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  • 1
    Keywords: ENVIRONMENT ; ANGIOGENESIS ; CANCER ; CELLS ; tumor ; CELL ; Germany ; human ; IN-VIVO ; MODEL ; MODELS ; THERAPY ; GENERATION ; DISTINCT ; PATIENT ; RESPONSES ; INDUCTION ; ANTIGEN ; ANTIGENS ; DENDRITIC CELLS ; LYMPH-NODES ; treatment ; tumor antigens ; MOUSE ; MALIGNANCIES ; resistance ; CANCER-PATIENTS ; IMMUNITY ; IMMUNOTHERAPY ; MOUSE MODEL ; REJECTION ; DE-NOVO ; CANCER PATIENTS ; CANCER-THERAPY ; EFFECTOR ; cancer therapy ; SOLID TUMORS ; T-CELL-ACTIVATION ; ANTIGENIC CANCER-CELLS ; ANTITUMOR LYMPHOCYTES ; EFFECTOR FUNCTION ; immune therapy ; transgenic tumor models ; TUMOR-ANTIGENS
    Abstract: In immunological cancer therapy, the current treatment emphasis is on the generation of effector cells that are specific for tumor antigens. However, there is a distressing lack of correlation between the induction of specific immunity in cancer patients and measurable clinical benefit. By studying mouse models of de novo tumongenesis we are beginning to understand that the tumor itself, in particular the manifestation of a distinct tumor environment, impairs immune effector function; this concept is yet to be applied in human malignancy
    Type of Publication: Journal article published
    PubMed ID: 15368278
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  • 2
    Keywords: CELLS ; tumor ; carcinoma ; CELL ; COMBINATION ; Germany ; IN-VIVO ; MODEL ; THERAPY ; VIVO ; MOLECULES ; TISSUE ; TUMORS ; MICE ; ACTIVATION ; DNA ; OLIGODEOXYNUCLEOTIDES ; T cell ; T cells ; T-CELL ; T-CELLS ; TOLERANCE ; treatment ; MOLECULE ; MOUSE ; UP-REGULATION ; EFFICACY ; ADHESION ; CARCINOMAS ; STRATEGIES ; CD8(+) ; IMMUNE-RESPONSE ; vaccination ; MOUSE MODEL ; REJECTION ; DE-NOVO ; ADJUVANT ; EFFECTOR ; CROSS-PRESENTATION ; AGENT ; CELL CARCINOMA ; INFILTRATION ; T-CELL-ACTIVATION ; ANTIGEN-TRANSGENIC MICE ; ESTABLISHED TUMORS ; INDUCE REJECTION
    Abstract: In a transgenic mouse model expressing SV40 T Ag (Tag) as a de novo tumor Ag, immune surveillance fails and islet cell carcinomas grow progressively. To develop an anticancer strategy that would be effective in eradicating solid, autochthonously growing tumors, we evaluated the effectiveness of immunostimulatory oligodeoxynucleotides (ODN) with cytosine-guanine-rich (CpG) motifs (CpG-ODN). In a classical vaccination protocol, Tag was administered with CpG-ODN as adjuvant. The antitumor vaccination, however, was only effective in a prophylactic setting, despite the successful activation of a Tag-specific CTL response in vivo. Histological examination demonstrated that even primed immune cells failed to infiltrate tumors once a malignant environment was established. To ensure that effector cells were not limiting, highly activated tumor Ag-specific T cells were transferred into tumor-bearing mice. However, this treatment also failed to result in tumor infiltration and rejection. Therefore, we further tested the efficacy of CpG-ODN as a proinflammatory agent in combination with the transfer of preactivated Tag-specific CD4(+) and CD8(+) T cells. Indeed, this combination therapy p. roved to be highly effective, because CpG-ODN rendered insulinomas permissive for massive infiltration and destruction. The opening of tumor tissue correlated with uptake of CpG-ODN by tissue-resident macrophages and a strong up-regulation of adhesion molecules such as ICAM and VCAM on blood vessel endothelia. These data demonstrate that systemic application of proinflammatory reagents drastically enhances extravasation of effector cells into tumor tissue, an observation that is of general importance for immunotherapy of solid tumors in a clinical setting
    Type of Publication: Journal article published
    PubMed ID: 15128765
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  • 3
    Keywords: CELLS ; CELL ; Germany ; IN-VIVO ; PATHWAY ; PATHWAYS ; GENERATION ; POPULATION ; MOLECULES ; RESPONSES ; CUTTING EDGE ; MECHANISM ; ANTIGEN ; DENDRITIC CELLS ; KERATINOCYTES ; T cells ; T-CELLS ; TISSUE ANTIGENS ; TOLERANCE ; IMMUNE-RESPONSES ; IDENTIFICATION ; UP-REGULATION ; LYMPHOCYTES ; INVOLVEMENT ; IMMUNE-RESPONSE ; REJECTION ; thymus ; RE ; LIFE ; TGF-beta 1 ; function ; regulatory T cells ; CD8(+) T cell ; immune responses ; immune regulation ; DOMINANT TOLERANCE ; parenchymal cells
    Abstract: In comparison with CD4(+) regulatory T cells, the generation and function of immunomodulatory CD8(+) T cells is less well defined. Here we describe the existence of regulatory anti-K-b-Specific CD8(+) T cells that are rendered tolerant during neonatal life via antigen contact exclusively on keratinocytes. These regulatory T cells maintain tolerance during adulthood as they prevent K-b-specific graft rejection by naive CD8(+) T cells. Third-party immune responses remain unaffected. Up-regulation of TGF-beta 1 and granzyme B in the regulatory CD8(+) T cell population suggests the involvement of these molecules in common suppressive pathways shared with CD4(+) regulatory T cells. In summary, CD8(+) regulatory T cells can be induced. extrathymically through antigen contact on neonatally accessible parenchymal cells and maintain tolerance throughout adult life
