Stromal fibroblasts shape the myeloid phenotype in normal colon and colorectal cancer and induce CD163 and CCL2 expression in macrophages
| Autor: | Rudolf Oehler, Wolfgang Sommergruber, Natalie Walterskirchen, Elisabeth Letellier, Julia Schüler, Hagen Klett, Karoline Pudelko, Anthoula Gaigneaux, Nathalie Harrer, Markus Hengstschläger, Mira Stadler, Alexander Biermeier, Claudia Weindorfer, Helmut Dolznig, Michael Bergmann |
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| Přispěvatelé: | Fonds National de la Recherche - FnR, the Fondation Marie-Jeanne and Edmond Schumacher, the Fondation Gustave and Simone Prévot. [sponsor] |
| Rok vydání: | 2021 |
| Předmět: |
Male
Cancer Research Colon Antigens Differentiation Myelomonocytic Receptors Cell Surface CCL2 Biology Biochemistry biophysics & molecular biology [F05] [Life sciences] Cancer-Associated Fibroblasts Antigens CD Cell Movement medicine Tumor Microenvironment Macrophage Humans Myeloid Cells Interleukin 8 Biochimie biophysique & biologie moléculaire [F05] [Sciences du vivant] Chemokine CCL2 Cell Proliferation Tumor microenvironment Monocyte Macrophage Colony-Stimulating Factor Cell Differentiation HCT116 Cells Cancer associated fibroblasts Colon cancer Gene Expression Regulation Neoplastic medicine.anatomical_structure Oncology Tumor progression Cancer research Female Colorectal Neoplasms CD163 Signal Transduction |
| Zdroj: | Cancer letters. 520 |
| ISSN: | 1872-7980 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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