bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3612: Effect of cancer associated fibroblast on gastric cancer cells under hypoxia
Authors: Kinoshita Haruhito , Yashiro Masakazu , Masuda Go , Kasashima Hiroaki , Morisaki Tamami , Fukuoka Tatsunari , Shibutani Masatune , Yamazoe Sadaaki , Sakurai Katsunobu , Nagahara Hisashi , Kimura Kenjiro , Toyokawa Takahiro , Amano Ryosuke , Kubo Naoshi , Tanaka Hiroaki , Muguruma Kazuya , Otani Hiroshi , Maeda Kiyoshi , Ohira Masaichi , Hirakawa Kosei 
Published: May 2015

Abstract
Background:
Cancer-associated fibroblasts (CAF) have been suggested to be associated with the scirrhous gastric cancer (SGC) progression. SGC have a heterogeneously hypoxic environment which has been currently considered to be associated with aggressive tumor phenotypes cancer. Stromal cell-derived factor (SDF)-1 and C-X-C chemokine receptor type 4 (CXCR4) form an important chemokine/receptor pair, and are supposed to be up-regulated by hypoxia inducible factor-1 (HIF-1). The aim of our study was to clarify the effect of hypoxic environment on the CAF and CXCR4/SDF-1 axis in SGC.
Experimental Design:
Proliferation of SGC cells grown in monoculture and co-culture with CAF under hypoxia. SGC and CAF expression level of CXCR4 and SDF-1 under hypoxia were examined by RT-PCR and ELISA. Proliferation and migration of SGC cells with SDF-1 or hepatocyte growth factor (HGF) or conditioned medium from CAF under hypoxia, furthermore, added c-Met inhibitor or CXCR4 inhibitor.
Results:
The proliferation that co-culture of SGC cells with CAF was significantly increased under hypoxia. The expression level of CXCR4 mRNA was significantly increased under hypoxia in all of SGC cells. SDF-1 concentration level was significantly increased under hypoxia. The proliferation of SGC cells with SDF-1 and CAF was significantly increased. The proliferation of SGC cells with CAF was inhibited by CXCR4 inhibitor under hypoxia. The migration of SGC cells with HGF and CAF was significantly increased. The migration of SGC cells with CAF was inhibited by c-Met inhibitor.
Conclusion:
CAF might up-regulate the proliferation and migration of SGC cells under hypoxia, in comparison with that under normoxia. CXCR4/SDF-1 axis might play an important role for the proliferation of SGC cells under hypoxia.
Citation Format: Haruhito Kinoshita, Masakazu Yashiro, Go Masuda, Hiroaki Kasashima, Tamami Morisaki, Tatsunari Fukuoka, Masatune Shibutani, Sadaaki Yamazoe, Katsunobu Sakurai, Hisashi Nagahara, Kenjiro Kimura, Takahiro Toyokawa, Ryosuke Amano, Naoshi Kubo, Hiroaki Tanaka, Kazuya Muguruma, Hiroshi Otani, Kiyoshi Maeda, Masaichi Ohira, Kosei Hirakawa. Effect of cancer associated fibroblast on gastric cancer cells under hypoxia. [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 3612. doi:10.1158/1538-7445.AM2014-3612
Abstract 3640: IL-9 is involved in the establishment of a tolerogenic milieu that prevents anti-tumor immunity
Authors: Hoelzinger Dominique B. , Dominguez Ana Lucia , Cohen Peter A. , Gendker Sandra J. 
Published: May 2015

Abstract
IL-9 is a Th2 cytokine associated with T regulatory cell function, parasite expulsion and allergic airway inflammation. In many tumors IL-9 contributes to the establishment of a tolerogenic / immunosuppressive environment or acts directly to drive tumor growth, whereas in melanomas it inhibits tumor growth. Little is known about the effect of IL-9 in breast cancer biology. Here we show that IL-9 is a key factor in establishing a permissive growth environment for two murine breast cancer cells lines: TUBO cells that express Her2/neu and 4T1 cells that resemble aggressive, triple-negative breast cancers. We observed that TUBO cells were rejected by 78%, and 4T1 cells by 68% of IL-9 -/- (IL-9ko) mice, and that in the remaining mice the tumors developed later and grew slower than in WT mice. Tumor rejection is CD8+ T cell dependent and is capable of producing a memory response against tumor rechallenge. Delayed depletion of CD8+ T cells in mice that had rejected 4T1 cells showed no tumor growth in 63 % of the mice, suggesting that in these mice the tumor had been completely eradicated and was not held in stasis by immune surveillance. Furthermore we found a 3.7 fold increase (p=0.007) in the number of activated CD8+ T cells derived from IL-9ko mice rejecting tumors as compared to CD8+ T cells from tumor bearing WT mice. More importantly, the transfer of activated splenocytes from IL-9ko mice led to tumor rejection in WT mice (p&lt;0.001). Moreover, WT mice treated with neutralizing anti-IL-9 evidenced slower 4T1 tumor growth compared to untreated and isotype control antibody treated mice. These data suggest that IL-9 neutralization should be examined as an adjuvant to immunotherapeutic or chemotherapeutic approaches.