    Type of Publication: Journal article published
    PubMed ID: 17008409
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  • 4
    Keywords: PEPTIDE ; CELLS ; ENDOTHELIAL-CELLS ; GROWTH ; SURVIVAL ; tumor ; CELL ; MODEL ; THERAPY ; tumor growth ; LONG-TERM ; MOLECULES ; TUMORS ; ACCUMULATION ; MICE ; ACTIVATION ; CARCINOGENESIS ; TOLERANCE ; MOLECULE ; antibodies ; MOUSE ; TRANSGENIC MICE ; IMMUNOTHERAPY ; MOUSE MODEL ; ADAPTIVE IMMUNITY ; IL-2 ; INTERLEUKIN-2 ; AGENT ; RECOMBINANT ; RE ; TUMOR-GROWTH ; THERAPIES ; CD40 LIGAND ; USA ; host ; MEDICINE ; ANTITUMOR RESPONSES ; LIGATION ; T-CELL HELP
    Abstract: Current anticancer therapy is a delicate balance between elimination of malignant cells and harmful side effects for the host. In this study, we used a tumor-homing peptide to engineer anti-CD40 agonist antibodies and recombinant IL-2 such that they were selectively delivered into spontaneously arising tumors in a transgenic mouse model of islet cell carcinogenesis. Intravenous injection of these agents, either separately or together, led to accumulation in the vicinity of tumor neovessels without toxic side effects. Although both molecules are critical for adaptive immunity, the most profound effects were seen in endothelial cells. Combined, local anti-CD40 and IL-2 therapy reduced tumor vascularity and significantly delayed tumor growth in mice. Remarkably, tumor-bearing mice remained disease-free long-term when targeted anti-CD40 and IL-2 were combined with transfers of preactivated antitumor immune cells. In this therapeutic setting, triggering of CD40 on endothelial cells induced an inflammatory response of the vessel wall and facilitated effector cell accumulation in the tumor parenchyma while IL-2 promoted antigen-specific immune cell persistence. We believe this is a novel and highly effective anticancer approach, whereby tumor stroma is "conditioned" for enhanced immune cell entry and survival, facilitating immune-mediated tumor destruction and leading to a sustained antitumor response
    Type of Publication: Journal article published
    PubMed ID: 18398504
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  • 5
    Keywords: EXPRESSION ; GROWTH-FACTOR ; IONIZING-RADIATION ; IN-VIVO ; TOLERANCE ; TRANSGENIC MICE ; IMMUNE-RESPONSE ; CANCER-IMMUNOTHERAPY ; INTERFERON-GAMMA ; INFILTRATING LYMPHOCYTES
    Abstract: In a transgenic mouse model of multistep carcinogenesis, highly angiogenic insulinomas contain an irregular vascular network and develop an intrinsic resistance to leukocyte infiltration and effector function. Even persistently high levels of activated tumor-specific T lymphocytes fail to eradicate the tumors. In contrast, we show that irradiation before adoptive transfer results in complete macroscopic tumor regression. Thus, effective tumor therapy requires a proinflammatory microenvironment that permits T cells to extravasate and to destroy the tumor. Early after initiation of the irradiation/adoptive transfer therapy, the capillary network reacquires an almost normal appearance, a likely consequence of strong induction of the chemokines monokine induced by IFN-gamma (Mig) and IFN-inducible protein 10 (IP10). This remodeling of the vasculature in a proinflammatory environment may directly affect lymphocyte extravasation and effector function. Therefore, irradiation/adoptive transfer therapy combines antigen-driven tumor cell eradication with anti-angiogenic effects on tumor endothelium, a powerful synergy that has not been previously appreciated.
    Type of Publication: Journal article published
    PubMed ID: 11888921
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  • 6
    Abstract: The cAMP response element binding protein (CREB) has been implicated as a key regulator in the transcriptional control of many genes. To assess the functional importance of CREB in vivo and its role in development, we used gene targeting to generate mice with a disruption of the CREB gene. Homozygous mutant mice appeared healthy and exhibited no impairment of growth or development. In this report we demonstrate that CREB and two other members of the CREB/ATF family, cAMP response element modulation protein (CREM) and activating transcription factor 1 (ATF1), appear to form a unique subgroup within this extensive class of transcription factors. Examination of CREM mRNA and protein levels in CREB mutant mice demonstrated overexpression of CREM in all tissues examined, but no change in ATF1 levels. These data demonstrate that CREB is not the sole mediator of cAMP-dependent transcriptional regulation and probably acts in concert with a specific subset of cAMP response element-binding proteins to transduce the cAMP signal and, in its absence, these same proteins can compensate for CREB function in vivo.
