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  1. Article ; Online: Altered B-Cell Expansion and Maturation in Draining Mesenteric Lymph Nodes of Inflamed Gut in Crohn's Disease.

    Kappel-Latif, Sonja / Kotagiri, Prasanti / Schlager, Lukas / Schuld, Gabor / Walterskirchen, Natalie / Schimek, Vanessa / Sewell, Gavin / Binder, Carina / Jobst, Johanna / Murthy, Supriya / Messner, Barbara / Dabsch, Stefanie / Kaser, Arthur / Lyons, Paul A / Bergmann, Michael / Stift, Anton / Oehler, Rudolf / Unger, Lukas W

    Cellular and molecular gastroenterology and hepatology

    2023  Volume 17, Issue 4, Page(s) 662–666

    MeSH term(s) Humans ; Crohn Disease/pathology ; Lymph Nodes/pathology ; Cell Cycle
    Language English
    Publishing date 2023-12-24
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2819778-1
    ISSN 2352-345X ; 2352-345X
    ISSN (online) 2352-345X
    ISSN 2352-345X
    DOI 10.1016/j.jcmgh.2023.12.006
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Tumour cell apoptosis modulates the colorectal cancer immune microenvironment via interleukin-8-dependent neutrophil recruitment.

    Schimek, Vanessa / Strasser, Katharina / Beer, Andrea / Göber, Samantha / Walterskirchen, Natalie / Brostjan, Christine / Müller, Catharina / Bachleitner-Hofmann, Thomas / Bergmann, Michael / Dolznig, Helmut / Oehler, Rudolf

    Cell death & disease

    2022  Volume 13, Issue 2, Page(s) 113

    Abstract: Sporadic apoptosis of tumour cells is a commonly observed feature of colorectal cancer (CRC) and strongly correlates with adverse patient prognosis. The uptake of apoptotic cell debris by neutrophils induces a non-inflammatory, pro-regenerative, and ... ...

    Abstract Sporadic apoptosis of tumour cells is a commonly observed feature of colorectal cancer (CRC) and strongly correlates with adverse patient prognosis. The uptake of apoptotic cell debris by neutrophils induces a non-inflammatory, pro-regenerative, and hence potentially pro-tumorigenic phenotype. In this study, we therefore sought to investigate the impact of apoptotic CRC cells on neutrophils and its consequence on other immune cells of the tumour microenvironment. Apoptosis induced by combined TNFα-treatment and UV-C irradiation, as well as various chemotherapeutic agents, led to a substantial release of neutrophil-attracting chemokines, most importantly interleukin-8 (IL-8), in both primary patient-derived and established CRC cells. Accordingly, conditioned media of apoptotic tumour cells selectively stimulated chemotaxis of neutrophils, but not T cells or monocytes. Notably, caspase-inhibition partially reduced IL-8 secretion, suggesting that caspase activity might be required for apoptosis-induced IL-8 release. Moreover, apoptotic tumour cell-conditioned media considerably prolonged neutrophil lifespan and induced an activated CD66b
    MeSH term(s) Apoptosis ; Caspases/metabolism ; Colorectal Neoplasms/pathology ; Culture Media, Conditioned/metabolism ; Culture Media, Conditioned/pharmacology ; Humans ; Interleukin-8/metabolism ; Neutrophil Infiltration ; Neutrophils/metabolism ; Tumor Microenvironment
    Chemical Substances Culture Media, Conditioned ; Interleukin-8 ; Caspases (EC 3.4.22.-)
    Language English
    Publishing date 2022-02-04
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2541626-1
    ISSN 2041-4889 ; 2041-4889
    ISSN (online) 2041-4889
    ISSN 2041-4889
    DOI 10.1038/s41419-022-04585-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Metastatic colorectal carcinoma-associated fibroblasts have immunosuppressive properties related to increased IGFBP2 expression.

    Walterskirchen, Natalie / Müller, Catharina / Ramos, Cristiano / Zeindl, Stephan / Stang, Simone / Herzog, Daniela / Sachet, Monika / Schimek, Vanessa / Unger, Lukas / Gerakopoulos, Vasileios / Hengstschläger, Markus / Bachleitner-Hofmann, Thomas / Bergmann, Michael / Dolznig, Helmut / Oehler, Rudolf

    Cancer letters

    2022  Volume 540, Page(s) 215737

    Abstract: Fibroblasts are the most abundant stromal constituents of the tumour microenvironment in primary as well as metastatic colorectal cancer (CRC). Their supportive effect on tumour cells is well established. There is growing evidence that stromal ... ...

