bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4983: The role of bone marrow derived tumor stromal cells in intestinal tumor response to Thymidylate Synthase Inhibitors inhibitors in the ApcMin/+ mouse.
Authors: Acharya Grishma , Davis Celestia , Tisdale Nikeya , Pena Maria Marjorette O. 
Published: August 2014

Abstract
Historically, most anti-cancer therapies have been developed to target cancer cells. For many decades, inhibitors of the enzyme thymidylate synthase (TS), such as fluoropyrimidines, have been used in the clinical management of various cancers. However, their clinical utility has been limited by their toxicity to normal cells and acquired resistance by tumor cells. More recently, the role of non-neoplastic cells in the tumor microenvironment on tumor initiation and progression has been firmly established. These non-neoplastic cells infiltrate the tumor and together with the extracellular matrix, blood vessels, connective tissue, and secreted molecules make up the tumor stroma. These cells are thought to play a role in tumor response to therapy. While therapeutic efficacy is often measured by its impact on tumor burden, the impact of TS inhibitors on tumor stromal cells is largely unknown.
Bone marrow derived cells (BMDCs) are a major component of the tumor stroma.The goal of this project is to determine theirin mediating tumor response to systemic therapy with TS inhibitors. We hypothesize that in addition to targeting tumor cells, tumor stromal cells are also direct of TS inhibitors and thattumor response to therapy may in fact be dictated by stromal sensitivity to the therapy.To test this hypothesis, we generated chimeric wherein the chemo-sensitivity of intestinal tumor stromal cells to TS inhibitors was different from that of the tumor cells. We transplanted ApcMin/+ mice, a genetic model of intestinal tumorigenesis, with bone marrow cells that weregenetically modified to express a drug-resistant TS molecule from E. coli. We found that tumors in these mice were more resistant to a combined therapy of TS inhibitors as compared to mice transplanted with non-modified marrow. We identified examine the response of BMDCs in the tumor stroma that have previously been shown to promote intestinal tumor development, namely, myeloid derived suppressor cells (MDSCs), mast cells and T-regulatory (Treg) cells. We found that MDSCs, but not mast cells or Tregs were specifically sensitive to 5-fluorouracil (5-FU). Our data suggest that tumor response to 5-FU are at least in part mediated by MDSCs. Current studies are aimed at examining the response of other stromal components to 5-FU with the goal of developing strategies to enhance tumor sensitivity to TS inhibitors.
Citation Format: Grishma Acharya, Celestia Davis, Nikeya Tisdale, Maria Marjorette O. Pena. The role of bone marrow derived tumor stromal cells in intestinal tumor response to Thymidylate Synthase Inhibitors inhibitors in the ApcMin/+ mouse. [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 4983. doi:10.1158/1538-7445.AM2013-4983
Abstract 5015: Ablation of a disintegrin and metalloproteinase 10 (ADAM 10) induces significant pancreatic tumor heterogeneity and blocks cancer metastasis.
Authors: Hall Jason C. , Crawford Howard C. 
Published: August 2014

Abstract
Pancreatic ductal adenocarcinoma (PDA) is the 4th leading cause of cancer related death in the U.S. This disease has a poor prognosis due to late detection and rapid progression to metastasis. ADAM10 is a membrane bound metalloproteinase responsible for shedding bioactive molecules and inducing regulated intra-membrane proteolysis of cell surface proteins such as Notch. Both ADAM10 and Notch are highly expressed in patients with PDA, with the latter being implicated in PDA progression. We have found that genetic ablation of ADAM10 in the KrasG12D/+;Ptf1aCre/+ mouse PDA model altered tumor character to favor a cystic phenotype, mixed with low grade pancreatic intraepithelial neoplasia (PanIN) and PDA. Though ADAM10 knockout mice retain the ability to form locally invasive cancer, they live 50% longer than control mice, essentially to a full 2-year life span. The phenotypes we observe closely mimic Notch-2 knockout mice, consistent with ADAM10’s role as the primary Notch activating proteinase. Further examination revealed that ADAM10 knockout mice did not show significant liver metastasis compared to control, despite their local invasiveness. The mechanism through which ADAM 10 controls a cancer cell's ability to establish distant metastases will be explored.
Citation Format: Jason C. Hall, Howard C. Crawford. Ablation of a disintegrin and metalloproteinase 10 (ADAM 10) induces significant pancreatic tumor heterogeneity and blocks 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 5015. doi:10.1158/1538-7445.AM2013-5015
Abstract 5022: Early progenitor cells but not late luminal progenitor cells preserve in invasive breast carcinoma.
Authors: Zhang Kevin J. , Liu Suling , Siegelmann-Danieli Nava , Zhang Ping L. 
Published: August 2014

