bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1002: Norrin controls colon cancer angiogenesis
Authors: Planutis Kestutis , Planoutene Marina , Holcombe Randall F. 
Published: May 2015

Abstract
The purposes of the study: Colorectal (CRC) tumors depend on mediators in the tumor microenvironment, such as vascular endothelial growth factor, to promote angiogenesis. Norrin is a ligand that binds to the cell surface Frizzled-4 receptor, stimulating canonical Wnt signaling, and is known to mediate blood vessel growth in the eye and ear. We investigate here the role of Norrin secreted by colon cancer cells in endothelial cell growth and motility as well as the expression of the Norrin signaling pathway components in the CRC tumor microenvironment.
Experimental procedures: Primary human umbilical vein endothelial cells (HUVEC) expressing green fluorescent protein and a HUVEC-derived endothelial cell line, EAhy926 were utilized for in vitro angiogenesis assays measuring cell motility and in vitro angiogenesis. Experiments were performed with and without the addition of Norrin-containing conditioned medium from a transfected CRC cell line CaCO2 and with and without blocking anti-Norrin antibodies. Tissue specimens from human CRC patients were evaluated with a double signal amplification system to define the expression of Norrin, Frizzled-4, LRP5 and TSPAN12 in tumor blood vessels.
Summary of data: Blocking generated by the endothelial cells themselves Norrin reduced endothelial cell motility, branch point number during in vitro angiogenesis (1/sq. mm), and the network length (mm/sq. mm) during in vitro angiogenesis. Norrin conditioned medium produced by CRC cell line CaCO2 transfected with Norrin expression construct increased endothelial cell motility. Colorectal tumors express Norrin protein. Endothelial cells in the colorectal tumor blood vessels contain all of the components of the Norrin signaling pathway needed for the endothelial cells to respond to Norrin in the tumor microenvironment.
Statement of the conclusions: This study presents both in vitro and in vivo data that colorectal tumors use Norrin protein as an alternative mechanism that promotes angiogenesis in the CRC tumor microenvironment.
Citation Format: Kestutis Planutis, Marina Planoutene, Randall F. Holcombe. Norrin controls colon cancer angiogenesis. [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 1002. doi:10.1158/1538-7445.AM2014-1002
Abstract 1005: Leptin increases VEGF expression and enhances angiogenesis in human chondrosarcoma cells
Authors: Hsu Kai-Hsiang , Tang Chih-Hsin , Tan Tzu-Wei 
Published: May 2015

Abstract
Leptin, the product of the obese gene that plays an important role in the regulation of body weight that induces neuroprotection, neurogenesis, and angiogenesis. However, the effect of leptin on VEGF expression in human chondrosarcoma cells is mostly unknown. The aim of study is try to examine the effect of leptin in VEGF expression and angiogenesis in human chondrosarcoma cells. We found that exogenous leptin with chondrosarcoma cells promoted VEGF expression and subsequently increased migration and tube formation in endothelial progenitor cells (EPC). Leptin-mediated VEGF and angiogenesis up-regulation were attenuated by OBRl receptor antisense oligonucleotide. In addition, leptin-induced VEGF expression was attenuated by ERK inhibitor (U0126), p38 inhibitor (SB203580), JNK inhibitor (SP600125) and AP-1 inhibitors (Curcumin and Tanshinone). Incubation of cells with leptin induced ERK, p38, JNK and c-Jun phosphorylation as well as AP-1 luciferase activity. Knockdown of leptin decreased VEGF expression and also abolished chondrosarcoma conditional medium-mediated angiogenesis in vitro as well as angiogenesis effects in the matrigel plug model in vivo. In addition, using xenograft tumor angiogenesis model, knockdown leptin significantly reduced tumor growth and tumor angiogenesis. Taken together, our results indicated that leptin enhances the VEGF expression in chondrosarcoma cells. One of the mechanisms underlying leptin-directed VEGF expression was through the ERK/p38/JNK and c-Jun signal transduction pathway.
Citation Format: Kai-Hsiang Hsu, Chih-Hsin Tang, Tzu-Wei Tan. Leptin increases VEGF expression and enhances angiogenesis in human chondrosarcoma 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 1005. doi:10.1158/1538-7445.AM2014-1005
Abstract 1008: Resveratrol causes biphasic apoptotic and proliferative effects and at higher/proapoptotic/anti-angiogenesis concentrations causes suppression of nitric oxide/cGMP/protein kinase G signaling and decreased expression of prosurvival proteins c-IAP1, c-IAP2, livin and XIAP in human umbilical vein endothelial cells
Authors: Wong Janica C. , Coffman Renee , Rosenberg Harry , Fiscus Ronald R. 
Published: May 2015

