bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3872: A lineage-selective transcriptional pathway linking lung differentiation and cancer metastasis.
Authors: Cheung William K.C. , Zhao Minghui , Liu Zongzhi , Cao Paul D. , Stevens Laura E. , Westbrook Thomas F. , Nguyen Don X. 
Published: August 2014

Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide. This poor prognosis is due to the rapid metastatic progression of this disease, yet the mechanisms that govern lung cancer dissemination and colonization are unclear. Through an integrated approach, we identified an alveolar cell-selective gene signature that stratifies lung adenocarcinoma (ADC) into molecular subtypes of distinct prognosis and differentiation states. This transcriptional program is regulated in part by the cell fate transcription factors, GATA6 and HOPX, which are normally required for proper alveolar differentiation. In an experimental model, suppression of GATA6 and HOPX cooperatively enhances metastatic competence of lung ADC cells. Whole genome RNA sequencing reveals that this transcriptional network can modulate specific target genes and pathways involved in airway epithelial differentiation and invasion. Our findings identify a novel cell lineage molecular program whose perturbation enhances lung cancer metastasis.
Citation Format: William K.C. Cheung, Minghui Zhao, Zongzhi Liu, Paul D. Cao, Laura E. Stevens, Thomas F. Westbrook, Don X. Nguyen. A lineage-selective transcriptional pathway linking lung differentiation and cancer metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3872. doi:10.1158/1538-7445.AM2013-3872
Abstract 3883: Robo1, a new target, by Wnt and androgen receptor signaling in castration resistant prostate cancer.
Authors: Yokoyama Noriko N. , Sun Zheng , Sakai Toshinori , Hoang Bang H. , Zi Xiaolin 
Published: August 2014

Abstract
Androgen receptor (AR) and β-catenin/TCF-4 signaling both play a critical role during prostate cancer progression to castration-resistance and cross-talk with each other. Therefore, identifying novel down-stream targets that are co-regulated by AR and β-catenin/TCF-4 signaling is important for understanding the development of castration-resistant prostate cancer (CRPC). Robo1, a transmembrane receptor of Slit, is known for its roles in neurogenesis and angiogenesis. Previous studies have shown that Robo/Slits are aberrantly expressing in different cancers. We have shown that Robo1 is over-expressed in androgen-insensitive prostate cancer cell lines (C4-2B, PC3, 22RV1) compared to androgen-sensitive lines (LNCaP and LAPC-4), and absent in normal prostate epithelial cells. Androgen deprivation resulted in enhanced expression of Robo1 and addition of synthetic androgen R1881decreased Robo1 expression in LNCaP cells. In addition, Wnt 3A and 5A conditioned medium stimulation increased Robo1 mRNA expression in LNCaP cells. Inhibition of Wnt signaling by overexpression of secreted Wnt antagonists Wnt-inhibitory factor-1 (WIF-1) and Frzb/sFRP3 in two CRPC cell lines, decreased the expression of Robo1. Using GenBank and MatInspector software, we have identified potential binding sites for TCF-4 in the 5’ flanking promoter region of the ROBO1 gene. Chromatin immunoprecipitation followed by real-time PCR analysis revealed that TCF-4 binds to the ROBO1 promoter at two predicted sites, and that WIF-1 and Frzb/sFRP3 expression inhibited its promoter binding. Overexpression of WIF-1 and Frzb/sFRP3 also inhibited the promoter activity of Robo1. Knock-down of Robo1 by short-hairpin RNA in PC3 cells resulted in dramatic morphological changes with increased cell aggregation and adhesion. Taken together, our results indicate that Robo1 is a co-target of Wnt and AR signaling. Further studies are in progress to define the functional role of Robo1 in CRPC.
Citation Format: Noriko N. Yokoyama, Zheng Sun, Toshinori Sakai, Bang H. Hoang, Xiaolin Zi. Robo1, a new target, by Wnt and androgen receptor signaling in castration resistant prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3883. doi:10.1158/1538-7445.AM2013-3883
Abstract 3886: Activated insulin-like growth factor (IGF) signaling pathway is a potential therapeutic target for brain metastasis from lung cancer.
Authors: Wu Pei-Fang , Lin Ching-Hung , Huang Wen-Chang , Feng Wen-Chi , Lu Yen-Shen , Yang Chih-Hsin , Cheng Ann-Lii 
Published: August 2014

