CC chemokine receptor 2 mediated regulation of macrophages is involved in pancreatic cancer progression in the tumor microenvironment

Objective : The interaction between pancreatic ductal adenocarcinoma (PDAC) cells and non-tumor cells is important in PDAC. In this study, we investigated the effects of CC chemokines in PDAC. Design: According to microarray data of cancer-associated fibroblasts (CAFs) stimulated by PDAC cells, the expression of Cc chemokines was analyzed by quantitative RT-PCR. Macrophages were induced from the bone marrow cells of Cc chemokine receptor 2 (Ccr2)-wild-type (WT) and Ccr2-knockout (KO) mice, and their interaction with PDAC cells was examined. Differences in RNA and protein expression between Ccr2 WT and KO macrophages were examined also. Systemic KO of Ccr2 in a geneticallyengineered murine PDAC model was established to analyze the survival impact and histopathological phenotype using immunohistochemistry. The RNA sequences of PDAC cells stimulated with Ccr2-WT or KO macrophages were also examined. Results: Ccl2 and Ccl7 expression was upregulated in CAFs. Ccr2 is expressed in macrophages in PDAC. Ccr2-WT macrophages promote the invasion of PDAC cells in vitro. Ccr2-KO decreases Cxc chemokine levels and increases interferon-a production in macrophages. Ccr2 KO PDAC mice showed significantly prolonged survival. Conclusions: CCLs-CCR2 signaling affects the profile and function of macrophages, and Ccr2-KO in macrophages may alter the microenvironment in a tumor-suppressive manner in PDAC.