Abstract
Background CD133 and CD117 represent markers of human breast tissue differentiation. CD133 is an early progenitor marker while CD117 represents late luminal progenitor marker (Lim, et al, Nature Medicine 2009). Morphologic expression of the two markers has not been well established in paraffin embedded tissue of human breast lesions.
Design In this study, we evaluated CD133 and C117 expression in different human breast lesions. Group 1 consisted of 15 benign breast cases (5 reduction mammoplasty cases with no significant pathology and 10 fibroadenoma or fibrocystic changes). Group 2 (malignant group 2) included 13 breast cases with invasive ductal carcinoma (IDC). Group 3 (malignant group 3) was composed of 12 BRCA-mutant breast cases but only six cases had IDC. All sections from paraffin embedded tissue were immunohistochemically stained for CD133 (AC133 clone) and CD117 (monoclonal antibody). Expression of the two markers in normal breast glands adjacent to lesions (normal controls), benign lesions (benign controls) and IDC were evaluated and positive rate was calculated.
Results Both CD133 and CD117 were expressed in normal breast glands (normal controls) of all three groups and benign breast lesions (Table 1). However, the expression of CD133 was detected in the majority of IDC lesions as compared to low positive percent of CD117 expression in both groups 2 and 3 (Table 1). Recombined tumor cases, based on the molecular luminal status, also showed 56 - 70% CD133 positivity but 0 - 20% CD117 positivity in IDC cells.
Table 1. CD133 and CD117 in benign and malignant breast lesions Group 1, total Group 2, total Group 3, total CD133+ in normal 15/15 (100%) 13/13 (100%) 12/12 (100%) CD117+ in normal 15/15 (100%) 13/13 (100%) 11/12 (91%) Group 1, Benign Lesions Group 2, Invasive cancer Group 3 Invasive cancer CD133+ in lesions 10/10 (100%) 8/13 (61%) 4/6 (67%) CD117+ in lesions 9/10 (90%) 1/13 (8%) 1/6 (17%)
Conclusions We show that normal breast glands expressed both CD133 and CD117, compatible with the presence of stem cell niche in normal breast ducts and acini. However our data suggest that in IDC, there is presence of early progenitor cells but not late luminal progenitor cells, regardless of the molecular luminal status, supporting the view that cancer stem cells exist in the invasive breast carcinoma.
Citation Format: Kevin J. Zhang, Suling Liu, Nava Siegelmann-Danieli, Ping L. Zhang. Early progenitor cells but not late luminal progenitor cells preserve in invasive breast carcinoma. [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 5022. doi:10.1158/1538-7445.AM2013-5022
Abstract 5023: Stem cell hypothesis and function of Lgr5 in the development of colon cancer.
Authors: Hirsch Daniela D. , Barker Nick , McNeil Nicole , Hu Yue , Camps Jordi , McKinnon Katherine , Clevers Hans , Ried Thomas , Gaiser Timo 
Published: August 2014

