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  • 1
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    Abstract 1521: Role of the guanylate-binding-protein 1 (GBP-1) in immunoediting of colorectal carcinoma.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 1521-1521
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 1521-1521
    Abstract: The human guanylate-binding protein 1 (GBP-1) is among the proteins the most highly induced by IFN-γ in every cell type investigated as yet. In vivo, GBP-1 expression is associated with the presence of inflammation and has been observed in autoimmune diseases, inflammatory bowel diseases (IBD) and cancer. In colorectal carcinoma (CRC), we previously reported that the expression of GBP-1 in the cells of the desmoplastic stroma correlates with the presence of an IFN-γ-dominated Th1 microenvironment and with an increased cancer-related 5-year survival. Moreover, GBP-1 expression in the blood vessels of CRC tissue was associated with a reduced angiogenesis. However, the expression and the role of GBP-1 in the tumor cells of CRC remained unknown. In the present study, the analysis of GBP-1 expression in a series of 185 CRCs by immunohistochemistry confirmed that GBP-1 is expressed in stroma cells of CRCs and revealed a significantly less frequent expression in tumor cells, which was contradictory with the broad inducibility of GBP-1. Furthermore, three of six CRC cell lines treated with IFN-γ were unable to express GBP-1 indicating a reduced inducibility in colorectal tumor cells. On the contrary, non-transformed colon epithelial cells strongly expressed GBP-1 in vitro in presence of IFN-γ and in vivo in IBD. Reconstitution of GBP-1 expression in a negative CRC cell line inhibited cell proliferation, migration, invasion and anchorage-independent growth. Using RNA interference, we showed that GBP-1 mediates the anti-proliferative, anti-migratory, anti-invasive and anti-clonogenic effects of IFN-γ in CRC cells. In addition, GBP-1 was able to inhibit tumor growth in vivo. Altogether these results suggested that GBP-1 acts directly as a tumor suppressor in CRC by mediating the effects of IFN-γ. In addition, the loss of GBP-1 expression in tumor cells indicated that tumor evasion from the IFN-γ-dominated Th1 immune response might have occured. This was confirmed by showing, first, that the absence of GBP-1 inducibility in CRC cell lines correlates with resistance to the anti-proliferative and pro-apoptotic effects of IFN-γ and, second, that the resistant cell lines exhibit defects in the IFN-γ signaling pathway. Citation Format: Nathalie Britzen-Laurent, Karoline Lipnik, Matthias Ocker, Elisabeth Naschberger, Vera Schellerer, Roland Croner, Michael Vieth, Maximilian Waldner, Pablo Steinberg, Christine Hohenadl, Michael Stürzl. Role of the guanylate-binding-protein 1 (GBP-1) in immunoediting of colorectal 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 1521. doi:10.1158/1538-7445.AM2013-1521
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-1521
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 2
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    A Systems Biology Approach To Identify the Combination Effects of Human Herpesvirus 8 Genes on NF-κB Activation
    American Society for Microbiology ; 2009
    In:  Journal of Virology Vol. 83, No. 6 ( 2009-03-15), p. 2563-2574
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 83, No. 6 ( 2009-03-15), p. 2563-2574
    Abstract: Human herpesvirus 8 (HHV-8) is the etiologic agent of Kaposi's sarcoma and primary effusion lymphoma. Activation of the cellular transcription factor nuclear factor-kappa B (NF-κB) is essential for latent persistence of HHV-8, survival of HHV-8-infected cells, and disease progression. We used reverse-transfected cell microarrays (RTCM) as an unbiased systems biology approach to systematically analyze the effects of HHV-8 genes on the NF-κB signaling pathway. All HHV-8 genes individually ( n = 86) and, additionally, all K and latent genes in pairwise combinations ( n = 231) were investigated. Statistical analyses of more than 14,000 transfections identified ORF75 as a novel and confirmed K13 as a known HHV-8 activator of NF-κB. K13 and ORF75 showed cooperative NF-κB activation. Small interfering RNA-mediated knockdown of ORF75 expression demonstrated that this gene contributes significantly to NF-κB activation in HHV-8-infected cells. Furthermore, our approach confirmed K10.5 as an NF-κB inhibitor and newly identified K1 as an inhibitor of both K13- and ORF75-mediated NF-κB activation. All results obtained with RTCM were confirmed with classical transfection experiments. Our work describes the first successful application of RTCM for the systematic analysis of pathofunctions of genes of an infectious agent. With this approach, ORF75 and K1 were identified as novel HHV-8 regulatory molecules on the NF-κB signal transduction pathway. The genes identified may be involved in fine-tuning of the balance between latency and lytic replication, since this depends critically on the state of NF-κB activity.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.01512-08
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2009
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  • 3