    Type of Publication: Journal article published
    PubMed ID: 8202542
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  • 7
    Keywords: brain ; ANGIOGENESIS ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; Germany ; MODEL ; THERAPY ; SITE ; SITES ; GENE-EXPRESSION ; transcription ; TUMORS ; MICE ; TIME ; MARKER ; CARCINOGENESIS ; INDUCTION ; DOWN-REGULATION ; MOUSE ; LESIONS ; REGULATOR ; molecular ; RE ; TUMORIGENESIS ; endothelial cells ; BLOOD-VESSELS ; astrocytoma ; ANGIOGENIC SWITCH ; TUMOR VASCULATURE ; PDGF-B ; RGS PROTEIN
    Abstract: We identified regulator of G-protein signaling-5 (RGS-5) as an angiogenic pericyte marker at sites of physiologic and pathologic angiogenesis. In a mouse model of pancreatic islet cell carcinogenesis, RGS-5 is specifically induced in the vasculature of premalignant lesions during the "angiogenic switch" and further elevated in tumor vessels. Similarly, RGS-5 is over-expressed in highly angiogenic astrocytomas but not in hypoxia-inducible factor-1alpha (HIF-1alpha)-deficient tumors, which grow along preexisting brain capillaries without inducing neovessels. Elevated levels of RGS-5 in pericytes are also observed during wound healing and ovulation indicating a strong correlation between RGS-5 expression and active vessel remodeling beyond tumor angiogenesis. Moreover, antitumor therapy, which reverses tumor vasculature to an almost normal morphology, results in down-regulation of RGS-5 transcription. Taken together, these data demonstrate for the first time a factor that is specific for "activated" pericytes. This further supports the notion that pericytes, like endothelial cells, undergo molecular changes during neovascularization that makes them a novel target for antiangiogenic therapy. (C) 2005 by The American Society of Hematology
    Type of Publication: Journal article published
    PubMed ID: 15459006
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  • 8
    Keywords: RECEPTOR ; tumor ; Germany ; TUMORS ; LIGAND ; INDUCTION ; T-CELLS ; TOLERANCE ; LYMPHOCYTES ; LIGANDS ; microenvironment ; inflammation ; AUTOIMMUNITY ; PROGRAM ; RE
    Type of Publication: Journal article published
    PubMed ID: 16239378
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  • 9
    Keywords: ANGIOGENESIS ; CANCER ; GROWTH-FACTOR ; tumor ; Germany ; RECRUITMENT ; HEMATOPOIETIC STEM-CELLS ; microenvironment ; chemokine ; RE ; TUMORIGENESIS ; progenitor ; MARROW-DERIVED CELLS ; MCP-1 ; MOBILIZATION ; neovascularization
    Type of Publication: Journal article published
    PubMed ID: 16326806
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  • 10
    Keywords: ANGIOGENESIS ; CANCER ; CELLS ; ENDOTHELIAL-CELLS ; GROWTH ; proliferation ; tumor ; Germany ; MODEL ; MODELS ; DISTINCT ; TUMORS ; MECHANISM ; CARCINOGENESIS ; fibroblasts ; MOUSE ; PROGRESSION ; TUMOR PROGRESSION ; RECRUITMENT ; MOUSE MODEL ; HEMATOPOIETIC STEM-CELLS ; MULTISTAGE CARCINOGENESIS ; PRECURSORS ; INTEGRATION ; RE ; TUMOR-GROWTH ; TUMORIGENESIS ; chemokines ; stem cells ; MARROW-DERIVED CELLS ; PROGENITORS ; endothelial progenitors
    Abstract: Bone marrow-derived endothelial precursor cells contribute to tumor neovascularization. However, it is unclear when during progressive tumor growth circulating precursors are recruited into the preexisting vascular network, and how they home specifically into the tumor microenvironment. Here, we summarize recent findings from mouse models of multistage carcinogenesis, which reveal distinct phases of angiogenic activity. Only advanced tumors with a highly heterogeneous, sprouting vasculature recruite endothelial progenitors into neovessels. Surprisingly, during progressive tumor growth endothelial cells acquire new characteristics and secrete CC chemokines, a group of chemoattractants with adjacent cysteins, which play a dual role by enhancing neovascularization in an autocrine and endocrine fashion. Locally, chemokines stimulate endothelial proliferation; systemically, they guide chemokine receptor-positive circulating progenitors into the tumor bed. Subsequently, endothelial progenitors are truly integrated into the network of preexisting vessels. This mechanism represents a novel concept where not the tumor itself, but endothelial cells as components of the tumor-induced stroma foster neovascularization in a self-amplifying loop
    Type of Publication: Journal article published
    PubMed ID: 16552180
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