Abstract
Anti-cancer/anti-angiogenesis effects of resveratrol have been reported. Resveratrol increases nitric oxide (NO) production via increased expression of endothelial-form-NO-synthase (eNOS). However, the role of cGMP/protein kinase G (PKG) signaling, a pathway activated by NO/eNOS, in the anti-angiogenic effects of resveratrol is still unclear. In the present study, involvement of endogenous NO/cGMP/PKG pathway and downstream pro-survival proteins (Inhibitor of Apoptosis Proteins, IAPs) are studied in relation to anti-angiogenic effects of resveratrol in human umbilical vein endothelial cells (HUVECs). Our results show that resveratrol at higher/anti-angiogenesis concentrations (&gt;50 μM) inhibits tube formation and cell migration/invasion. Resveratrol stimulates proliferation/DNA synthesis at lower concentration (10 µM), but inhibits proliferation/DNA synthesis at higher concentrations (100 and 500 µM). Moreover, resveratrol at lower concentrations (10, 20 and 50 µM) protects HUVECs against spontaneous apoptosis, but induces higher-level apoptosis at higher concentration (500 µM). ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one), inhibitor of endogenous NO-induced activation of soluble-guanylyl-cyclase and subsequent cGMP biosynthesis, completely abolishes the anti-apoptotic/cytoprotective effects of low-concentration resveratrol. 8-Br-cGMP, a direct stimulator of PKG kinase-activity, protects against pro-apoptotic effects of high-concentration resveratrol, establishing a cytoprotective role of activated-PKG in HUVECs. Western blot analyses show that higher/pro-apoptotic/anti-angiogenesis concentrations of resveratrol cause suppression of PKG kinase-activity (indicated by decreased VASP phosphorylation at Ser239) and decreased expression of eNOS and four IAPs, c-IAP1, c-IAP2, livin and XIAP. Overall, our results suggest a cytoprotective role of NO/cGMP/PKG signaling in HUVECs and further suggest that resveratrol (&gt;50 μM)-induced anti-angiogenesis/pro-apoptosis involves suppression of NO/cGMP/PKG signaling and decreased expression of pro-survival proteins c-IAP1, c-IAP2, livin and XIAP.
Citation Format: Janica C. Wong, Renee Coffman, Harry Rosenberg, Ronald R. Fiscus. Resveratrol causes biphasic apoptotic and proliferative effects and at higher/proapoptotic/anti-angiogenesis concentrations causes suppression of nitric oxide/cGMP/protein kinase G signaling and decreased expression of prosurvival proteins c-IAP1, c-IAP2, livin and XIAP in human umbilical vein endothelial 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 1008. doi:10.1158/1538-7445.AM2014-1008
Abstract 1010: Paradoxic effects of metformin on endothelial cells and angiogenesis
Authors: Bruno Antonino , Dallaglio Katiuscia , Cantelmo Anna Rita , Esposito Alessia I. , Ruggiero Luca , Orecchioni Stefania , Callieri Angelica , Bertolini Francesco , Pfeffer Ulrich , Noonan Douglas M. , Albini Adriana 
Published: May 2015