    Abstract Fibroblasts are the most abundant stromal constituents of the tumour microenvironment in primary as well as metastatic colorectal cancer (CRC). Their supportive effect on tumour cells is well established. There is growing evidence that stromal fibroblasts also modulate the immune microenvironment in tumours. Here, we demonstrate a difference in fibroblast-mediated immune modulation between primary CRC and peritoneal metastasis. Cancer-associated fibroblasts (CAFs) were isolated from primary cancer and from peritoneal metastases (MAFs) from a total of 17 patients. The ectoenzyme CD38 was consistently expressed on the surface of all MAFs, while it was absent from CAFs. Furthermore, MAFs secreted higher levels of IGFBP2, CXCL2, CXCL6, CXCL12, PDGF-AA, FGFb, and IL-6. This was associated with a decreased activation of macrophages and a suppression of CD25 expression and proliferation of co-cultivated T-cells. Downregulation of IGFBP2 abolished these immunosuppressive effects of MAFs. Taken together, these results show that MAFs contribute to an immunosuppressive tumour microenvironment in CRC metastases by modulating the phenotype of immune cells through an IGFBP2-dependent mechanism.
    MeSH term(s) Cancer-Associated Fibroblasts/metabolism ; Cell Movement/genetics ; Cell Proliferation/genetics ; Colorectal Neoplasms/pathology ; Fibroblasts/metabolism ; Humans ; Tumor Microenvironment/genetics
    Language English
    Publishing date 2022-05-13
    Publishing country Ireland
    Document type Journal Article
    ZDB-ID 195674-7
    ISSN 1872-7980 ; 0304-3835
    ISSN (online) 1872-7980
    ISSN 0304-3835
    DOI 10.1016/j.canlet.2022.215737
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Stromal fibroblasts shape the myeloid phenotype in normal colon and colorectal cancer and induce CD163 and CCL2 expression in macrophages.

    Stadler, Mira / Pudelko, Karoline / Biermeier, Alexander / Walterskirchen, Natalie / Gaigneaux, Anthoula / Weindorfer, Claudia / Harrer, Nathalie / Klett, Hagen / Hengstschläger, Markus / Schüler, Julia / Sommergruber, Wolfgang / Oehler, Rudolf / Bergmann, Michael / Letellier, Elisabeth / Dolznig, Helmut

    Cancer letters

    2021  Volume 520, Page(s) 184–200

    Abstract: Colorectal cancer (CRC) accounts for about 10% of cancer deaths worldwide. Colon carcinogenesis is critically influenced by the tumor microenvironment. Cancer associated fibroblasts (CAFs) and tumor associated macrophages (TAMs) represent the major ... ...

    Abstract Colorectal cancer (CRC) accounts for about 10% of cancer deaths worldwide. Colon carcinogenesis is critically influenced by the tumor microenvironment. Cancer associated fibroblasts (CAFs) and tumor associated macrophages (TAMs) represent the major components of the tumor microenvironment. TAMs promote tumor progression, angiogenesis and tissue remodeling. However, the impact of the molecular crosstalk of tumor cells (TCs) with CAFs and macrophages on monocyte recruitment and their phenotypic conversion is not known in detail so far. In a 3D human organotypic CRC model, we show that CAFs and normal colonic fibroblasts are critically involved in monocyte recruitment and for the establishment of a macrophage phenotype, characterized by high CD163 expression. This is in line with the steady recruitment and differentiation of monocytes to immunosuppressive macrophages in the normal colon. Cytokine profiling revealed that CAFs produce M-CSF, and IL6, IL8, HGF and CCL2 secretion was specifically induced by CAFs in co-cultures with macrophages. Moreover, macrophage/CAF/TCs co-cultures increased TC invasion. We demonstrate that CAFs and macrophages are the major producers of CCL2 and, upon co-culture, increase their CCL2 production twofold and 40-fold, respectively. CAFs and macrophages expressing high CCL2 were also found in vivo in CRC, strongly supporting our findings. CCL2, CCR2, CSF1R and CD163 expression in macrophages was dependent on active MCSFR signaling as shown by M-CSFR inhibition. These results indicate that colon fibroblasts and not TCs are the major cellular component, recruiting and dictating the fate of infiltrated monocytes towards a specific macrophage population, characterized by high CD163 expression and CCL2 production.
    MeSH term(s) Antigens, CD/genetics ; Antigens, Differentiation, Myelomonocytic/genetics ; Cancer-Associated Fibroblasts/metabolism ; Cancer-Associated Fibroblasts/pathology ; Cell Differentiation/genetics ; Cell Movement/genetics ; Cell Proliferation/genetics ; Chemokine CCL2/genetics ; Colon/metabolism ; Colon/pathology ; Colorectal Neoplasms/blood ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/metabolism ; Colorectal Neoplasms/pathology ; Female ; Gene Expression Regulation, Neoplastic/genetics ; HCT116 Cells ; Humans ; Macrophage Colony-Stimulating Factor/genetics ; Male ; Myeloid Cells/metabolism ; Myeloid Cells/pathology ; Receptors, Cell Surface/genetics ; Signal Transduction/genetics ; Tumor Microenvironment/genetics
    Chemical Substances Antigens, CD ; Antigens, Differentiation, Myelomonocytic ; CD163 antigen ; CSF1 protein, human ; Chemokine CCL2 ; Receptors, Cell Surface ; Macrophage Colony-Stimulating Factor (81627-83-0)
    Language English
    Publishing date 2021-07-10
    Publishing country Ireland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 195674-7
    ISSN 1872-7980 ; 0304-3835
    ISSN (online) 1872-7980
    ISSN 0304-3835
    DOI 10.1016/j.canlet.2021.07.006
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Hepatectomy-induced apoptotic extracellular vesicles stimulate neutrophils to secrete regenerative growth factors.