Supported by the NCI : CA155295
Citation Format: Dominique B. Hoelzinger, Ana Lucia Dominguez, Peter A. Cohen, Sandra J. Gendker. IL-9 is involved in the establishment of a tolerogenic milieu that prevents anti-tumor immunity. [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 3640. doi:10.1158/1538-7445.AM2014-3640
Abstract 3642: Cancer therapy by resuscitating Notch immune surveillance
Authors: Dudimah Duafalia F. , Pellom Samuel T. , Uzhachenko Roman V. , Carbone David P. , Dikov Mikhail M. , Shanker Anil 
Published: May 2015

Abstract
The immunosuppressive tumor microenvironment perturbs numerous immune regulatory networks and usurps host anti-tumor immunity. We discovered that tumor interferes with host hematopoietic Notch system in lung cancer patients. The resultant decrease in immune Notch signaling could be a major causative link in the inadequate induction of anti-tumor immunity. Interestingly, we found that tumor-induced decrease in immune Notch in various mouse solid tumor models could be restored therapeutically by the following two agents. Administration of a novel Delta-like ligand 1 (DLL1) multivalent cluster and the FDA-approved proteasome inhibitor drug bortezomib - which also sensitizes tumors to death signals - could activate Notch 1 signaling in lymphoid cells of tumor-bearing mice without increasing tumor cell proliferation or clonogenicity. Systemic activation of DLL1-Notch signaling could attenuate tumor vascularization as well as increase T cell infiltration in tumor, decrease proportion of regulatory T cells and enhance antitumor T cell function and memory in multiple mouse tumor models. New data also show that bortezomib affects the expression of notch receptors and ligands differentially in lymphocytes and in a wide range of solid tumor cells. Moreover, bortezomib administration increased the expression of Notch target genes Hes 1 and Hey 1 in thymus, lymph node, and spleen, as well as decreased the proportion of regulatory T cells and enhanced T cell production of IFN-γ in tumor-bearing mice. Results indicate that bortezomib-induced activation of Notch target genes Hes 1 and Hey 1 is through its inhibition of NFkB while its activation of another Notch target gene Deltex 1 is mediated via PI3K. The findings suggest a potential synergistic action of bortezomib and DLL1 activation of Notch signaling. The potential of modulating anti-tumor Notch signaling by the prototypic DLL1 cluster in combination with bortezomib presents exciting opportunities to uncover multi-pronged immune stimulatory regimens. Therapeutic restoration of immune Notch signaling could provide effective treatment and recurrence-free survival in cancer patients by breaking tumor resistance, enhancing immune surveillance, and sustaining robust anti-tumor immunity.
Citation Format: Duafalia F. Dudimah, Samuel T. Pellom Jr., Roman V. Uzhachenko, David P. Carbone, Mikhail M. Dikov, Anil Shanker. Cancer therapy by resuscitating Notch immune surveillance. [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 3642. doi:10.1158/1538-7445.AM2014-3642
Abstract 3648: Expression of tolerogenic enzymes IDO-1, IDO-2 and TDO in commonly used mouse tumor models and impact on model selection for evaluation of immunosuppression reversal by novel therapeutics
Authors: Noubade Rajkumar , Kohrt Holbrook , Marshall Lisa , Sagiv-Barfi Idit , Hebb Jonathan , Chester Cariad , Rajapaksa Amanda , Waller Erin , Young Steve , Powers Jay , Jaen Juan 
Published: May 2015

Abstract
Objective:
Inhibition of indoleamine-2,3-dioxygenase-1 (IDO-1), indoleamine-2,3- dioxygenase-2 (IDO-2), and/or tryptophan-2,3-dioxygenase (TDO) represent novel opportunities for reversing the immunosuppressed microenvironment found in cancer patients. However, little is known about the relative expression of these enzymes in tumors and associated lymph nodes of mouse tumor models, including those previously utilized in the preclinical characterization of tool compounds or even clinical candidates that inhibit one of these enzymes. This report describes the systematic characterization of expression of these enzymes in several of the most commonly used mouse tumor models.
