bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1958: Interrogating hedgehog pathway and smoothened inhibition by PF-04449913 in patient-derived acute myeloid leukemia models
Authors: Jackson-Fisher Amy , Whalen Pamela , Elliott Mark , McMahon Melissa , Chen Enhong , Zheng Xianxian , Ozeck Mark , Huang Donghui , Lira Paul , Lee Joseph , Zhang Cathy , Lam Justine , Spilker Mary , Deng Shibing , Lappin Patrick , Venne Penny , Heinlein Cynthia , Schairer Annelie , McLachlan Karen , VanArsdale Todd 
Published: May 2015

Abstract
Aberrant activation of the Hedgehog (Hh) signaling pathway has been implicated in a variety of cancers and a small molecule inhibitor of Smoothened (SMO), Vismodegib, has been approved for the treatment of basal cell carcinoma, a disease frequently driven by Hh pathway signaling due to pathway mutations. SMO dependent Hh signaling has also been implicated in models of myeloid leukemia, primarily CML, where genetic loss of SMO or pharmacological inhibition limits disease progression in part through targeting the leukemic stem cell (LSC). Outside of BCR-ABL driven leukemia the role of Hh signaling and impact of SMO inhibition on disease progression and the LSC remains unclear. To explore the role of Hedgehog pathway signaling and interrogate responses to SMO inhibition in AML, a panel of primary AML patient-derived models was utilized to examine responses to PF-04449913, an oral small molecule SMO inhibitor currently in early phase clinical trials targeting myeloid malignancies. AML patient samples were characterized for Hh pathway expression levels and screened for responses to PF-04449913. Ex vivo treatment of AML bone marrow cells showed PF-04449913 was capable of inhibiting Hh pathway activity, reducing expression of key LSC regulators and decreasing populations of cells expressing LSC markers. Use of AML xenotransplant models to assess in vivo responses to PF-04449913 as single agent and in combination with Cytarabine have shown potential for combination efficacy of the two agents in select models suggesting patient selection strategies may be critical for SMO inhibitor-based therapies in AML.
Citation Format: Amy Jackson-Fisher, Pamela Whalen, Mark Elliott, Melissa McMahon, Enhong Chen, Xianxian Zheng, Mark Ozeck, Donghui Huang, Paul Lira, Joseph Lee, Cathy Zhang, Justine Lam, Mary Spilker, Shibing Deng, Patrick Lappin, Penny Venne, Cynthia Heinlein, Annelie Schairer, Karen McLachlan, Todd VanArsdale. Interrogating hedgehog pathway and smoothened inhibition by PF-04449913 in patient-derived acute myeloid leukemia models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1958. doi:10.1158/1538-7445.AM2014-1958
Abstract 1985: Vitronectin expression in primary lung cancers
Authors: Salazar-Pelaez Lina M. , Martinez-Forero Ivan 
Published: May 2015

Abstract
Rationale
Vitronectin (Vn) plays a role in extracellular matrix (ECM) remodeling during tumorigenesis. Vn is present in human bronchial submucosal glands and it is secreted by A549 lung adenocarcinoma cell line. However, whether Vn is differentially expressed in tissues of primary lung cancer has not been explored.
Methods
Lung tissue from 22 primary lung carcinoma and 36 non-lung cancer subjects were obtained from fibrobronchoscopy. Sections were analyzed by histo- immunohistochemical methods. The total area occupied by ECM, surface and gland epithelium, as well as the percentage area occupied by Vn at each of these localizations were measured. Chi-square, t-student, U-Mann Whitney and ANOVA tests were used in group comparisons. Statistical significance was tested at P&lt;0.05.
Results
Vn expression was observed in bronchial glandular and surface epithelium, as well as in ECM . In total, the average area of ECM, surface or glandular epithelium was 0.289mm2 (± 0.032), 0.043mm2 (±0.009), 0.084mm2 (±0.031), respectively. The percentage area occupied by Vn in ECM, surface or glandular epithelium, was 4.899 (±1.186), 7.279 (±1.623), 3.285 (±1.038), respectively; with not significant statistical differences between lung cancer and non-cancer subjects or within different types of primary lung cancer (Table 1).