Abstract
Epidemiological evidence has suggested that metformin, an anti-hyperglycemic agent commonly used in the treatment of type 2 diabetes, is a potential cancer preventive agent. Anti-angiogenesis represents a key mechanism in cancer prevention, a concept termed angioprevention. Since conflicting data concerning the anti-angiogenic action of metformin are emerging, we elucidate the effects of metformin, on endothelial and tumor cells as well as on angiogenesis using in vitro, in vivo and transcriptomic approaches. We show that metformin inhibits endothelial cell ability to organize into capillary-like networks; this effect is partially dependent on the energy sensor AMPK. Gene expression and proteins profiling revealed paradoxic effects on several angiogenesis associated factors. We found induction of VEGF, COX2 and CXCR4 at the mRNA level and down-regulation of ADAMTS1. Interestingly, antibody array analysis showed essentially opposite regulation of numerous angiogenesis-associated proteins in endothelial and breast cancer cells.
We also show that endothelial production of cytochrome p450 family member CYP1B1 was up-regulated by tumor cell supernatants, while metformin blocked this effect by acting on AMPK. The metformin anti-angiogenic activity was exerted through inhibition of ERK1/2 activation, even in the presence of VEGF, while blocking AMPK activity abrogated this effect. Metformin inhibited angiogenesis induced by VEGF in matrigel pellets in vivo and contrasted the increase in microvessel density in obese mice on a high fat diet. Further, it down-regulated the number of endothelial precursor cells from white adipose tissue in obese mice. Our data show that metformin has an anti-angiogenic activity in vitro and in vivo, which is associated with a contradictory enhancement of chemokines and other inflammatory pro-angiogenic mediators, as well as a different regulation in endothelial and breast cancer cells.
Citation Format: Antonino Bruno, Katiuscia Dallaglio, Anna Rita Cantelmo, Alessia I. Esposito, Luca Ruggiero, Stefania Orecchioni, Angelica Callieri, Francesco Bertolini, Ulrich Pfeffer, Douglas M. Noonan, Adriana Albini. Paradoxic effects of metformin on endothelial cells and angiogenesis. [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 1010. doi:10.1158/1538-7445.AM2014-1010
Abstract 1017: Id-1 gene and protein as therapeutic target for head and neck squamous cell carcinoma
Authors: Murase Ryuichi , McAllister Sean , Fujita Yohei , Sumida Tomoki , Nakashiro Koichi , Desprez Pierre , Hamakawa Hiroyuki 
Published: May 2015

Abstract
Squamous cell carcinoma is one of the most common malignancies in head and neck region. Primary tumors, especially derived from undifferentiated cells, tend to have aggressive phenotypes, which are mainly characterized by local recurrence and distant metastasis. In this study we found that Id-1, a negative regulator of tissue specific transcription factors, is highly expressed in head and neck squamous carcinoma cells (HNSCC), and that the expression is correlated with the malignant phenotype, i.e., cell proliferation and invasion. Id-1 knockdown dramatically reduces squamous cell invasion that is accompanied by profound morphologic changes and robust reduction in expression levels of mesenchymal markers.In addition, reduction in tumor growth and neoangiogenesis were observed in vivo, indicating that knock-down of Id-1 drastically suppresses VEGFA expression. Our results also suggested that VEGFA-autocrine loop activates tylosine kinase pathways including Srk and FAK, and therefore manifests invasive phenotype. With clinical materials obtained from HNSCC patients, significant correlation was observed between Id-1 and VEGFA. Furthermore, we demonstrated that a non toxic compound, cannabidiol, significantly downregulates Id-1 gene expression and associated squamous cell proliferation and invasiveness. Taken together, these results suggest that Id-1 controls cancer cell phenotype in culture and in vivo, and that drugs targeting Id-1 represent a novel and promising strategy for improving the therapy and outcome of patients with HNSCC.
Citation Format: Ryuichi Murase, Sean McAllister, Yohei Fujita, Tomoki Sumida, Koichi Nakashiro, Pierre Desprez, Hiroyuki Hamakawa. Id-1 gene and protein as therapeutic target for head and neck squamous cell carcinoma. [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 1017. doi:10.1158/1538-7445.AM2014-1017
Abstract 102: A longitudinal, orthotopic mouse imaging model using modified hNIS-A549 human lung adenocarcinoma cells and SPECT/CT imaging
Authors: McBride Amber Alane , Price Dominique Nicole , Norenberg Jeffrey P. , MacKenzie Debra A. , Thompson Todd Anthony , Muttil Pavan 
Published: May 2015