Study Design:
Tumor models evaluated included B16F10 melanoma, B16-GMCSF melanoma and PAN02 pancreatic in C57BL/6 mice, and 4T1 breast and CT26 colon in Balb/c mice. Cells were injected s.c. into the flanks of 8-week old female mice. In each model, tumors and draining lymph nodes were collected from separate cohorts of mice when the mean tumor volumes reached 100 and 1,000 mm3, respectively. Expression of the 3 enzymes of interest was assessed using a variety of techniques, including qRT-PCR, Western blot and FACS.
Results:
A highly complex picture arises from our study. Expression levels of each of the enzymes studied here were highly dependent on the choice of tumor cell, the tissue analyzed (tumor vs. lymph node), as well as the stage of growth of the tumor. In general, the most commonly expressed of the 3 enzymes was IDO-1, primarily on tumor cells and dendritic cells in the lymph nodes.
Conclusion:
It is critically important, in the preclinical evaluation of potential new drugs, to select mouse models that recapitulate specific and well-characterized elements of the signaling pathway targeted by those drugs. The results presented in this communication should be of particular interest to those investigators pursuing a therapeutic strategy of immunosuppression reversal.
Citation Format: Rajkumar Noubade, Holbrook Kohrt, Lisa Marshall, Idit Sagiv-Barfi, Jonathan Hebb, Cariad Chester, Amanda Rajapaksa, Erin Waller, Steve Young, Jay Powers, Juan Jaen. Expression of tolerogenic enzymes IDO-1, IDO-2 and TDO in commonly used mouse tumor models and impact on model selection for evaluation of immunosuppression reversal by novel therapeutics. [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 3648. doi:10.1158/1538-7445.AM2014-3648
Abstract 3650: PI3-kinase gamma controls the macrophage M1-M2 switch, thereby promoting tumor immunosuppression and progression
Authors: Kaneda Megan , Gorjestani Sara , Varner Judith A. 
Published: May 2015

Abstract
Innate immune cells (macrophages, monocytes and neutrophils) rapidly migrate to sites of tissue damage where they initially activate T cells (M1 classical response). These cells gradually transition to suppress T cell responses, while stimulating wound healing (M2 alternative response). In tumors, however, the normal immune response is chronically disrupted and an exaggerated immunosuppressive, wound healing, tumor-promoting (M2) response prevails. In order to identify the mechanisms regulating this M2 response in tumor inflammation and to develop novel therapeutics to control it, we set out to explore the role of macrophage signaling in control of the M1-M2 switch.
Using RNA seq analysis of gene expression patterns in M1 and M2 macrophages in vitro and gene expression analysis of myeloid cells in spontaneous and orthotopic mouse models of lung, pancreatic and breast cancer, we found that myeloid cell PI3Kinase gamma controls the switch between the M1-M2 phenotype in human and murine macrophages. PI3Kinase gamma signaling stimulates an immunosuppressive, wound healing gene expression program exemplified by expression of immunosuppressive and pro-angiogenic factors, such as Arginase1, TGFbeta1, PDGFBB, MMP9, and MMP13, and suppression of pro-inflammatory factors such as IL12, iNos, and interferon gamma. Blockade of this pathway by genetic or pharmacological inhibition of PI3Kgamma blocks this immunosuppressive, wound healing gene expression program and stimulates instead a T cell activating gene expression program as well as T cell mediated tumor cell killing. PI3Kgamma blockade inhibits tumor growth and metastasis in mouse models of lung, pancreatic and breast carcinoma. Our studies demonstrate the critical role of PI3Kgamma signaling in the control of the M1-M2 macrophage switch and demonstrate that this kinase is an important therapeutic target to suppress tumor growth by targeting inflammation that is associated with all solid tumors.