Abstract
Background: Brain metastasis is a formidable challenge in lung cancer treatment. The incidence has been increasing recently because of the advances of treatment which leads to prolonged survival of many patients.
Methods: We established xenograft model of brain metastasis. Repeated rounds of in vivo selection and ex vivo primary cultures of the brain metastases resulted in a cell line with a high propensity to metastasize to the brain. Brain-tropism was confirmed by bioluminescence study. Gene expression profiles between parental lung cancer cells (PC9) and brain-tropic cells (PC9-Br) was compared by Agilent Gene Expression Microarray followed by Ingenuity Pathway Analysis. The biologic effects and clinical implications of the candidate molecules were further investigated.
Results: Significant activation of IGF and WNT signaling pathways was detected in PC9-Br, as compared with the parental cells. We selected IGF pathway as the first step to explore the potential therapeutic implication. Western blot and RT-PCR validated the results of IGF2 overexpression and activated IGF1R (pIGF1R) in PC9-Br cells. In vitro drug sensitivity tests showed that PC9-Br, in comparison to parental cells, was more resistant to erlotinib, an EGFR TKI (IC50: 30nM for PC9 and 189nM for PC9-Br). Knocking down IGF2 expression in PC9-Br reversed the drug resistance, while adding IGF2 to PC9 enhanced the resistance. In clinical samples, there was a significantly higher expression of pIGF1R in 26 brain metastases as compared to their paired primary lung tumors (mean of H score differences=40.96, 95% C.I.=10.96∼70.96, P=0.0094).
Conclusions: IGF signaling pathway is activated in brain-tropic lung cancer cells and could potentially be a therapeutic target for brain metastasis.
Acknowledgement: This study was supported by Research Grant 101-M2002 from the National Taiwan University Hospital.
Citation Format: Pei-Fang Wu, Ching-Hung Lin, Wen-Chang Huang, Wen-Chi Feng, Yen-Shen Lu, Chih-Hsin Yang, Ann-Lii Cheng. Activated insulin-like growth factor (IGF) signaling pathway is a potential therapeutic target for brain metastasis from lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3886. doi:10.1158/1538-7445.AM2013-3886
Abstract 3889: GRM1 over-expression in melanoma cells promotes microvesicle formation which functions in stimulating angiogenesis.
Authors: Koo Jasmine J. , Wen Yu , Li Jiadong , Chen Suzie , Goydos James 
Published: August 2014

Abstract
Our group has reported that metabotropic glutamate receptor 1 (GRM1) as an oncogene and a potential therapeutic target for melanoma. More than 60% of human melanoma expresses GRM1, while normal melanocytes do not. In a Phase-0 trial of riluzole (an oral inhibitor of GRM1) in patients with advanced melanoma we showed suppression of the PI3K/AKT and MAPK pathways in melanoma specimens in 34% of the patients.
Our group found that enhanced expression of GRM1 in a subclone of a melanoma cell line (UACC903) that normally expresses low levels of GRM1 stimulated angiogenesis via activation of the AKT-mTOR-HIF1-IL8, VEGF signaling pathway. Increasing GRM1 expression promoted membrane blebbing (a phenomenon that appears to lead to microvesicle formation) and riluzole treatment inhibited this effect. Suppression of GRM1 expression using an inducible siRNA construct inhibits the blebbing phenomena and microvesicle formation. Therefore, we hypothesize that GRM1 expression promotes microvesicle formation that may be involved in stimulating angiogenesis and tumor progression. Through electron-microscope and flow cytometry analysis, we have confirmed that increased GRM1 expression enhanced microvesicle secretion into the medium in cell culture and that knocking down GRM1 expression significantly reduced the quantity of microvesicle secretion. Furthermore, intra-tumor injection of collected microvesicles into two different melanoma xenograft tumors (UACC903 and C8161) demonstrated that the microvesicles formed from high GRM1 expressing cells promoted tumor growth and angiogenesis. We also showed that microvesicles from high GRM1 expressing cells increased endothelial cell proliferation exhibited measured using a BrdU incorporation assay.
Our preliminary data demonstrate that GRM1 expression promotes microvesicle formation and that these microvesicles are associated with angiogenesis. Research on the molecular events associated with the phenomenon is ongoing.
Citation Format: Jasmine J. Koo, Yu Wen, Jiadong Li, Suzie Chen, James Goydos. GRM1 over-expression in melanoma cells promotes microvesicle formation which functions in stimulating angiogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3889. doi:10.1158/1538-7445.AM2013-3889
Abstract 3892: BATF3 is a novel regulator of breast cancer cell invasion.
Authors: Stein Elliot , Jia Di , Moses Marsha 
Published: August 2014

