Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by remarkable desmoplasia with infiltration of distinct cellular components. Cancer‐associated fibroblasts (CAFs) has been shown to be among the most prominent cells and played a significant role in shaping the tumor microenvironment by interacting with other type of cells. Here, we aimed to investigate the effect of CAFs in modulating phenotype of tumor‐associated macrophages (TAM). Under treatment of CAFs conditioned medium (CM) or direct co‐culture with CAFs, monocytes exhibited enhanced expression of CD206 and CD163 compared with control group (P < 0.01). The induction of M2 polarization was mediated by increased reactive oxygen species (ROS) production in monocytes as ROS elimination abolished the effect of CAFs (P < 0.05). The supernatant analysis showed that pancreatic CAFs produced increased macrophage colony‐stimulating factor (M‐CSF). Upon treatment of M‐CSF neutralizing antibody, the ROS generation and M2 polarization of CAFs CM‐stimulated monocytes were significantly inhibited (P < 0.05). In addition, the CAFs‐induced M2 macrophages significantly enhanced pancreatic tumor cell growth, migration, and invasion. Collectively, our data revealed that pancreatic CAFs were able to induce a tumor‐promoting TAM phenotype partly through secreted M‐CSF and enhanced ROS production in monocytes, indicating possible treatment strategies by targeting stromal cell interaction within PDAC microenvironment.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal of malignancies with a median survival of 4–6 months [1]
PDAC is uniquely featured by a striking desmoplastic reaction caused by proliferation of activated pancreatic stellate cells, which is equivalent to cancer-associated fibroblasts (CAFs) in other type of cancers [2]
To investigate the effect of CAFs on the polarization states of monocytes, CD14+ human peripheral blood mononuclear cells (PBMC) were treated with conditioned medium (CM) from pancreatic CAFs
Summary
Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal of malignancies with a median survival of 4–6 months [1]. It has been revealed that CAFs in PDAC is tightly associated with tumor progression through direct interaction with cancer cells, like promoting tumor cell survival, growth, and invasion as well [3, 4]. In PDAC, large amount of monocytes in bone marrow, peripheral blood, and spleen were recruited into tumor. Upon arriving, these cells were transformed toward distinct functional status induced by local cytokines and other signals within microenvironment, among which M1 and M2 macrophage are well characterized [9]. It has been shown that M1 macrophage enhances inflammation and involves in early tumor development, whereas M2 is associated with tumor progression by promoting angiogenesis and immune suppression [10,11,12]
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