Conclusion
There were no statistically significant differences in Vn expression between lung cancer and non-cancer subjects, or within primary lung carcinomas.
Demographic characteristics and measurement comparisons of subjects studiedConditionNon-cancer(n=36)Cancer(n=22)PAge (Years)59.810(+/- 13.556)65.790(+/- 10.648)0.074Sex*0.752Male18 (50.0%)11 (50.0%)Female18 (50.0%)11 (50.0%)ECM area (mm2)0.311(+/- 0.204)0.424(+/- 0.246)0.059Area occupied by Vn in ECM (percentage)2.894(+/- 2.717)3.584(+/- 3.220)0.384Surface epithelium area (mm2)0.221(+/- 0.678)0.052(+/- 0.023)0.398Area occupied by Vn in surface epithelium (percentage)5.583(+/- 3.939)6.478(+/- 7.757)0.662Gland epithelium area (mm2)0.142(+/- 0.129)0.086(+/- 0.079)0.389Area occupied by Vn in glandular epithelium (percentage)4.151(+/- 2.810)1.424(+/- 0.505)0.200
Note: This abstract was not presented at the meeting.
Citation Format: Lina M. Salazar-Pelaez, Ivan Martinez-Forero. Vitronectin expression in primary lung 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 1985. doi:10.1158/1538-7445.AM2014-1985
Abstract 1988: MenaINV interaction with α5β1 promotes tumor cell invasion in response to gradients of growth factors and fibronectin
Authors: Oudin Madeleine J. , Broye Liliane C. , Lussiez Alisha , Asokan Sreeja B. , Miller Miles A. , Lauffenburger Douglas A. , Bear James E. , Gertler Frank B. 
Published: May 2015

Abstract
To metastasize and disseminate, carcinoma cells must invade the surrounding extracellular matrix (ECM) and migrate to reach blood or lymphatic vessels. Collagen (CN) and fibronectin (FN), two components of the ECM surrounding tumors, are highly expressed in metastatic tumors and their patterns of expression can correlate with metastatic outcome in patient samples. Mena, an actin regulatory protein, is upregulated in breast cancer and is alternatively spliced to produce protein isoforms with distinct functions during tumor progression. The invasion-specific MenaINV isoform increases metastasis by potentiating tumor cell motility and invasion responses to various growth factors. All Mena isoforms bind directly to the α5 subunit of the α5β1 integrin, an FN receptor. We hypothesized that the interaction between MenaINV and α5β1 plays an important role in integrating signals from the ECM as well as growth factors to drive invasion.
MDA-MB-231 breast cancer cells expressing MenaINV showed increased adhesion to FN alone as well as mixture of FN and CN, compared to control cells. MenaINV cells also had an increased number of α5-positive adhesions as well as increased signalling at focal adhesions as measured by phospho-Paxilin, compared to control. In 3D invasion assays, addition of FN to a CN gel drove invasion of MenaINV-expressing cells even in the absence of any growth factor ligand, an effect driven by its interaction with α5 and dependent on signalling via EGFR and Met. Furthermore, addition of FN caused an even greater potentiation of EGF-induced invasion by MenaINV, an effect that was dependent upon its interaction with α5. Next, we examined how MenaINV affects tumor cell responses to a gradient of FN within a 3D collagen gel. Control cells failed to respond to an FN gradient, while cells expressing MenaINV migrated preferentially towards FN and significantly reorganized both the collagen and FN surrounding them. Deletion of the α5 binding site or treatment with an α5 function blocking antibody ablated the effects MenaINV on movement towards a FN gradient as well ECM reorganization.
Overall, these results suggest that some aspects of the pro-metastatic effects of MenaINV involve its ability to bind α5 and regulate bidirectional signaling with FN and growth factors in the tumor microenvironment.