Abstract
The escape from tumor dormancy has been shown to be mediated by the acquisition of the angiogenic phenotype. Utilizing an in vivo model that reliably recapitulates the transition from the preangiogenic to the angiogenic phenotype, we have identified and validated the differential expression of a number of genes including a basic leucine zipper transcription factor, ATF-like-3 (BATF3). We further found that the mRNA level of BATF3 is significantly upregulated in angiogenic tumor lesions compared to preangiogenic lesions. In order to investigate the role of BATF3 in breast cancer neovascularization, we established a panel of ER+ and ER- breast cancer cell lines, MCF7 and MDA-MB-231, respectively, which stably overexpress BATF3 by lentiviral transduction. Cells overexpressing BATF3 exhibited significantly increased levels of VEGF (vascular endothelial growth factor) compared to their wild type counterparts. Overexpression of BATF3 also significantly increased cell invasion in both cell lines. Moreover, MMP-9 (Matrix Metalloproteinase-9) levels and activity were significantly increased in MDA-MB-231-BATF3 cells. This latter observation suggested that the increased invasiveness observed might be due to elevated levels of MMP-9, which has been shown to regulate tumor cell invasion by remodeling the surrounding extracellular matrix. TIMP-1, an endogenous inhibitor of MMP-9 activity, was also significantly increased in MDA-MB-231-BATF3 cells, however the ratio of MMP-9 to TIMP-1 is dramatically higher in these cells as compared with control cells. Interestingly, BATF3 also significantly suppressed cell proliferation in both the MDA-MB-231 and MCF7 cell lines. Taken together, these data support the conclusion that BATF3 may play a dual role in the regulation of tumor angiogenesis, growth and progression. (Supported by NIH P01 CA045548, The Breast Cancer Research Foundation, The Advanced Medical Research Foundation, and the Harvard College Research Program).
Citation Format: Elliot Stein, Di Jia, Marsha Moses. BATF3 is a novel regulator of breast cancer cell invasion. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3892. doi:10.1158/1538-7445.AM2013-3892
Abstract 3903: AltaBluTM and Microfil 3D imaging of tumor vasculature.
Authors: Small Daniel , Weinstein David , O'Day Christine , Knitter Glenn , Ouellette Naveen , Pinkos Liane , Vasquez Sergio X. , Shah Neha 
Published: August 2014