Citation Format: Megan Kaneda, Sara Gorjestani, Judith A. Varner. PI3-kinase gamma controls the macrophage M1-M2 switch, thereby promoting tumor immunosuppression and 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 3650. doi:10.1158/1538-7445.AM2014-3650
Abstract 3651: Natural killer cells eradicate galectin-1 deficient glioma in the absence of adaptive immunity
Authors: Baker Gregory J. , Yadav Viveka Nand , Chockley Peter , Doherty Robert , Ritt Michael , Sivaramakrishnan Sivaraj , Castro Maria G. , Lowenstein Pedro R. 
Published: May 2015

Abstract
Natural killer (NK) cells safeguard against early tumor formation by seeking out and destroying transformed target cells in a process referred to as NK immunosurveillance. While it is clear that malignant brain tumors such as glioblastoma (GBM) evade NK-mediated tumor suppression, the precise mechanisms by which this occurs remain unknown. We now show that shRNA-mediated knockdown of the β-galactoside-binding lectin, galectin-1 (gal-1), in malignant glioma cells leads to the failure to form lethal intracranial tumors in RAG1-/- mice, a mouse strain devoid of adaptive immunity. However, gal-1 deficient glioma growth is fully restored on implantation into the brain of severely immunocompromised NOD-scid IL2Rg null mice, which lack both adaptive and innate immune function, thus implicating the innate immune response in the early rejection of gal-1 deficient glioma. Immunodepletion of NK cells in RAG1-/- or C57BL/6J mice using anti-asialo GM1 or anti-NK1.1 antibodies permit the growth of large gal-1 deficient gliomas, while macrophage depletion with clodronate liposomes only permits limited tumor growth. This combined result suggests that NK cells and macrophages may work together to achieve gal-1 deficient glioma rejection. Antigen-specific IFN-γ ELISpot assays using splenocytes from immunocompetent C57BL/6J mice indicate that gal-1 deficient glioma is cleared prior to the onset of an adaptive anti-tumor immune response. Flow cytometric analysis of brain tumor-infiltrating immune cells reveal that gal-1 deficient gliomas contain significantly more macrophages and granzyme B+ NK cells compared to gal-1 expressing gliomas. In-vitro experiments further show that gal-1 deficient glioma cells are inherently over 3-times more sensitive to NK-mediated tumor lysis, fail to suppress pro-inflammatory (M1) microglial activation, and secrete pro-inflammatory cytokines IL-1β, IL-12p70, and CXCL2. We conclude that glioma-derived gal-1 is a powerful inhibitor of NK-mediated cytotoxicity in-vivo, and predict that its suppression will be of therapeutic value in the treatment of human malignant brain tumors by dramatically heightening anti-tumor NK immunosurveillance.
Citation Format: Gregory J. Baker, Viveka Nand Yadav, Peter Chockley, Robert Doherty, Michael Ritt, Sivaraj Sivaramakrishnan, Maria G. Castro, Pedro R. Lowenstein. Natural killer cells eradicate galectin-1 deficient glioma in the absence of adaptive immunity. [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 3651. doi:10.1158/1538-7445.AM2014-3651
Abstract 3652: Surface expression and shedding of NKG2D ligands by (metastasizing) tumor cells is altered by platelets leading to impaired NK cell immunosurveillance
Authors: Raab Stefanie , Kropp Korbinian Nepomuk , Steinle Alexander , Klein Gerd , Kopp Hans-Georg , Salih Helmut R. 
