Abstract 1568: The role of CCL2 CCL17 CCL22-CCR4 axis in prostate cancer metastasis

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Abstract BACKGROUND: Multiple steps and factors are involved in prostate carcinogenesis and tumor progression. The early studies have found that tumor-associated macrophages (TAMs) have great effects on tumor developments. TAMs release a variety of cytokines, and chemokines enabling cancer cells to proliferate, migrate, invade, and metastasize. Some chemokines and their receptors were reported to play a key role during these processes of prostate cancer. Prostate cancer cells themselves also have been shown to express various chemokines and their receptors, such as CCL2, CCR2, CXCR4. Recently, CCR4 has been reported to be expressed in breast cancer cells and is associated with lung metastasis. However, the possible role of CCR4 in prostate cancer has not been well elucidated, and little is known about the relationship between TAMs and CCL2/CCL17/CCL22-CCR4 axis in tumor invasion of prostate cancer. AIM: The aim of our study was to investigate whether TAMs and the chemokine CCL2 (a low-affinity ligand for CCR4 and a high-affinity ligand for CCR2), CCL17 and CCL22 (high-affinity ligands for CCR4) -CCR4 axis promotes prostate cancer progression. METHODS: Human prostate cancer cell lines and monocyte cell lines were used in this study. To evaluate effects of chemokines on prostate cancer cells, we performed transwell migration and invasion assay co-cultured with or without macrophages. PCR, western blot, immunocytochemistry, immunohistochemistry, human chemokine array, ELISA were done to elucidate the mechanisms of prostate cancer progression caused by macrophages. RESULTS: Chemokine receptor CCR2 and CCR4 were expressed in human prostate cancer cell lines both in mRNA and protein level. Prostate cancer tissue also expressed both CCR2 and CCR4. In vitro co-culture system of prostate cancer cell lines and macrophages showed that the level of chemokine CCL2 from both prostate cancer cell lines and macrophages was increased and chemokine receptor CCR2 and CCR4 expressions were increased in prostate cancer cell lines. They promoted the migration and invasion of prostate cancer cell lines via their receptors and also enhanced phosphorylation of protein kinase Akt and extracellular signal-regulated kinase (ERK). Our results suggested that CCL2/CCL17/CCL22-CCR4 axis might play an important role in prostate cancer progression. CONCLUSION: We demonstrate that chemokine receptor CCR2 and CCR4, for the first time, were expressed by prostate cancer cell lines. CCL2/CCL17/CCL22-CCR4 axis, which is activated by TAMs, may be a potential candidate for molecular targeted therapy in the future. Citation Format: Aerken Maolake, Kouji Izumi, Ariunbold Natsagdorji, Hiroaki Iwamoto, Atsushi Mizokami. The role of CCL2 CCL17 CCL22-CCR4 axis in prostate cancer metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1568.