Antineoplastic effects of targeting CCR5 and its therapeutic potential for colorectal cancer liver metastasis

Abstract

Purpose: Liver metastasis is observed in up to 50% of colorectal cancer (CRC) patients. Available treatment options are limited and disease recurrence is often. Chemokine receptor 5 (CCR5) has attracted attention as novel therapeutic target for treating cancers. In this study, we reinforced the importance of CCR5 as therapeutic target in CRC and its liver metastasis by applying in vitro, in vivo and clinical investigations. Methods: By targeting CCR5 via siRNAs or an FDA approved antagonist (maraviroc), we investigated the ensuing antineoplastic effects in three CRC cell lines. An animal model for CRC liver metastasis was used to evaluate time-dependent expressional modulation of the CCR5 axis by cDNA microarray. The model was also used to evaluate the in vivo efficacy of targeting CCR5 by maraviroc. Circulatory and tumor associated levels of CCR5 and its cognate ligands (CCL3, CCL4, CCL5) were analyzed by ELISA, qRT-PCR and immunohistochemistry. Results: Targeting the CCR5 inhibited proliferative, migratory and clonogenic properties and interfered with cell cycle-related signaling cascades. In vivo findings showed significant induction of the CCR5 axis during the early liver colonization phase. Treatment with maraviroc significantly inhibited CRC liver metastasis in the animal model. Differential expression profiles of circulatory and tumor associated CCR5/ligands were observed in CRC patients and healthy controls. Conclusion: The findings indicate that targeting the CCR5 axis can be an effective strategy for treating CRC liver metastasis.