Abstract
As angiogenesis inhibitors have proven to be valuable agents in oncology there is a need to measure changes in vasculature for these and other related agents. Many of the angiogenesis inhibitors, though reducing tumor volume by reducing nutrient access to the tumor, do not always show decreased density of vasculature. This paradox, however, may be attributable to the difficulties of measuring the vasculature. One reason for this problem has been the heterogeneity of vessels in the tumor. With the ability to now scan 360o by 3D microCT imaging of the tumor, all image captured vessels can be measured. Another problem is the limitation of vessel size measured by microCT scanning resolution. Vessels smaller than ∼20 microns cannot be distinguished by size at scan parameters of 10 micron voxel resolution. In addition, agents used for imaging have their own limitations. Microfil is a polymer based radiopaque imaging reagent whereas AltaBlu is a proprietary formulation of a non-soluble radiopaque colloid suspension. For reasons not entirely clear, we do not believe Microfil enters capillaries since we have not observed it in the venous side of an arterial infusion. We believe AltaBluTM, can pass into smaller vessels since we have occasionally seen small amounts on the venous side, but these smaller vessels cannot be adequately measured in diameter by microCT scanning. We hypothesized that even though we may not be able to see smaller vessels by AltaBluTM, we might be able to see more of the smaller vessels due to improved reagent penetration and would therefore be more sensitive to changes in small vessel populations. Herein, we have compared perfusion of tumors via AltaBluTM and Microfil to determine the benefits/detractions of the various agents and used a variety of measuring parameters such as vessel radius, average vessel length, vessel density, tortuosity, and vessel branching factors in AltaViewerTM software to determine the sensitivity of each agent to vascular imaging.
Citation Format: Daniel Small, David Weinstein, Christine O'Day, Glenn Knitter, Naveen Ouellette, Liane Pinkos, Sergio X. Vasquez, Neha Shah. AltaBluTM and Microfil 3D imaging of tumor vasculature. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3903. doi:10.1158/1538-7445.AM2013-3903
Abstract 3916: Differential roles of microglia and macrophages for glioma progression.
Authors: Osswald Matthias , Gramlich Miriam , Liao Yunxiang , Wick Wolfgang , Winkler Frank 
Published: August 2014

Abstract
Glioblastomas belong to the tumors with the worst prognosis. One reason for the short survival time after diagnosis is the invasiveness of these tumors, which makes a total resection impossible, and hinders effective local therapies. So far, the exact role of the resident microglia and blood macrophages in the process of tumor cell invasion remains unclear. We investigated the role of these immune cells using CX3CR1 transgenic BL/6 mice. In heterozygous CX3CR1-GFP mice, the function of microglia or macrophages is not impaired but both cell types can be tracked over time by stable GFP expression; homozygous mice have both GFP-labeled microglia and macrophages, but lack a functional CX3CR1 chemokine receptor. Both mice strains received a chronic cranial window with subsequent stereotactic Gl261 glioma cell injection into the brain three weeks later. The invasion dynamics of the stably dsRed-transduced tumor cells was monitored using intravital two photon microscopy. In homozygous animals, tumor cells migrated faster than in heterozygous mice (4,6 μm/h vs. 3 μm/h, p&lt;0.001). Both groups showed a perivascular tumor cell invasion pattern. Moreover, single microglia or macrophage cells showed intracellular RFP-positive fragments as a sign of glioma cell phagocytosis; this was observed only in heterozygous animals and not in homozygous animals lacking a functional CX3CR1 receptor. To decipher the role of resident microglia vs. macrophages in glioma invasion, blood macrophages were depleted in heterozygous CX3CR1 mice by intravenous injection of clodronate liposomes. In those mice tumor cell invasion was dramatically reduced. Pre-existing brain resident microglia was not affected by clodronate treatment. All in all, these results implicate a CX3CR1-dependent proinvasive role for blood-borne macrophages in glioma cell invasion in the live mouse brain, whereas residential microglia seems to exert anti-glioma effects. This microglia - macrophage dichotomy has implications for therapies aiming at inhibition of glioma invasion, via CX3CR1 targeting and beyond.
Citation Format: Matthias Osswald, Miriam Gramlich, Yunxiang Liao, Wolfgang Wick, Frank Winkler. Differential roles of microglia and macrophages for glioma progression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3916. doi:10.1158/1538-7445.AM2013-3916
Abstract 3917: Utilizing optical imaging technologies to screen candidate ADC antibodies.
Authors: Lin Xin , Peterson Norman , Wilson George , Kamal Adeela , Harper Jay 
Published: August 2014