Abstract
Similar to normal colonic epithelium, colorectal carcinomas (CRC) comprise subpopulations of cells with stem-like properties. Leucine-rich-repeat-containing G-protein-coupled receptor 5 (Lgr5) is associated with these stem cells in normal colonic epithelium and CRC. Here, we analyzed the functional and molecular consequences of shRNA-mediated silencing of Lgr5 in CRC cell lines SW480 and HT-29. Additionally, we exposed Lgr5-EGFP-IRES-Cre-ERT2 mice to azoxymethane/dextrane sodium sulfate (AOM/DSS) which induces inflammation-driven colon tumors. Tumors were then flow-sorted into Lgr5 high and low epithelial cell fractions and molecularly characterized using gene expression profiling and array comparative genomic hybridization. Silencing of Lgr5 in SW480 cells resulted in a depletion of the spheroid cell fraction, yet did not affect the adherently growing cell population. It also reduced proliferation, migration, and colony formation in vitro as well as tumorigenicity in vivo, consistent with a down-regulation of Notch signaling. Spheroid cells were enriched for several stem cell-associated genes including Lgr5. Lgr5 high cells of AOM/DSS-induced mouse colon tumors displayed higher Wnt signaling compared to both their Lgr5 low tumor cell counterparts as well as Lgr5 high normal colon stem cells. Lgr5 high and low tumor cells were both chromosomally stable. In conclusion, our data suggest Lgr5 as a functionally important marker for stem-like cells in CRC, representing a potential therapeutic target.
Citation Format: Daniela D. Hirsch, Nick Barker, Nicole McNeil, Yue Hu, Jordi Camps, Katherine McKinnon, Hans Clevers, Thomas Ried, Timo Gaiser. Stem cell hypothesis and function of Lgr5 in the development of colon 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 5023. doi:10.1158/1538-7445.AM2013-5023
Abstract 5026: Targeting non-canonical Wnt signaling in acute myeloid leukemia.
Authors: de Boer Jasper , Walf-Vorderwulbecke Vanessa , Horton Sarah J. , Williams Owen 
Published: August 2014

Abstract
Childhood acute myeloid leukemia (AML) is a heterogeneous disease, with distinct cytogenetic sub-groups and responses to chemotherapy. Greater understanding of the molecular mechanisms underlying the different forms of this disease offers the possibility of developing novel therapies targeting disease-specific signaling pathways. We have recently analysed the role of non-canonical Wnt signaling induced Rac activation in the most frequent sub-type of childhood AML, associated with chromosomal translocations affecting the mixed lineage leukemia (MLL) gene. Our data indicate that MLL-fusions utilize non-canonical Wnt signaling, by inducing transcriptional activation of Frat gene expression and stimulating Rac activation through a signaling pathway involving GSK3 and DVL1 components. This pathway can be disrupted by shRNA-mediated silencing of Frat or Dvl expression, or by pharmacological inhibition of GSK3. Interestingly, the DVL-GSK3 signaling pathway can be disrupted by expression of a dominant negative FRATN mutant, that lacks the GSK3-binding domain, even in the absence of endogenous FRAT expression. FRATN inhibits growth, survival and disease progression of MLL-fusion expressing leukemic cells. These experiments have now been extended to the analysis of the anti-leukemia effects of FRATN expression in non-MLL-rearranged leukemia cell lines. This study highlights the potential of this novel signaling pathway as a target for future novel therapies of AML.
Citation Format: Jasper de Boer, Vanessa Walf-Vorderwulbecke, Sarah J. Horton, Owen Williams. Targeting non-canonical Wnt signaling in acute myeloid leukemia. [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 5026. doi:10.1158/1538-7445.AM2013-5026
Abstract 5049: Targeting the Notch and mTOR pathways in diffuse intrinsic pontine glioma.
Authors: Hutt Marianne , Goldstein Wendy , Nazarian Javad , Price Antoinette , Lim Kah Jing , Warren Katherine , Chang Howard , Eberhart Charles , Raabe Eric 
Published: August 2014