Published: May 2015

Abstract
NK cells play an important role in anti-tumor immunity. The mechanisms leading to NK cell activation are described by the ‘missing-self’ and ‘induced-self' hypotheses, implying that cells with low or absent expression of MHC class I and stress-induced expression of ligands for activating receptors such as NKG2D (NKG2DL), are targeted by NK cells. Besides the direct interaction with their target cells, NK activity is also influenced by various other hematopoietic cells. In mouse models, thrombocytopenia impairs metastasis, and this is reversed by additional depletion of NK cells. Hence, the knowledge of the underlying molecular mechanisms by which platelets influence NK cells is still fragmentary. We already showed that release of TGF-β by platelets upon their interaction with (metastasizing) tumor cells downmodulates the activating receptor NKG2D on NK cells (Kopp et al, Cancer Res. 2009; Placke, J Innate Immun. 2011). Moreover, platelets transfer ´healthy´ MHC class I to the tumor cell surface. Thus, platelets may facilitate metastasis by interfering with both, ‘induced and missing self' NK cell recognition. Here we provide evidence for a yet unknown mechanism by which platelets further impair NKG2D-mediated immunosurveillance. Tumor cells were incubated with platelets from healthy donors resulting in coating of tumor cells and activation of the platelets, or treated with platelet-derived soluble factors (releasate) obtained either by tumor cell-induced platelet activation (TCIPA) or the platelet agonist thrombin. Presence of platelet derived factors derived either from coating of tumor cells or contained in platelet releasate substantially reduced surface expression of NKG2DL on tumor cells. This was paralleled by enhanced levels of soluble NKG2DL in culture supernatants, indicating that platelet-derived factors mediate NKG2DL shedding from the tumor cell surface. Diminished NKG2DL surface expression resulted in diminished NKG2D-dependent natural cytotoxicity of NK cells, as revealed by blocking experiments using NKG2D antibody and NKG2DL-specific F(ab)2 fragments targeting the specifically modulated NKG2DL. Our data thus identify induction of NKG2DL shedding as novel mechanism by which interaction of platelets with metastasizing tumor cells impairs NK cell immunosurveillance.
Citation Format: Stefanie Raab, Korbinian Nepomuk Kropp, Alexander Steinle, Gerd Klein, Hans-Georg Kopp, Helmut R. Salih. Surface expression and shedding of NKG2D ligands by (metastasizing) tumor cells is altered by platelets leading to impaired NK cell immunosurveillance. [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 3652. doi:10.1158/1538-7445.AM2014-3652
Abstract 3669: IDH mutant glial cell resistance to natural killer cell cytotoxicity
Authors: Zhang Xiaoran , Chang Yigang , Li Aofei , Glorioso Joseph C. , Grandi Paola , Lotze Mike , Amankulor Nduka 
Published: May 2015

Abstract
Mutations in IDH 1 and 2 are common in gliomas. Methylation-related epigenetic repression of gene expression is a feature of IDH mutant (IDHmut) tumors. Epigenetic repression of NK cell ligands is a common occurrence in cancer, but it is unknown if this occurs in gliomas. Here, we demonstrate transcriptional repression of NKG2D activating ligands (NKG2DLs) in IDHmut tumors, and correlate this with decreased susceptibility to natural killer (NK) cell-mediated cytolysis in vitro We compared IDHmut and IDHwt gene expression values for annotated immune response genes and examined NKG2DL HM450 mean methylation values in glioma patients using TCGA data. cDNA was synthesized from cultured IDHwt or IDHmut astrocytes. NKG2DL expression was assayed using primers for NKG2D ligands ULBP1, ULBP2, ULBP3 and RAET1G. IDHwt astrocytes, U87 cells and IDHmut astrocytes were cultured with activated NK cells. Cytotoxicity was measured by flow cytometry. mRNA expression values for NKG2DLs ULBP1 and ULBP3 were significantly reduced in IDHmut gliomas. Conversely, methylation values were significantly increased. NKG2DL hierarchical clustering of gene expression of shows genotype-based expression clusters. IDHmt astrocytes expressed a two to eight-fold reduction in the relative gene expression of NKG2DLs compared with IDHwt astrocyte. Cytotoxicity is significantly lower in IDHmut astrocytes/NK cell co-cultures compared with IDHmut/NK or U87/NK co-cultures. Our data demonstrates evidence for the transcriptional repression of NKG2DLs in IDHmut gliomas in silico and in vitro. Reduced NKG2D levels in IDHmut cells correlates with impaired NK-mediated cytotoxicity and suggests a role for NK cell resistance in IDH mutant tumors. Further studies are in progress to utilize HSV vectors that express ULBP3 to determine whether restoration of ULBP3 expression in cancer cells will enhance susceptibility to NK activation and tumor cell killing. Results of these experiments will be reported.
Citation Format: Xiaoran Zhang, Yigang Chang, Aofei Li, Joseph C. Glorioso, Paola Grandi, Mike Lotze, Nduka Amankulor. IDH mutant glial cell resistance to natural killer cell cytotoxicity. [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 3669. doi:10.1158/1538-7445.AM2014-3669