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    Cellular and molecular features of HIV-associated Kaposiʼs sarcoma
    Ovid Technologies (Wolters Kluwer Health) ; 1992
    In:  AIDS Vol. 6, No. 9 ( 1992-09), p. 895-914
    Details
    In: AIDS, Ovid Technologies (Wolters Kluwer Health), Vol. 6, No. 9 ( 1992-09), p. 895-914
    Type of Medium: Online Resource
    ISSN: 0269-9370
    URL: Article
    DOI: 10.1097/00002030-199209000-00001
    RVK:
    XA 16838
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 1992
    detail.hit.zdb_id: 2012212-3
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  • 4
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    High Throughput Screening of Gene Functions in Mammalian Cells Using Reversely Transfected Cell Arrays: Review And Protocol
    Bentham Science Publishers Ltd. ; 2008
    In:  Combinatorial Chemistry & High Throughput Screening Vol. 11, No. 2 ( 2008-02-01), p. 159-172
    Details
    In: Combinatorial Chemistry & High Throughput Screening, Bentham Science Publishers Ltd., Vol. 11, No. 2 ( 2008-02-01), p. 159-172
    Type of Medium: Online Resource
    ISSN: 1386-2073
    URL: Article
    DOI: 10.2174/138620708783744499
    Language: English
    Publisher: Bentham Science Publishers Ltd.
    Publication Date: 2008
    SSG: 15,3
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  • 5
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    Abstract 4687: COL10A1, MMP-11 and ABHD2 expression in colorectal carcinoma primary tumors indicates metastatic disease.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 4687-4687
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 4687-4687
    Abstract: Purpose: Metastasis is the primary cause of death in patients suffering from colorectal carcinomas (CRC). In order to identify patients at risk for metastatic tumor spread prior to clinical manifestation specific molecular markers are required. These markers will allow to adapt therapy early during clinical routine. Respective markers should be expressed in the primary tumor. In order to foster clinical implementation these markers should exhibit high validity and robust performance in routinely asservated material. Patients and Methods: Five metastasis associated markers (ABDH2, COL10A1, MMP-11, C8orf30A, SLC35D1) were identified by microarray comparison of non-metastatic and metastatic fresh frozen CRC samples (n = 80). They were validated by TaqMan quantitative RT-PCR in two further independent patient cohorts either retrospectively (n = 82) or prospectively (n = 203). RNA for validation was isolated with a fully automated procedure (Tissue Preparation System, Siemens Healthcare Diagnostics) from routinely harvested formaldehyde-fixed, paraffin-embedded (FFPE) CRC tissues. Relation of marker expression to disease recurrence was analyzed in UICC II stage tumors. Prognostic power was evaluated by different multiparametric tests (Bagging, SVM, LDA). Results were controlled with immunohistochemistry at the protein level. Results: ABDH2, COL10A1, MMP-11, C8orf30A and SLC35D1 were significantly differently expressed in stage UICC I, II vs. III by microarray analyses (p & lt;0.001). Retrospective and prospective RT-PCR validation in FFPE tissues confirmed that COL10A1, MMP-11, and ABHD2 were robustly expressed and significantly (p & lt; 0.001) associated with metastasis (stage UICC III/VI). Analyses of follow up in stage UICC II CRC patients indicated a relation to tumor recurrence. Multiparametric tests identified AUC values between 0.714 (Bagged trees) and 0.736 (LDA) for these markers. Controlling of the results with immunohistochemistry demonstrated that high prognostic power was selectively obtained at the RNA expression level. Conclusion: Automated RNA extraction from FFPE tissues and subsequent qRT-PCR analysis provide a robust technology which can be implemented into clinical routine processes of molecular cancer diagnostics. COL10A1, MMP-11 and ABHD2 are robustly expressed in a metastasis-related manner in CRC primary tumors. All three markers may be used as prognostic profilers to identify high risk patients. Citation Format: Michael Stürzl, Ralph Wirtz, Andreas Konrad, Olaf Gefeller, Werner Adler, Elisabeth Naschberger, Hans-Ullrich Prokosch, Arndt Hartmann, Tilman Rau, Franz Rödel, Werner Hohenberger, Roland S. Croner. COL10A1, MMP-11 and ABHD2 expression in colorectal carcinoma primary tumors indicates metastatic disease. [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 4687. doi:10.1158/1538-7445.AM2013-4687
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-4687
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 6
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    Abstract 780: Immune escape in colorectal carcinoma: role of the IFN-γ pathway
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 780-780
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 780-780
