Aerken Maolake

Tumor-associated macrophages promote prostate cancer migration through activation of the CCL22-CCR4 axis

Previous 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. The CCR4 (receptor of CCL17 and CCL22) expression level in breast cancer was reported to be associated with lung metastasis. The aim of this study was to elucidate the role of CCR2 and CCR4 in prostate cancer progression. CCR2 and CCR4 were expressed in human prostate cancer cell lines and prostate cancer tissues. In vitro co-culture of prostate cancer cells and macrophages resulted in increased CCL2 and CCR2 levels in prostate cancer cells. The addition of CCL2 induced CCL22 and CCR4 production in prostate cancer cells. The migration and invasion of prostate cancer cells via enhanced phosphorylation of Akt were promoted by CCL17 and CCL22. CCR4 may be a potential candidate for molecular-targeted therapy.

The relationship between prostate-specific antigen and TNM classification or Gleason score in prostate cancer patients with low prostate-specific antigen levels

Prostate‐specific antigen (PSA) is a useful biomarker for risk classification in patients with prostate cancer. However, it is unclear whether a correlation exists between low PSA levels (<10 ng/ml) at diagnosis and prognosis.

Serum chemokine (CC motif) ligand 2 level as a diagnostic, predictive, and prognostic biomarker for prostate cancer

Prostate-specific antigen (PSA) is regarded as the most sensitive biomarker for prostate cancer. Although androgen/androgen receptor (AR) signaling promotes prostate cancer progression, suppression of AR signaling induces chemokine (CC motif) ligand 2 (CCL2), which enables prostate cancer cells to gain metastatic potential. AR-controlled PSA alone may be an unreliable biomarker for patients receiving androgen deprivation therapy. Therefore, we investigated the validity of CCL2 as a complementary biomarker to PSA for prostate cancer. Our in vitro approach of enriching for prostate cancer cells with higher migration potential showed that CCL2 activated cellular migration. Importantly, we found that CCL2 levels were significantly different between men (n = 379) with and without prostate cancer. Patients with CCL2 ≥ 320 pg/mL had worse overall survival and prostate cancer -specific survival than those with CCL2 < 320 pg/mL. A novel risk classification was developed according to the risk factors CCL2 ≥ 320 pg/mL and PSA ≥ 100 ng/mL, and scores of 2, 1, and 0 were defined as poor, intermediate, and good risk, respectively, and clearly distinguished patient outcomes. CCL2 may serve as a novel biomarker for prostate cancer. The novel risk classification based on combining CCL2 and PSA is more reliable than using either alone.

C-C motif ligand 5 promotes migration of prostate cancer cells in the prostate cancer bone metastasis microenvironment

Chemokines and their receptors have key roles in cancer progression. The present study investigated chemokine activity in the prostate cancer bone metastasis microenvironment. Growth and migration of human prostate cancer cells were assayed in cocultures with bone stromal cells. The migration of LNCaP cells significantly increased when co‐cultured with bone stromal cells isolated from prostate cancer bone metastases. Cytokine array analysis of conditioned medium from bone stromal cell cultures identified CCL5 as a concentration‐dependent promoter of LNCaP cell migration. The migration of LNCaP cells was suppressed when C‐C motif ligand 5 (CCL5) neutralizing antibody was added to cocultures with bone stromal cells. Knockdown of androgen receptor with small interfering RNA increased the migration of LNCaP cells compared with control cells, and CCL5 did not promote the migration of androgen receptor knockdown LNCaP. Elevated CCL5 secretion in bone stromal cells from metastatic lesions induced prostate cancer cell migration by a mechanism consistent with CCL5 activity upstream of androgen receptor signaling.

Predictive factor and antihypertensive usage of tyrosine kinase inhibitor‑induced hypertension in kidney cancer patients

Hypertension (HT) is the common adverse event associated with vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKI). The present study was performed to identify the predictive factors of TKI-induced HT and to determine the classes of antihypertensive agents (AHTA) that demonstrate optimal efficacy against this type of HT. The charts of 50 cases of patients that had received VEGFR-TKI treatment were retrospectively examined. The association between patient background and TKI-induced HT, and the effect of administering AHTA were analyzed. High systolic blood pressure at baseline was identified to be a predictive factor for HT. In addition, there was no difference observed between calcium channel blockers (CCBs) and angiotensin receptor II blockers (ARBs) as first-line AHTA for the control of HT. The findings of the present study may aid with predicting the onset of TKI-induced HT, as well as for its management via the primary use of either CCBs or ARBs.

MP87-02 TUMOR-ASSOCIATED MACROPHAGES PROMOTE PROSTATE CANCER METASTASIS VIA CCL2-CCR2 AXIS-INDUCED CCL22-CCR4 AXIS

INTRODUCTION AND OBJECTIVES: 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.

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

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.