Citation Format: Madeleine J. Oudin, Liliane C. Broye, Alisha Lussiez, Sreeja B. Asokan, Miles A. Miller, Douglas A. Lauffenburger, James E. Bear, Frank B. Gertler. MenaINV interaction with α5β1 promotes tumor cell invasion in response to gradients of growth factors and fibronectin. [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 1988. doi:10.1158/1538-7445.AM2014-1988
Abstract 20: Adiponectin increases VEGF expression and promotes angiogenesis in human chondrosarcoma
Authors: Shih Jhao-Sheng , Tang Chih-Hsin 
Published: May 2015

Abstract
Vascular endothelial growth factor (VEGF) is an angiogenic mediator in tumors and has been implicated in the pathogenesis and progression of cancer. Adiponectin is a protein hormone secreted by adipose tissue. We recently found that adiponectin increased metastasis in human chondrosarcoma. However, the effect of adiponectin on VEGF expression and angiogenesis in human chondrosarcoma cells is mostly unknown. Here we found that adiponectin promoted VEGF expression in human chondrosarcoma and subsequently increased migration and tube formation in endothelial progenitor cells (EPCs). Pretreatment of cells for 30 min with PI3K inhibitors (LY294002 and wortmannine), Akt inhibitor, mTOR inhibitor (Rapamycin) or HIF-1α inhibitor abolished adiponectin-induced VEGF expression, EPC migration and tube formation. In addition, transfection of cells with PI3K, Akt, mTOR, or HIF-1α siRNA also reduced adiponectin-induced VEGF expression, EPC migration and tube formation. Knockdown adiponectin decreased VEGF expression in vitro as well as angiogenesis effects the chick chorioallantoic membrane and matrigel-plug nude mice model in vivo. In addition, using xenograft tumor angiogenesis model, knockdown adiponectin significantly reduced tumor growth and tumor angiogenesis. Finally, we analyzed from chondrosarcoma patients by immunohistochemical staining and found that the expression of adiponectin and VEGF was significantly higher in chondrosarcoma tissue than normal cartilage. Taken together this study showed that adiponectin mediates VEGF expression and angiogenesis of human chondrosarcoma cells. One of the mechanisms underlying adiponectin induced VEGF expression and angiogenesis was activation of PI3K, Akt, mTOR and HIF1-α pathways.
Citation Format: Jhao-Sheng Shih, Chih-Hsin Tang. Adiponectin increases VEGF expression and promotes angiogenesis in human chondrosarcoma. [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 20. doi:10.1158/1538-7445.AM2014-20
Abstract 2017: Development of a novel 3D tri-culture system in an in vitro non-small cell lung cancer (NSCLC) model
Authors: Amann Arno , Zwierzina Marit , Huber Julia M. , Gamerith Gabriele , Bitsche Mario , Pechriggl Elisabeth J. , Hilbe Wolfgang , Zwierzina Heinz 
Published: May 2015

Abstract
Introduction: Different molecular processes lead to metastatic spread and the occurrence of tumor cell resistance to therapeutic interventions. Among them, the stromal compartment of tumors plays a key role. We describe the development of our 3D co-culture to a novel tri-culture model, using non-small cell lung cancer (NSCLC) cell lines in combination with a lung fibroblast and two different endothelial cell lines in a hanging drop technology.
Methods: 96-well hanging drop microtiter plates (InSphero AG, Zürich, Switzerland) were applied for the production of 3D mono-, co- and tri-cultures including the human lung cancer cell lines A549 or Colo699 alone or in combination with a human lung fibroblast cell line (SV-80) and either the human umbilical vein endothelial cell line (HUVEC) or the human lung microvascular endothelial cell line (HMVEC-L). In addition, to conventional histology (H&E, PAS) tumor fibroblast spheroid aggregation was displayed immunohistochemically (IHC) by protein expression of e-cadherin, vimentin, Ki67, CD31 and α-smooth muscle actin (α-SMA). Viability of each cell compartment of the microtissue was determined by a modified AnnexinV/Propidium Iodide staining for flow cytometry.
Results: Endothelial cells aggregated either in small colonies with Colo699 or as single cells mainly in the stromal compartment of A540 microtissues. Simultaneously an up-regulation of vimentin and a downregulation of E-Cadherin was observed in co- and tri-cultures compared to monocultures. Furthermore, Ki67 expression increased significantly from mono- to co- and tri-cultures in both cancer cell lines, indicating a high metabolic activity. In addition, a morphological alteration of A549 tumor cells resembling “signet ring cells” was observed for the first time in both endothelial tri-cultures with a significantly increased glycoprotein expression demonstrated by a Periodic acid-Schiff (PAS) stain.