    Brandel, Victoria / Schimek, Vanessa / Göber, Samantha / Hammond, Thomas / Brunnthaler, Laura / Schrottmaier, Waltraud Cornelia / Mussbacher, Marion / Sachet, Monika / Liang, Ying Yu / Reipert, Siegfried / Ortmayr, Gregor / Pereyra, David / Santol, Jonas / Rainer, Marlene / Walterskirchen, Natalie / Ramos, Cristiano / Gerakopoulos, Vasileios / Rainer, Carina / Spittler, Andreas /
    Weiss, Tamara / Kain, Renate / Messner, Barbara / Gruenberger, Thomas / Assinger, Alice / Oehler, Rudolf / Starlinger, Patrick

    Journal of hepatology

    2022  Volume 77, Issue 6, Page(s) 1619–1630

    Abstract: Background & aims: Surgical resection of the cancerous tissue represents one of the few curative treatment options for neoplastic liver disease. Such partial hepatectomy (PHx) induces hepatocyte hyperplasia, which restores liver function. PHx is ... ...

    Abstract Background & aims: Surgical resection of the cancerous tissue represents one of the few curative treatment options for neoplastic liver disease. Such partial hepatectomy (PHx) induces hepatocyte hyperplasia, which restores liver function. PHx is associated with bacterial translocation, leading to an immediate immune response involving neutrophils and macrophages, which are indispensable for the priming phase of liver regeneration. Additionally, PHx induces longer-lasting intrahepatic apoptosis. Herein, we investigated the effect of apoptotic extracellular vesicles (aEVs) on neutrophil function and their role in this later phase of liver regeneration.
    Methods: A total of 124 patients undergoing PHx were included in this study. Blood levels of the apoptosis marker caspase-cleaved cytokeratin-18 (M30) and circulating aEVs were analyzed preoperatively and on the first and fifth postoperative days. Additionally, the in vitro effects of aEVs on the secretome, phenotype and functions of neutrophils were investigated.
    Results: Circulating aEVs increased at the first postoperative day and were associated with higher concentrations of M30, which was only observed in patients with complete liver recovery. Efferocytosis of aEVs by neutrophils induced an activated phenotype (CD11b
    Conclusions: These data suggest that the clearance of PHx-induced aEVs leads to a population of non-inflammatory but regenerative neutrophils, which may support human liver regeneration.
    Lay summary: In this study, we show that the surgical removal of a diseased part of the liver triggers a specific type of programmed cell death in the residual liver tissue. This results in the release of vesicles from dying cells into the blood, where they are cleared by circulating immune cells. These respond by secreting hepatocyte growth factors that could potentially support the regeneration of the liver remnant.
    MeSH term(s) Humans ; Hepatectomy ; Neutrophils ; Extracellular Vesicles ; Biological Transport ; Liver Regeneration ; Focal Nodular Hyperplasia
    Language English
    Publishing date 2022-08-17
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 605953-3
    ISSN 1600-0641 ; 0168-8278
    ISSN (online) 1600-0641
    ISSN 0168-8278
    DOI 10.1016/j.jhep.2022.07.027
    Database MEDical Literature Analysis and Retrieval System OnLINE

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