Tumor-associated macrophage-derived CCL20 enhances the growth and metastasis of pancreatic cancer

Abstract

Pancreatic cancer is an aggressive malignancy with a high metastatic potential that results in a high mortality rate worldwide. Although macrophages have the potential to kill tumor cells and elicit immune responses against tumors, there is evidence that tumor-associated macrophages (TAMs) promote tumor progression and suppress T-cell responses. CC-chemokine ligand 20 (CCL20) and its unique receptor CC-chemokine receptor 6 (CCR6) are exploited by cancer cells for migration and metastasis and play important roles in the development and progression of cancer. Recent studies have shown that the expression of CCL20 is upregulated in pancreatic cancer; however, the mechanism of action of CCL20 remains to be fully elucidated. In this study, the aberrant expression of CCL20 in TAMs of pancreatic cancer tissue, including metastatic pancreatic cancer tissue, was detected. CCL20 expression was considerably higher in macrophages than in pancreatic cancer cell lines, particularly in interleukin-4-treated (M2) macrophages. Using Boyden chamber assays of pancreatic cancer cells, we found that CCL20 secreted by M2 macrophages promoted the migration, epithelial-mesenchymal transition, and invasion of pancreatic cancer cells. RNA interference results showed that CCR6 is a receptor for CCL20 in pancreatic cancer cells, mediating the increased invasive properties of these cells promoted by CCL20. Using a mouse model, we confirmed the roles of CCR6/CCL20 in promoting pancreatic cancer growth and liver metastasis in vivo Our findings provide insight into the important role of macrophage-secreted CCL20 in pancreatic cancer and implicate CCR6/CCL20 as potential therapeutic targets.

c‐Jun N‐terminal kinase in pancreatic tumor stroma augments tumor development in mice

“…reported that Ccl20 promotes PDAC cell invasion, and Liu et al . reported that Ccl20, derived from tumor‐associated macrophages, enhances PDAC cell growth and metastatic ability . Moreover, Rubie et al .…”

“…Campbell et al reported that Ccl20 promotes PDAC cell invasion, (43) and Liu et al reported that Ccl20, derived from tumor-associated macrophages, enhances PDAC cell growth and metastatic ability. (44) Moreover, Rubie et al showed that Ccl20 was significantly upregulated in human PDAC tissue and associated with advanced T stage based on the UICC TNM classification. (45) However, in other carcinomas, such as esophageal, gastric, ovarian, and colorectal cancers, upregulation of Ccl20 expression and infiltration of DC and CD8 + T cells represent a positive prognostic factor for survival.…”

Tumor-Associated Macrophages Induce Migration of Renal Cell Carcinoma Cells via Activation of the CCL20-CCR6 Axis

“…In our in vitro study, macrophage-like cells similar to TAMs enhanced RCC cell migration. Among the various immune factors involving mechanisms of TAM-induced cancer cell migration, chemokines have been reported as critical factors for the promotion of migration in cancers [11,17,18]. Therefore, we focused on chemokines as a contributing factor to tumor promotion in RCC cells.…”

Nicotine promotes brain metastasis by polarizing microglia and suppressing innate immune function

“…The expression of CCL20 has been shown to be overexpressed in a variety of tumors including lung cancer (Liu et al, 2016;Wang et al, 2015Wang et al, , 2016. In pancreatic cancer, CCL20 has been found to be overexpressed in metastatic tumor tissues (Liu et al, 2016). It was reported to promote epithelial-mesenchymal transition and invasive ability of tumor cells by activating the MAPK and PI3K pathways and matrix metallopeptidase signaling (Marsigliante et al, 2016;Wang et al, 2016).…”