Abstract
The human sodium iodide symporter (hNIS; SLC5A5) is a membrane glycoprotein that is a transporter for iodide uptake and also concentrates the radiotracer technetium 99mTc-pertechnetate (99mTc). In this study, we investigated the use of hNIS as an imaging reporter gene expressed in lung cancer cells in nude mice that can be quantified using single-photon emission computed tomography (SPECT) imaging. The radionuclide 99mTc was selected for its rapid clearance from the body and its short physical half-life (i.e., 6 hours). These characteristics allowed for the development a highly sensitive spatial and temporal tumor-imaging model. Human lung adenocarcinoma A549 cells were genetically modified using plasmid and lentiviral vectors to stably express hNIS. Using these modified cells, we monitored xenograft and orthotopic tumor growth using SPECT/CT for a total of 47 days. hNIS expression was quantified using qPCR and tumor progression was monitored by SPECT voxel analysis and validated using H&E staining of pulmonary tumors. hNIS-lentiviral vector tumors exhibited significant 99mTc uptake over hNIS-plasmid vector cells and A549 unmodified control cells in vitro and in vivo. Furthermore, this mouse study achieved a 100% orthotopic tumor take rate. Thus, a highly sensitive preclinical imaging mouse lung cancer model was developed. This model can be imaged longitudinally, which is made possible through the stable incorporation of hNIS into the tumor cell, allowing for 99mTc uptake and SPECT/CT analysis of tumor burden. In future studies, we will investigate whether chemotherapeutic regimens can effectively reduce the growth of hNIS-expressing A549 tumors over time using this preclinical in vivo model. This novel lung cancer animal model could significantly reduce animal numbers, improve the quality of data by avoiding inter-animal variation, and allow for longitudinal analysis and efficacy of experimental chemotherapeutics.
Citation Format: Amber Alane McBride, Dominique Nicole Price, Jeffrey P. Norenberg, Debra A. MacKenzie, Todd Anthony Thompson, Pavan Muttil. A longitudinal, orthotopic mouse imaging model using modified hNIS-A549 human lung adenocarcinoma cells and SPECT/CT imaging. [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 102. doi:10.1158/1538-7445.AM2014-102
Abstract 1039: Downregulation of beta1 integrins in E-cadherin positive triple negative breast cancer cells elicits pro-metastatic shift in migration strategy through TGFbeta/miR200/ZEB signaling network
Authors: Danen Erik H. 
Published: May 2015

Abstract
Interactions with the extracellular matrix (ECM) through integrin adhesion receptors provide cancer cells with physical and chemical cues that act in concert with growth factors to support survival and proliferation. Preclinical studies testing β1 integrin antagonists in (breast) cancer models have shown inhibition of tumor growth and sensitization to radio- or chemotherapy and these strategies are currently evaluated in clinical trials. Here, we show that downregulation of β1 integrins attenuates breast tumor growth but dissemination to the lungs from such small tumors can be markedly enhanced. β1 integrin downregulation induces compensatory upregulation of β3 integrins, but increased β3 expression does not lead to enhanced lung metastasis. Instead, β1 integrin downregulation in human and mouse triple negative, E-cadherin positive breast cancer cells elicits a switch from collective invasion to individual cell migration in 3D ECM. This involves alterations in the TGFβ-BMP signaling network shifting the balance between miR-200 and ZEB, which causes a block in E-cadherin transcription. The switch is fully reversible: restored β1 expression reinstates E-cadherin expression and cell cohesion. Moreover, restoring the network at the level of TGFβR, ZEB/miR-200 balance, or E-cadherin, restores cohesion and prevents the induction of lung metastasis without affecting tumor growth. These findings reveal that integrin-mediated ECM-attachments regulate a signaling network in control of epithelial characteristics that suppress metastatic spread. This raises concerns with respect to the use of β1 integrins as cancer drug targets.
Citation Format: Erik H. Danen. Downregulation of beta1 integrins in E-cadherin positive triple negative breast cancer cells elicits pro-metastatic shift in migration strategy through TGFbeta/miR200/ZEB signaling network. [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 1039. doi:10.1158/1538-7445.AM2014-1039
Abstract 1041: TGF-β1-induced EMT is suppressed by berberine in triple negative breast cancers
Authors: Lee Jeongmin 
Published: May 2015