Abstract
Diffuse intrinsic pontine glioma (DIPG) is a universally fatal pediatric brain tumor which is known to have frequent alteration of mTOR signaling. Analysis of DIPG tissue obtained through the Mid-Atlantic DIPG Consortium (MADC) also shows high level activation of Notch pathway effectors HES4 and HES5. We have established JHH DIPG1, a human DIPG xenograft and neurosphere cell line from a rapid autopsy specimen obtained through the MADC. Notch 1 and 3 and Notch downstream effectors, Hes1, Hes5 and Hey1, are highly expressed in JHH DIPG1 and a second DIPG line, SU DIPG1. These DIPG cell lines also express high level phospho-S6 and phospho-AKT 473, indicating activation of TORC1 and TORC2. Notch and mTOR pathway signaling is equal to or exceeding that observed in glioblastoma neurosphere cell lines. Notch targeting using a gamma-secretase inhibitor leads to a dose-dependent reduction in cell proliferation of up to 30% (p=0.05) as well as inhibition of phospho-AKT 473, suggesting that inhibition of the NOTCH pathway targets TORC2 complexes. BrdU incorporation also showed that treatment of DIPG cell lines with a TORC1 inhibitor also has up to a 60% attenuation of cell proliferation (p&lt;0.005) in treated DIPG cells compared to non-treated cells and a dose-dependent reduction in phospho-S6, with concomitant upregulation of phospho-AKT 473 indicating TORC2 activation. Dual TORC1 and TORC2 inhibition by combining a rapalog and a gamma-secretase inhibitor may prove to be synergistic in DIPG. Simultaneous treatment with a rapalog and gamma-secretase inhibition suppresses TORC1 and TORC2, as measured by western blot. We are currently investigating the possible mechanism of action of these drugs in DIPG. Our laboratory is investigating additional metabolic inhibitors that can be used with TORC1 and TORC2 inhibitors to further improve treatment options for DIPG. We are currently exploring the role of the Notch and mTOR pathways in DIPG in pre-clinical studies in mice, with the goal of moving targeted inhibitors into clinical trials for these currently highly lethal tumors.
Citation Format: Marianne Hutt, Wendy Goldstein, Javad Nazarian, Antoinette Price, Kah Jing Lim, Katherine Warren, Howard Chang, Charles Eberhart, Eric Raabe. Targeting the Notch and mTOR pathways in diffuse intrinsic pontine glioma. [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 5049. doi:10.1158/1538-7445.AM2013-5049
Abstract 5053: Sonic hedgehog inhibition reduces in vitro tumorigenesis and alters expression of GLI1-target genes in a desmoplastic medulloblastoma cell line.
Authors: Garcia-Lopez R , Vera-Cano B , Vacas-Oleas A , de la Rosa J , Gallo-Oller G , Shahi M H. , Fan X , Alonso M M. , Rey J A. , Castresana Javier S. 
Published: August 2014

Abstract
Medulloblastoma is one of the most frequent and aggressive tumors of childhood. The Sonic hedgehog (Shh) pathway, related to human development, is altered in most medulloblastomas: genes like Ptch, Smo, or Sufu suffer mutations in 15% to 25% of these tumors. We tested Shh inhibition in the Daoy medulloblastoma cell line by two methods: a molecular one (direct Gli1 siRNA inhibition); and a pharmacological inhibition of Smo, upstream of Gli1, by cyclopamine. Afterwards, a comparison of cellular and molecular responses was done. We proved that MTT cell viability, and cell migration assessed by the scratching assay decreased after Shh inhibition. Furthermore, colony formation assay in culture decreased by 70%, and colony formation assay in soft agar decreased up to 90% when Shh inhibition was applied. As a whole, Shh inhibition conferred a less in vitro tumorigenic status to Daoy cells. Moreover, we assessed the expression of different Gli1 target genes and other genes, before and after Shh inhibition, and found that Shh shows a crosstalk with oncogenes and tumor suppressor genes that have been described in numerous tumors. Therefore, we found downregulation of Ptch1, Cyclin D2, Plakoglobin, Nkx2.2, Bmi1, Smo and N-myc after Shh inhibition. Sufu and Gli3 showed parallel results, where Gli1 siRNA did neither decrease nor increase expression of both genes, whereas cyclopamine reduced them in 15-25%. Pax6 mRNA levels were upregulated by either Gli1 siRNA or cyclopamine. Finally, Notch1 was upregulated after inhibition of Shh, while Notch2 showed contrasting results, as siRNA inhibition decreased its expression, while cyclopamine increased it. All these experiments give an overview of the Shh pathway in medulloblastoma, its relationship with other genes, and the demonstration of the efficacy of cyclopamine and Gli 1 siRNA Shh inhibition in vitro.
Citation Format: R Garcia-Lopez, B Vera-Cano, A Vacas-Oleas, J de la Rosa, G Gallo-Oller, M H. Shahi, X Fan, M M. Alonso, J A. Rey, Javier S. Castresana. Sonic hedgehog inhibition reduces in vitro tumorigenesis and alters expression of GLI1-target genes in a desmoplastic medulloblastoma cell line. [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 5053. doi:10.1158/1538-7445.AM2013-5053
Abstract 5070: Cell-free endo180 reveals additional level of endocytic receptor functioning in meningioma.
Authors: Gogineni Venkateswara Rao , Nalla Arun Kumar , Velpula Kiran Kumar , Rao Jasti S. 
Published: August 2014

