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

Abstract

This study investigated tumor-associated macrophages activity in the microenvironment of renal cell carcinoma. Via a co-culture with macrophage-like cells differentiated from human monocyte cell line THP-1 and U937 cells, the migration ability of ACHN and Caki-1 cells, which are human renal cell carcinoma cell line cells, was significantly increased, as was the epithelial–mesenchymal transition change. A chemokine array identified the CCL20-CCR6 axis as a concentration-dependent signal in ACHN and Caki-1 cell migration. Akt in the ACHN and Caki-1 cells was activated by macrophage-like cells, and the CCL20 neutralizing antibody suppressed migration ability, epithelial–mesenchymal transition, and Akt phosphorylation in the ACHN and Caki-1 cells. Akt inhibitor AZD5363 also decreased the epithelial–mesenchymal transition change and migration ability in the ACHN and Caki-1 cells. In 42 renal cell carcinoma tissues, patients with CCR6 and macrophage infiltration indicated poor prognoses. In the tumor microenvironment of renal cell carcinoma, cancer cells are activated by CCL20 secreted by tumor-associated macrophages through Akt activation, followed by epithelial–mesenchymal transition and an acquired migration ability. Thus, inhibition of the CCL20-CCR6 axis may be a potential therapeutic strategy for renal cell carcinoma.

CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of Receptors CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 Ligands

“…CCL20 expression is elevated in many cancers, such as breast cancer [ 60 ], hepatocellular carcinoma [ 161 ], and pancreatic cancer [ 162 , 163 ]. While its expression occurs in cancer cells [ 63 , 162 ], TAM are also a significant source of this chemokine in the tumor [ 162 , 164 , 165 ]. CCR6 expression has also been shown on tumor cells.…”

“…In addition to recruiting cells to a tumor niche, CCL20 increases cancer cell proliferation [ 166 , 177 ], causes cancer cell migration and invasion [ 167 , 177 , 178 , 179 ], and induces EMT of cancer cells [ 165 , 180 , 181 ]. It also participates in organ-specific patterns of metastasis—high expression of CCL20 in the liver results in the metastasis of tumor cells with high expression of CCR6 to this organ [ 182 , 183 , 184 ].…”

Hypoxia Alters the Expression of CC Chemokines and CC Chemokine Receptors in a Tumor–A Literature Review

“…Another therapeutic approach is the use of anti-CCR4 antibodies or CCR4 antagonists ( receptor for CCL17/TARC and CCL22/MDC) in cancer therapy [257][258][259] to reduce the accumulation of T reg and thus enhance the immunotherapy and anticancer response of the immune system. Some researchers also postulate targeting the CCL20/LARC→CCR6 axis [260,261], which causes chemoresistance and migration of neoplastic cells, and so any disorder in the function of CCL20/LARC should increase the activity of anticancer drugs. The data presented above also show that hypoxia increases the expression of CCR7 and thus causes metastasis to lymph nodes.…”

Macrophage‑derived exosomes attenuate the susceptibility of oral squamous cell carcinoma cells to chemotherapeutic drugs through the AKT/GSK‑3β pathway

“…For example, CCL-2 secretion by TAM activated the PI3K/AKT pathway in tumor cells to promote chemoresistance of breast cancer and migration of prostate cancer cells (44,45). CCL-20 secreted by TAM-activated EMT and the migratory ability of renal cell carcinoma cells via AKT activation (46). CXCL-8 derived from macrophages promoted the migration and invasion of esophageal squamous cell carcinoma cells via the phosphorylation of AKT and ERK1/2 through C-X-C motif chemokine receptor (CXCR)-1 and CXCR-2 in vitro (47).…”