C-mannosyl tryptophan dynamics in a mouse model of the peritoneal dissemination of ovarian cancer.

C-Mannosyl tryptophan (C-Man-Trp), a unique monomeric glycosyl amino acid, is up-regulated in the blood of ovarian cancer patients; however, the underlying mechanisms remain unclear. In the present study, C-Man-Trp production and its dynamics were investigated in female B6C3F1 mice transplanted with mouse ovarian cancer OV2944-HM-1 (HM-1) cells. After transplantation, C-Man-Trp levels increased in the plasma, urine, ascites, peritoneal exudate cells (PECs), and tumor masses of mice. Furthermore, changes in the transcriptional expression of C-Man-Trp metabolism-related genes, C-mannosyltransferases (Dpy19l1 and Dpy19l3), and thrombospondin type I repeat superfamily genes (Thbs1, Spon1, and cellular communication network factor 1) were noted in tumor-associated cells and tissues. A cell-sorting analysis revealed that PECs mainly comprised myeloid-derived immune cells, such as macrophages and myeloid-derived suppressor cells, in addition to a small population of HM-1 tumor cells. C-Man-Trp levels were high in the macrophage fraction, but lower in the myeloid-derived suppressor cell fraction. C-Man-Trp was also produced in the ex vivo culture medium of macrophages isolated from PECs. Under macrophage depletion using clodronate liposomes, the ovarian cancer-stimulated up-regulation of C-Man-Trp was significantly suppressed in the plasma, ascites, PECs, and tumor masses of HM-1 cell-transplanted mice. C-Man-Trp levels in the plasma and peritoneal cavity cells of normal healthy mice were also suppressed by clodronate liposomes, whereas the expression of C-Man-Trp metabolism-related genes showed different changes from those in mice transplanted with HM-1 cells. Collectively, these results demonstrate that tumor-stimulated macrophages play a pivotal role in the dynamics of C-Man-Trp in mice with ovarian cancer.