Abstract
Endo180, also known as uPAR associated protein (uPARAP), is a member of the tri-molecular complex formed by uPA along with uPAR in the endocytic processing of collagen degradation. In the present study, we found that this membrane-bound protein was released into culture supernates of meningioma and other cancer cell types. In addition, we report a tremendous increase of Endo180 transcript and protein levels in irradiated meningioma cells and their culture filtrates. While non-denaturing immunoprecipitation studies suggested that Endo180 interacts with uPA in cell-free conditions, uPA binding was significantly quenched by deglycosylation of solubilized Endo180. Myc-tagged cDNA expression suggested shedding of Endo180 against secretion from meningioma cells. Function blocking and knockdown of Endo180 adversely affected the proliferation of meningioma cells with concomitant decrease in uPA activity and uPAR expression. We also observed a significant rise of Endo180 expression in meningioma clinical samples and tumors in animal models. A further increase of expression was observed among the brain sections of mice infused with irradiated meningioma cells. Taken together, our results demonstrate that solubilization of Endo180 characterizes a different hierarchy of endocytic receptor functioning in meningioma.
Citation Format: Venkateswara Rao Gogineni, Arun Kumar Nalla, Kiran Kumar Velpula, Jasti S. Rao. Cell-free endo180 reveals additional level of endocytic receptor functioning in meningioma. [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 5070. doi:10.1158/1538-7445.AM2013-5070
Abstract 5076: Identification and anti-angiogenic effects of small molecule inhibitors of TEM8.
Authors: Cryan Lorna , Roznik Marinya , McBride Aaron , D'Amato Robert , Christensen Kenneth , Rogers Michael S. 
Published: August 2014

Abstract
Tumor endothelial marker 8 (TEM8) is a gene upregulated on colonic tumor endothelium compared to quiescent normal endothelium. Inhibition of TEM8 using antibodies potently inhibits the growth of a variety of tumor types in mice. This inhibition of tumor growth is accompanied by a reduction in microvessel density within the tumors. Thus, TEM8 appears to represent a tumor specific endothelial marker that has a functional role in tumor angiogenesis. TEM8 is also a receptor for anthrax toxin. In the current study, we used chemical libraries to identify small molecule inhibitors of TEM8 that may have efficacy as inhibitors of tumor angiogenesis and anthrax toxin.
We conducted a fluorescence resonance energy transfer (FRET) based screen of over 270,000 small molecules in order to identify molecules that inhibit the interaction of TEM8 with its well-known ligand anthrax protective antigen (PA). We describe here the identification and anti-angiogenic effects of small molecules that bind to TEM8.
From the initial screen 280 molecules inhibited TEM8/PA interaction by greater than 50%. A secondary screen involved the elucidation of IC50 values for these 280 compounds as inhibitors of the TEM8/PA interaction. Twelve compounds had measurable IC50s in the micromolar range. The anti-angiogenic effects of these compounds were studied in vitro. Of the 12 compounds tested in a human microvascular endothelial cell (HMVEC) proliferation assay, 3 compounds significantly inhibited endothelial cell proliferation after 24 hours (P &lt;0.05), and 5 compounds significantly inhibited proliferation at 72 hours (P &lt;0.05). None of the compounds exhibited measurable cytotoxicity. One of the five compounds tested for effects on HMVEC migration, significantly inhibited migration on a fibronectin coated-surface by 78% (P&lt;0.01).
We have identified a number of small molecule inhibitors of TEM8, some of which display anti-angiogenic effects in vitro. Should these inhibitors also display potent anti-angiogenic effects in vivo, they may serve as lead compounds for the future development of TEM8 therapeutic small molecules. Future studies will focus on determining the effects of these molecules on tumor growth and angiogenesis in mouse models.
Citation Format: Lorna Cryan, Marinya Roznik, Aaron McBride, Robert D'Amato, Kenneth Christensen, Michael S. Rogers. Identification and anti-angiogenic effects of small molecule inhibitors of TEM8. [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 5076. doi:10.1158/1538-7445.AM2013-5076