ABSTRACT
BACKGROUND: Colonic cancer is associated with a low incidence of peritoneal metastasis compared with gastric cancer; however, the reason for this remains unclear. In this study, a model of peritoneal dissemination using the CT26 murine colon cancer cell line was used to analyze the physiological roles of cancer-derived exosomes. MATERIALS AND METHODS: Exosomes were collected from the supernatant of CT26 cell culture by ultracentrifugation. The number of peritoneal disseminations in two mouse models of colonic cancer pre-administered exosomes or phosphate-buffered saline were compared. RESULTS: Cancer-derived exosomes suppressed peritoneal dissemination compared to phosphate-buffered saline. After administration of exosomes, the number of intraperitoneal macrophages and the expression of inducible nitric oxide synthase increased. Furthermore, cancer-derived exosomes increased activated natural killer cells and interferon-γ expression. CONCLUSION: Tumor-derived exosomes from colonic cancer may suppress peritoneal metastasis via an immunological mechanism.
Subject(s)
Colonic Neoplasms/immunology , Exosomes/immunology , Immunologic Surveillance/immunology , Peritoneal Neoplasms/immunology , Animals , Cell Line, Tumor , Cell Movement/immunology , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Disease Models, Animal , Exosomes/metabolism , Female , Humans , Interferon-gamma/immunology , Interferon-gamma/metabolism , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Macrophages/immunology , Macrophages/metabolism , Mice , Mice, Inbred BALB C , Mice, Nude , Nitric Oxide Synthase Type II/immunology , Nitric Oxide Synthase Type II/metabolism , Peritoneal Neoplasms/secondary , RAW 264.7 CellsABSTRACT
BACKGROUND: Tumor microenvironment including fibrosis has a pivotal role in cancer growth and distant metastasis. Fibrosis is a known risk factor for carcinogenesis, but its biological role in disease invasion and metastasis in colorectal cancer (CRC) remains unclear. In particular, there is no report on how fibrosis of metastatic lymph nodes (MLNs) in CRC contributes to prognosis. METHODS: We reviewed 94 colorectal adenocarcinoma patients with MLNs who underwent colectomy. Both the primary tumors and MLNs were analyzed for alpha-smooth muscle actin (α-SMA) expression and collagen deposition. RESULTS: Higher α-SMA expression and collagen deposition in MLNs were associated with significantly shorter relapse-free survival and overall survival in CRC patients. α-SMA expression in MLNs (HR, 1.53; p = 0.034) was independent predictive factor of overall survival in multivariate Cox proportional hazards regression analysis of clinicopathological factors. In the Stage III patient subgroup, α-SMA expression in MLNs was a strong prognostic marker (HR, 3.01; p = 0.006). On the other hand, higher α-SMA expression and collagen deposition in primary tumors were associated with short overall survival, but they were not significant factors in multivariate Cox regression analyses. In MLNs, the podoplanin signals co-localized with α-SMA expression and were confirmed by the dual immunofluorescence staining, implying that the MLN stromal cells were fibroblastic reticular cells. CONCLUSION: Both high collagen deposition and high α-SMA expression in MLNs predicted poor prognosis in CRC.