Abstract
Elevated TGF-β secretion plays an important role in the development of cancer such as tumor metastasis, invasion, and the epithelial-to-mesenchymal transition (EMT). In addition, TGF-β-responsive gene signature is highly activated in chemotherapy-treated triple negative breast cancer (TNBC). Here, we investigated the effect of berberine (BBR) on TGF-β1-induced EMT in TNBC cells. Our results showed that TGF-β1 significantly increased the level of mesenchymal markers such as fibronectin, vimentin, and MMP-2 in Hs578T and BT549. To verify the effect of BBR on these phenomenons, we treated with BBR and then BBR decreased TGF-β1-induced mesenchymal markers in Hs578T and BT549 cells. Furthermore, we investigated the regulatory mechanism of TGF-β1-induced mesenchymal markers. TGF-β1-induced mesenchymal markers were prevented by a MEK1/2 inhibitor, U0126 or a Smad3 inhibitor, SIS3, respectively. Interestingly, BBR significantly decreased TGF-β1-induced the phosphorylation of ERK and Smad3 in Hs578T and BT549. Taken together, we demonstrated that BBR may act as a blocker in TGF-β1-induced EMT in TNBC.
Citation Format: Jeongmin Lee. TGF-β1-induced EMT is suppressed by berberine in triple negative breast cancers. [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 1041. doi:10.1158/1538-7445.AM2014-1041
Abstract 1043: Distinctive roles of Smad3 C-tail and linker phosphorylation between cancer progression and suppression in TGF-beta1/Smad3 signal
Authors: Bae Eunjin , Ooshima Akira , Kim Seong-Jin 
Published: May 2015

Abstract
Transforming growth factor B1 (TGF-B) is the prototype of a large family of pleiotropic polypeptide cytokines that regulate a multitude of physiological functions. The ability of TGF-B1/Smad3 signal to inhibit proliferation of epithelial, neuronal and hematopoietic cells from which most human neoplasms originate suggests a role of TGF-B in tumor suppression. Smad3, a key transcription factor in TGF-B signaling, functions as both a positive and negative regulator in carcinogenesis. TGF-B induces phosphorylation of Smad3 C-terminal SXS motif in its canonical pathway as well as the serine/threonine residues in the linker region. The linker region has been known to contain multiple phosphorylation sites for proline-directed kinases such as CDK, c-Jun, p38 MAPK, Erk and GSK-3B. Here we present that the blockade of Smad3 C-terminal phosphorylation by adenoviral dominant-negative mutant promotes tumorigenesis, but markedly inhibits metastasis to the lung as induced by tail-vein injection and orthotopic transplant of human and mouse breast cancer cell lines. Conversely, mutation of Smad3 linker phosphorylation sites greatly suppresses tumorigenesis, while it enhances metastatic dissemination to the lung. In vitro study revealed that the Smad3 linker region is constitutively phosphorylated in the cancer cells, and that the mutation of Smad3 linker phosphorylation sites enhances the TGF-B1-induced EMT, growth arrest and apoptosis, suggesting that the canonical TGF-B1 signal mediated through C-tail phosphorylation is modulated by negative inputs from the linker phosphorylation. Furthermore, the blockade of linker phosphorylation reduces the stem cell population following suppression of mammosphere formation and downregulation of embryonic transcription factors including Oct4, NANOG and Sox-2, and induces apoptosis by repressing an antiapoptotic protein Bcl-2, suggesting that the Smad3 linker phosphorylation retains function for the maintenance of cancer stemness and survival. These results indicate that oncogenic and cancer-suppressive TGF-B1/Smad3 signals are regulated by the site-specific phosphorylation of Smad3 protein, imparting a new aspect to anti-cancer therapies that target the TGF-B signal pathway.
This work was supported by a National Research Foundation grant of Korea (2009-0081756) funded by the Korea government.
Citation Format: Eunjin Bae, Akira Ooshima, Seong-Jin Kim. Distinctive roles of Smad3 C-tail and linker phosphorylation between cancer progression and suppression in TGF-beta1/Smad3 signal. [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 1043. doi:10.1158/1538-7445.AM2014-1043