[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Stadler, Mira; Institute of Medical Genetics, Medical University of Vienna, W¨ahringer Straße 10, A-1090 Vienna, Austria
Pudelko, Karoline; Institute of Medical Genetics, Medical University of Vienna, Währinger Straße 10, A-1090 Vienna, Austria
Biermeier, Alexander; Institute of Medical Genetics, Medical University of Vienna, Währinger Straße 10, A-1090 Vienna, Austria
Walterskirchen, Natalie; Department of Surgery, Medical University of Vienna, Währinger Gürtel 20, A-1090 Vienna, Austria
Gaigneaux, Anthoula ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
Weindorfer, Claudia; Institute of Medical Genetics, Medical University of Vienna, Währinger Straße 10, A-1090 Vienna, Austria
Harrer, Nathalie; Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria, Dr. Boehringer-Gasse 5-11, A-1130 Vienna, Austri
Klett, Hagen; Charles River Research Services Germany GmbH, Am Flughafen 12-14, 79108 Freiburg, Germany
Hengstschläger, Markus; Institute of Medical Genetics, Medical University of Vienna, Währinger Straße 10, A-1090 Vienna, Austria
Schüler, Julia; Charles River Research Services Germany GmbH, Am Flughafen 12-14, 79108 Freiburg, Germany
Sommergruber, Wolfgang; Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria, Dr. Boehringer-Gasse 5-11, A-1130 Vienna, Austria
Oehler, Rudolf; Department of Surgery, Medical University of Vienna, Währinger Gürtel 20, A-1090 Vienna, Austria
Bergmann, Michael; Department of Surgery, Medical University of Vienna, Währinger Gürtel 20, A-1090 Vienna, Austria
Letellier, Elisabeth ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
Dolznig, Helmut; Institute of Medical Genetics, Medical University of Vienna, Währinger Straße 10, A-1090 Vienna, Austria