Liver metastases of C26 colon carcinoma cells recruit GATA6+ large peritoneal macrophages
Mokarram Hossain1, Liane Babes1 and Paul Kubes1*
1Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
We have recently reported a novel nonvascular pathway of macrophage recruitment into an injured liver directly from the peritoneal cavity (Wang & Kubes, 2016). Macrophages recruited in this pathway were GATA6+ large peritoneal macrophages that quickly switched into alternatively activated phenotype (M2) and helped repair the damaged tissue. We want to explore the scope of this discovery beyond injury. In this line, we are testing the hypothesis that in a growing tumor in organs within the peritoneum, cavity macrophages are recruited from the peritoneum. Tumor environment trains the recruited cavity macrophages to take on an alternative (M2) phenotype and help contribute to a pro-tumorigenic environment including improved vascularization. In this study, we used a liver metastasis model in which colon carcinoma (C26-iRFP) cells were injected into the spleen of syngeneic BALB/c mice. Using multi-channel spinning disk intravital microscopy, we observed robust recruitment of massive amount of F4/80+ macrophages specifically in the tumor area. Selective labeling of peritoneal macrophages with PKH26 dye revealed that many of these recruited F4/80+ cells are in fact peritoneal macrophages. Flow cytometric analysis of the non-parenchymal cells isolated from livers bearing C26 metastases confirmed the presence of GATA6+ large peritoneal macrophages that express high level of F4/80 and CD11b. This recruitment appears to be extracellular ATP-dependent since intraperitoneal injection of P2RX7 (receptor for ATP) antagonist dramatically reduced the number of recruited peritoneal macrophages to the liver metastases. This study confirms that peritoneal macrophages can directly be recruited to visceral organ in the presence of altered tissue such as cancer.
Wang, Jing, & Kubes, Paul. (2016). A Reservoir of Mature Cavity Macrophages that Can Rapidly Invade Visceral Organs to Affect Tissue Repair. Cell, 165(3), 668-678. doi: https://dx.doi.org/10.1016/j.cell.2016.03.009
MH is a recipient of Alberta Cancer Foundation Postdoctoral Fellowship. The PK lab is supported by Canadian Institute of Health Research and Alberta Innovates Health Solutions