Conclusion: We demonstrate that our method is a promising tool for the generation of multicellular tumor microtissues and reflects in vivo conditions closer than traditional 2D cell culture. Furthermore, it represents an appropriate alternative method to investigate endothelial cell interactions with tumor and stromal cells.
Citation Format: Arno Amann, Marit Zwierzina, Julia M. Huber, Gabriele Gamerith, Mario Bitsche, Elisabeth J. Pechriggl, Wolfgang Hilbe, Heinz Zwierzina. Development of a novel 3D tri-culture system in an in vitro non-small cell lung cancer (NSCLC) model. [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 2017. doi:10.1158/1538-7445.AM2014-2017
Abstract 2033: A comprehensive 3D triple coculture model for evaluating breast cancer progression
Authors: Benton Gabriel J. , George Jay , DeGray Gerald , Arnaoutova Irina , Kleinman Hynda K. 
Published: May 2015

Abstract
Current models for evaluating breast cancer progression lack a comprehensive, physiological approach to modeling the complex tumor microenvironment. There has been much evidence supporting the use of tumor spheroids to mimic tumor physiology; they exhibit cell-cell bond formation, comparable morphology, elevated cell survival and proliferation in the outer cell layers, reduced proliferation rates in the intermediate layers, and a hypoxic core. While the tumor spheroid provides a physiological tumor model, other cell types within the surrounding tumor microenvironment are essential for tumor behavior and subsequent cancer progression. The tissue vasculature provides a critical component for tumor progression given the metabolic requirements of a growing tumor, and by incorporating endothelial tubules with the tumor spheroid, we are able to model interactions between vascular networks and growing tumors. At the same time, there is also an important stromal component involved in cancer progression where stromal cells have been shown to promote cell proliferation, dissemination, and drug resistance during cancer development. By using extracellular matrix proteins, we are able to promote the proper physiology for each of these cell types in triple cell coculture and compartmentalize their activities. To evaluate interactions between each cell type, they are fluorescently labeled with fluorophores with different excitation and emission spectra; MCF7 and MDA-MB-231 human breast cancer cell lines express a red fluorescence protein, while human umbilical vein endothelial cells (HUVECs) and human adipose-derived mesenchymal stem cells (hMSCs) are labeled with stable lipophilic membrane dyes. Tumor spheroids are formed using low adhesion microwells and deposited into fully formed HUVEC tubular networks, and the hMSCs are then added within a hydrogel overlay matrix. Cellular interactions and dissemination are monitored via fluorescence microscopy and cell proliferation of the breast cancer cells is monitored using a fluorescence plate reader. The breast cancer spheroids exhibit cell-cell interactions with endothelial tubules and stromal cells, and there is an increase in cell proliferation and invasion over standard spheroid monoculture model.
Citation Format: Gabriel J. Benton, Jay George, Gerald DeGray, Irina Arnaoutova, Hynda K. Kleinman. A comprehensive 3D triple coculture model for evaluating breast cancer progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2033. doi:10.1158/1538-7445.AM2014-2033
Abstract 2041: Development and analysis of mouse brain tumor models derived from neural stem cells expressing activated ALK
Authors: Onishi Nobuyuki , Sampetrean Oltea , Sugihara Eiji , Saya Hideyuki 
Published: May 2015

Abstract
Neural Stem Cells (NSCs), having self-renewal and multipotent ability, are considered one of the cells-of-origin of glioblastoma maltifome (GBM). Although NSCs can be enriched in neurosphere floating culture with serum-free media containing EGF/FGF as a classical method, neurosphere is composed of not only NSCs but also differentiated and apoptotic cells. Therefore, we utilize the method for efficient derivation of NSCs with long-term self-renewal and differentiate capacity in adherent culture. Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase first identified in a chromosomal translocation associated with anaplastic large cell lymphomas. Subsequently, new ALK translocations were found in a fraction of non-small-cell lung cancers and in other solid tumors. The function of full-length ALK is involved in neuronal cell differentiation, regeneration and synapse formation. Recently, gene amplification and mutations of full-length ALK were identified in neuroblastoma. Furthermore, it is reported that ALK and PTN, ligand of ALK, are required for maintenance of the stem cell population in GBM. Although constitutive activation of ALK signaling results in cell transformation, little is known about the tumorigenic mechanisms induced by activated ALK. We reasoned that ALK activity has a crucial role in GBM. To verify this hypothesis, human GBM stem cell lines were treated with crizotinib, ALK inhibitor. Crizotinib could suppress the proliferation of human GBM stem cell lines in dose-dependent-manner. Next, we have established a stable mouse model of brain tumor transplanting the genetically modified NSCs. Active mutant of H-RAS could transform the Ink4a/Arf KO NSCs but not WT NSCs. However, transplanting of WT NSCs transduced activated ALK could rapidly formed highly proliferative and invasive brain tumors. Histological characteristics of these tumors resembled human GBM phenotype demonstrating necrosis, perivascular cuffing and giant cell formation. Although the activated H-RAS increased expression of Ink4a in WT NSCs, but the activated ALK never changed. On the basis of these findings, we propose a specific regulation against tumor suppressor genes by activated ALK.