    Abstract: The presence of a Th1 adaptive immune response in colorectal carcinoma (CRC) has been associated with improved clinical outcome and survival of patients. The Th1 adaptive immune response is mediated by IFN-γ, a known anti-proliferative, pro-apoptotic and pro-immunogenic cytokine. We have previously identified the guanylate-binding protein 1 (GBP-1), one of the proteins the most highly induced by IFN-γ, as a sensitive marker for the detection of this immune response in CRC in vivo. In a tissue microarray study with 388 CRC tumors, 30% showed GBP-1 expression. Interestingly, in these tumors the expression of GBP-1 was only induced in the cells of the desmoplastic stroma and not observed in adjacent tumor cells. This suggested that CRC tumor cells might undergo an immune escape from the Th1 adaptive immune response, characterized by the loss of IFN-γ responsiveness. Therefore, we investigated the responsiveness to IFN-γ in sixth different CRC cell lines and in normal colon epithelial cells. After treatment with IFN-γ, three of the sixth CRC cell lines (DLD-1, SW480 and HCT116) failed to express GBP-1 as well as other IFN-induced proteins such as caspase-1 and MxA. On the contrary, a robust GBP-1 induction was present in normal colon epithelial cells, in T84, WiDr and HT29 cells. We then investigated whether the loss of expression of IFN-γ target genes was associated with phenotypic changes in CRC cells. In fact, we found that DLD-1, HCT116 and SW480 were resistant to IFN-γ-induced apoptosis. Furthermore, the loss of IFN-γ responsiveness correlated in SW480 and HCT116 with the absence of expression of the IFN-γ receptor alpha chain (IFNγRα). Tumor xenotransplant experiments using DLD-1 cells with reconstituted GBP-1 expression resulted in significantly reduced tumor growth as compared to xentotransplants with control vector transfected DLD-1 cells. This indicated that GBP-1 expression may mediate the anti-tumorigenic effects of the Th1 response. Overall, these data suggested that loss of IFN-γ responsiveness may be a common event in CRC and may protect tumor cells against the anti-tumorigenic (e.g. pro-apoptotic) effects of IFN-γ. The presence of an immune escape from the Th1 adaptive immune response may have important repercussions for prognosis and patients recruitment for immune-based therapy in CRC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 780. doi:10.1158/1538-7445.AM2011-780
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-780
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 7
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    Abstract 1255: A novel chip-based parallel transfection assay to evaluate paracrine cell interactions
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 8_Supplement ( 2012-04-15), p. 1255-1255
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 1255-1255
    Abstract: Introduction: The analysis of how genes are regulating interactions between different cell types is of highest importance for the understanding of physiologic and pathologic processes in multi-cellular organisms. We present a novel method for the highly parallel analysis of gene functions in paracrine interactions between different cell types at the microarray level on a chip. The basic idea was to apply a mixture of two different cell types to the technique of reverse transfection with expression plasmids spotted in an ordered array on chips. The goal was to establish conditions that exclusively result in the transfection of one cell type (effector cells) and to use the other cell type as the indicator cells to determine paracrine gene effects (either directly exerted by the secreted product of the transfected gene or induced by the transfected gene). Methods: Reverse transfection was carried out spotting plasmid DNA in Lipofectamine 2000 and 0.2% gelatin on a slide. Subsequently, HEK 293T cells (effector cells) alone or in a mixture with different indicator cells (human fibroblasts, HUVEC, HaCaT, HT29, WiDr) were seeded. After 5 h a pre-warmed diffusion restricting matrix was gently poured onto the slides. The slides were further incubated for 43 h at 37 °C. Then, the matrix was removed, and the slides were washed gently and subjected to immunofluorescence analysis. Results: We successfully solved the two key problems required for this approach: (1) exclusive, differential transfection of the effector cells and not the indicator cells and (2) restriction of diffusion to localize gene effects to the specific transfection area. With the established methodology presented in our study, 192 parallel tests of paracrine gene activations can be conducted on a single chip. Demonstrating the broad applicability of the method, we used different indicator cells such as human primary fibroblasts (of relevance for inflammatory tissue reconstruction and invasion), endothelial cells (of relevance for angiogenesis research), keratinocytes (of relevance for wound healing research) and two different colorectal cancer cell lines (of relevance for cancer research). In addition, we used different indicator genes such as GBP-1 (indicates IFN-gamma like activation), COX-2 (of relevance for tumor research), ICAM-1 and VCAM-1 (of relevance for angiogenesis and inflammation research) and different paracrine inducers by including IFN-γ, TNF-α and IFN-γ. Discussion: Our method provides a significant improvement over current methodologies for the analysis of paracrine gene functions. It is highly relevant to systematically investigate single and combination effects of disease-associated gene clusters in intercellular communication in many different research applications including cancer, inflammation, angiogenesis and infectious diseases research. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1255. doi:1538-7445.AM2012-1255
