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

Suguru Kadomoto,Hiroki Nakata,Hiroshi Yaegashi,Renato Naito,Taito Nakano,Hiroaki Iwamoto,Kazuyoshi Shigehara,Yoshifumi Kadono,Yohei Saito,Kaoru Hiratsuka,Tomoyuki Makino,Kyoko Nakagawa-Goto,Kouji Izumi,Atsushi Mizokami

doi:10.3390/cancers12010089

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.

Highlights

The most dominant histological phenotype of kidney cancer is renal cell carcinoma (RCC), which accounts for 3–4% of all cases of adult cancer in the United States [1]
We identified CCL20, of which CCR6 is the sole receptor, as a key player mediating Akt activation and the epithelial–mesenchymal transition (EMT) of RCC cells
THP-1proliferation, and U937 cellsadhered were treated with phorbol (PMA), thesuspended cells stopped to the surface of12-myristate the plate, 13-acetate and, after(PMA), 24 h, the cells stopped adhered surface of the plate,(hereinafter and, after 24 h, differentiated differentiated intoproliferation, M1L macrophage cells to as the we previously reported referred to as M1Linto macrophage we previously reported

Summary

Introduction

The most dominant histological phenotype of kidney cancer is renal cell carcinoma (RCC), which accounts for 3–4% of all cases of adult cancer in the United States [1]. A total of 20–40% of RCC patients have recurrent metastatic disease after a primary nephrectomy; approximately 50%. Of all patients who are diagnosed with RCC should receive systemic therapy during the course of their disease [2]. The prognosis of advanced and metastatic RCC is not satisfactory, even with the recent evolution of treatment methods [3]. RCC, which accounts for 70% of all RCC [4]. As clear cell RCC shows immunogenicity, immunotherapy, such asof interferon-α and played a central role in RCC treatment until which accounts for all RCC [4]. Asinterleukin-2, clear cell RCC shows immunogenicity, immunotherapy, the 1990s [5]. Many and studies have shown the involvement cells that induce immune such as interferon-α interleukin-2, played a central roleofinimmune

Methods

Results

Conclusion