Login to Access Video or Poster Abstract: MP87-02
Sources of Funding: JSPS KAKENHI (Grant No. 25861413 to K. Izumi and Grant No. 26462405 to K. Narimoto)

Introduction

Early studies have found that tumor-associated macrophages (TAMs) promote cancer progression. We previously reported that TAMs promote prostate cancer metastasis via activation of the CCL2-CCR2 axis. Recently, it was reported that the CCR4 (receptor of CCL17 and CCL22) expression level in breast cancer was associated with lung metastasis. However, the role of CCR4 and the relationship between CCR2 and CCR4 in prostate cancer is unclear. The aim of this study was to elucidate the role of CCR4 and the relationship between CCL2-CCR2 axis and CCL17/CCL22-CCR4 axis in prostate cancer progression.

Methods

Human prostate cancer cell line cells and monocyte-lineage cells were used. Transwell migration and invasion assays co-cultured with or without macrophages were performed. Chemokines and their receptors in prostate cancer cells were measured. CCR2 and CCR4 in prostate cancer tissue were immunohistochemically analyzed.

Results

Co-culture of macrophages and prostate cancer cells increased prostate cancer cell migration and invasion and induced secretion of CCL2. CCL2 promoted prostate cancer cell migration in an autocrine manner and induced CCR2, CCR4 expressions, and CCL22 secretion of prostate cancer cells. RT-PCR, western blotting, and immunocytochemical staining revealed both CCR2 and CCR4 expressions in prostate cancer cells. CCL22 also promoted prostate cancer cell migration. Blockade of the CCL2-CCR2 or CCL17/22-CCR4 axis with receptor antagonist inhibited the migration of prostate cancer cells. The CCL2-CCR2 and CCL22-CCR4 axes increased phosphorylation of Akt and Erk1/2. Although both CCR2 and CCR4 antagonists could inhibit phosphorylation of Akt and Erk1/2, the CCR4 antagonist, compared with the CCR2 antagonist, strongly inhibited phosphorylation of Akt. CCR4 may have contributed more to prostate cancer cell migration than did CCR2. CCR4 and CCR2 were increased in prostate cancer tissues by IHC staining. Interestingly, the staining intensities of CCR2 and CCR4 in each specimen were significantly correlated. Moreover, the staining intensity of CCR4 was correlated with the progression of TNM stage.

Conclusions

This is the first study to show that CCR4 was expressed in prostate cancer cell lines and human prostate cancer tissues and that the CCL22-CCR4 axis contributed to prostate cancer migration and invasion. Targeting of the CCL22-CCR4 axis, which is activated by TAMs, may be a novel therapeutic target and a potential biomarker for prostate cancer.

Funding

JSPS KAKENHI (Grant No. 25861413 to K. Izumi and Grant No. 26462405 to K. Narimoto)