Citation Format: Nobuyuki Onishi, Oltea Sampetrean, Eiji Sugihara, Hideyuki Saya. Development and analysis of mouse brain tumor models derived from neural stem cells expressing activated ALK. [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 2041. doi:10.1158/1538-7445.AM2014-2041
Abstract 2084: RhoGDI2 is associated with HGF-mediated tumor invasion through VEGF in stomach cancer
Authors: Koh Sung A. , Lee Kyung Hee , Choi Eun Young , Kim Min Kyoung , Jang Byung Ik , Lee Si Hyung , Kim Kyeong Ok , Kim Kook Hyun , Kim Jae Ryong , Kim Sang Woon , Kim Se Won 
Published: May 2015

Abstract
RhoGDP dissociation inhibitor 2(RhoGDI2) has been identified as a regulator of tumor metastasis; however, its role in cancer remains controversial. The aims of this study were to analyze RhoGDI2 in gastric cancer growth and metastasis, and to determine its possible signaling pathway.The level of expression of RhoGDI2 was further confirmed by real time RT-RCR and Western blot analysis. Transfection of cells with RhoGDI2 shRNA resulted in no effects of cell proliferation, as determined with MTT assays. In an in vitro invasion assay, significantly fewer cells transfected with RhoGDI2 shRNA,compared with control cells, were able to invade across a Matrigel membrane barrier. The role of RhoGDI2 in the level of HGF-induced up-regulation of VEGF was measured by knockdown of RhoGDI2 with RhoGDI2 shRNA and a chromatic immuno-precipitation assay.The levels of RhoGDI2 and VEGF were up-regulated in cells treated with HGF in a dose-dependent manner. HGF-induced up-regulation of VEGF was repressed by RhoGDI2 knockdown. HGF-induced upregulation of phosphorylated ERK and P38 levels was inhibited in RhoGDI2 knockdown cells. HGF enhanced the binding activity of RhoGDI2 to the VEGF promoter in control cells, but not in RhoGDI2-shRNA cells. Findings of this study also showed a statistically significant difference in the mean RhoGDI2 level before and after surgery (p&lt;0.01) and the mean level of RhoGDI2 before surgery showed a statistically significant difference depending on lymphatic, neural invasion and stage (p&lt;0.05).
In conclusion, RhoGDI2 might play an important role in up-regulation of VEGF induced by HGF and contributes to HGF-mediated tumor invasion and metastasis, which may serve as a promising target for gastric cancer therapy.
Note: This abstract was not presented at the meeting.
Citation Format: Sung Ae Koh, Kyung Hee Lee, Eun Young Choi, Min Kyoung Kim, Byung Ik Jang, Si Hyung Lee, Kyeong Ok Kim, Kook Hyun Kim, Jae Ryong Kim, Sang Woon Kim, Se Won Kim. RhoGDI2 is associated with HGF-mediated tumor invasion through VEGF in stomach cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2084. doi:10.1158/1538-7445.AM2014-2084