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2012-1255
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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    detail.hit.zdb_id: 1432-1
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  • 8
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    Engineering of Vascularized Transplantable Bone Tissues: Induction of Axial Vascularization in an Osteoconductive Matrix Using an Arteriovenous Loop
    Mary Ann Liebert Inc ; 2006
    In:  Tissue Engineering Vol. 0, No. 0 ( 2006-06-05), p. 060802052515051-
    Details
    In: Tissue Engineering, Mary Ann Liebert Inc, Vol. 0, No. 0 ( 2006-06-05), p. 060802052515051-
    Type of Medium: Online Resource
    ISSN: 1076-3279
    URL: Issue
    URL: Article
    DOI: 10.1089/ten.0.0.issue-0
    DOI: 10.1089/ten.2006.12.ft-98
    Language: English
    Publisher: Mary Ann Liebert Inc
    Publication Date: 2006
    detail.hit.zdb_id: 2401807-7
    SSG: 12
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  • 9
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    Inflammatory Cytokines Synergize with the HIV-1 Tat Protein to Promote Angiogenesis and Kaposi’s Sarcoma Via Induction of Basic Fibroblast Growth Factor and the αvβ3 Integrin
    The American Association of Immunologists ; 1999
    In:  The Journal of Immunology Vol. 163, No. 4 ( 1999-08-15), p. 1929-1935
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 163, No. 4 ( 1999-08-15), p. 1929-1935
    Abstract: The Tat protein of HIV-1, a transactivator of viral gene expression, is released by acutely infected T cells and, in this form, exerts angiogenic activities. These have linked the protein to the pathogenesis of Kaposi’s sarcoma (KS), a vascular tumor frequent and aggressive in HIV-1-infected individuals (AIDS-KS). In this study, we show that a combination of the same inflammatory cytokines increased in KS lesions, namely IL-1β, TNF-α, and IFN-γ, synergizes with Tat to promote in nude mice the development of angioproliferative KS-like lesions that are not observed with each factor alone. Inflammatory cytokines induce the tissue expression of both basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), two angiogenic molecules highly produced in primary KS lesions. However, bFGF, but not VEGF, synergizes with Tat in vivo and induces endothelial cells to migrate, to adhere, and to grow in response to Tat in vitro. Tat angiogenic effects correlate with the expression of the αvβ3 integrin that is induced by bFGF and binds the arginine-glycine-aspartic acid (RGD) region of Tat. In contrast, no correlation is observed with the expression of αvβ5, which is promoted by VEGF and binds Tat basic region. Finally, KS lesion formation induced by bFGF and Tat in nude mice is blocked by antagonists of RGD-binding integrins. Because αvβ3 is an RGD-binding integrin that is highly expressed in primary KS lesions, where it colocalizes with extracellular Tat on vessels and spindle cells, these results suggest that αvβ3 competitors may represent a new strategy for the treatment of AIDS-KS.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.163.4.1929
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 1999
    detail.hit.zdb_id: 1475085-5
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  • 10
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    IFN-γ Induces Endothelial Cells to Proliferate and to Invade the Extracellular Matrix in Response to the HIV-1 Tat Protein: Implications for AIDS-Kaposi’s Sarcoma Pathogenesis
    The American Association of Immunologists ; 1999
    In:  The Journal of Immunology Vol. 162, No. 2 ( 1999-01-15), p. 1165-1170
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 162, No. 2 ( 1999-01-15), p. 1165-1170
    Abstract: Previous studies indicated that the Tat protein of HIV functions as a progression factor in Kaposi’s sarcoma (KS), an angioproliferative disease common and aggressive in HIV-1-infected individuals (AIDS-KS). In particular, Tat that is released by infected cells stimulates the growth and invasion of spindle cells of endothelial origin derived from KS lesions (KS cells). Other work suggested that inflammatory cytokines may act as initiating factors in KS since they induce normal endothelial cells to acquire the same phenotype and functional features of KS cells, including the responsiveness to Tat. In this study, we show that among the inflammatory cytokines increased in AIDS-KS lesions, IFN-γ alone is sufficient to induce endothelial cells to proliferate and to invade the extracellular matrix in response to Tat. This is because IFN-γ up-regulates the expression and activity of the receptors for Tat identified as the integrins α5β1 and αvβ3. These results suggest that, by triggering Tat effects, IFN-γ plays a major role in AIDS-KS pathogenesis.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.162.2.1165
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 1999
    detail.hit.zdb_id: 1475085-5
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