pathways, including homologous recombination (HR), a process that gives rise to double-strand breaks (DSBs). Trabectedin treatment at nanomolar concentrations does indeed produce a high proportion of DSB-positive tumor cells with abundant γ-H2AX foci and an S-phase delay/arrest by activation of the DNA replication checkpoints. We had previously shown the synergism (CI &lt; 1) of the combination of Trabectedin with Olaparib (AZD-2281) in the breast cancer cell lines HCC-1937, MCF-7, MDA-MB-231 and MDA-MB-436. In this work we have investigated the mechanism of this synergistic effect at the molecular level. While the treatment with either compound alone (0.05 nM Trabectedin or 5 μM Olaparib for 72 hours) induced only a mild antiproliferative effect, the combination of both compounds at the mentioned concentrations induced strong apoptosis in all the breast cancer cell lines. Exposure to 0.5 and 2.5 nM Trabectedin for 72 hours induced a clear accumulation of γ-H2AX foci. Exposure to Olaparib alone induced only a mild DNA damage at 72 hours with all the concentrations tested. Olaparib induced a clear inhibition of PARylation at concentrations from 1-2.5 μM of the compound. The combination of both drugs, keeping Olaparib at 5 μM and varying the concentrations of Trabectedin from 0.05 to 2.5 nM, demonstrated a synergistic effect on the accumulation of histone H2AX phosphorylation, as analyzed both by western blotting and immunofluorescence microscopy. When comparing all these results, it was clearly seen that, although Trabectedin or Olaparib generated a considerable amount of DSBs, the combination of both drugs induced a higher proportion of DNA damage that remained at very high levels even after 72 hours of treatment. Thus, the observed synergistic effect seems to be the result of higher accumulation of DSBs after the administration of the combination of Trabectedin with Olaparib.
Citation Format: Sonia Avila, Marta Martínez, Victoria Moneo, Juan F. Martínez-Leal, Carmen Cuevas, Luis F. Garcia-Fernández, Carlos M. Galamarini. Synergistic combination of Trabectedin and Olaparib in breast cancer tumor 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 1686. doi:10.1158/1538-7445.AM2014-1686