Abstract
Antibody-drug conjugates (ADCs) represent a promising new therapeutic option to treat cancer where powerful cytotoxic compounds are conjugated to antibodies targeting a tumor-associated antigen. Molecular imaging allows relatively quick, non-invasive assessment of biological and biochemical processes in living subjects and when applied to research and development of ADC therapeutics, it has the potential to expedite the drug development process. The current study aims to evaluate optical imaging as a tool to aid in the selection of antibody candidates by using imaging data to predict in vivo efficacy of ADC therapeutics. In this study, candidate antibodies with engineered cysteines for site-specific conjugation of payloads were successfully labeled with the near-infrared fluorescent dye, alexa fluor 750, to achieve a degree of labeling of 2 dyes per antibody. Mice bearing target-positive tumors were treated with the dye-labeled antibodies, and were imaged at 1, 2, and 6 days post-injection using a fluorescence molecular tomography (FMT) in vivo imaging system. The tumor and major organs were subjected to ex vivo optical imaging and confirmatory immunofluorescence staining. Differences were observed in the tumor uptake, biodistribution profiles, and penetration of the four candidate antibodies. Concurrently, in vivo efficacy studies are being conducted with ADCs comprised of these lead antibodies, and the imaging data, along with the binding affinity and internalization rate of each antibody, will be compared to the pharmacology data to determine if a predictive correlation exists. Once established, correlations between the imaging data and efficacy results would justify the use of molecular imaging to screen large panels of antibodies to aid in the lead selection for ADCs, thus enabling significant time and cost reduction for the development of ADC therapeutics.
Citation Format: Xin Lin, Norman Peterson, George Wilson, Adeela Kamal, Jay Harper. Utilizing optical imaging technologies to screen candidate ADC antibodies. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3917. doi:10.1158/1538-7445.AM2013-3917
Abstract 3922: A comparative study of affibody, antibody and EGF for near-infrared fluorescence imaging of EGFR- and EGFRvIII-expressing tumors.
Authors: Gong Haibiao , Kovar Joy L. , Cheung Lael , Rosenthal Eben L. , Olive David M. 
Published: August 2014

Abstract
Aberrant overexpression and/or activation of epidermal growth factor receptor (EGFR) is associated with many types of cancers. EGFR variant III (EGFRvIII) is a common in-frame deletion mutant, which lacks a large part of the extracellular portion (exons 2-7), including components of the ligand-binding domain. Although EGFR has been extensively studied as
a molecular imaging target, information about EGFRvIII-targeted molecular imaging is lacking. In this study, an EGFR-specific affibody, a therapeutic antibody (panitumumab) and the ligand EGF were labeled with IRDye 800CW (Ex/Em: 774/789 nm), and named as Aff800, Pan800 and EGF800 respectively. The binding affinities of the labeled agents were compared in cell-based assays using a rat glioma cell line F98 parental (F98-p) lacking EGFR, and two F98-derived transgenic cell lines expressing EGFR or EGFRvIII (designated as F98-EGFR and F98-vIII respectively). Results showed that all agents could bind to F98-EGFR, with Pan800 having the highest binding affinity, followed by Aff800 and EGF800. Pan800 and Aff800, but not EGF800, bound to F98-vIII with similar affinities. In vivo animal imaging studies demonstrated that compared to F98-p tumor signals, F98-EGFR tumor generated higher signals for all three agents. However, in the case of F98-vIII, only Pan800 and Aff800 signals were higher. Analysis of tissue lysates showed that a large portion of Pan800 was degraded into small fragments in F98-EGFR and F98-vIII tumors, possibly due to proteolytic digestion after its specific binding and internalization. In conclusion, Pan800 and Aff800 could be used as imaging agents for both wild type EGFR and EGFRvIII, whereas EGF800 only targets wild type EGFR.
Citation Format: Haibiao Gong, Joy L. Kovar, Lael Cheung, Eben L. Rosenthal, David M. Olive. A comparative study of affibody, antibody and EGF for near-infrared fluorescence imaging of EGFR- and EGFRvIII-expressing tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3922. doi:10.1158/1538-7445.AM2013-3922