CCR5 Antagonism by Maraviroc Reduces the Potential for Gastric Cancer Cell Dissemination

The chemokine (C-C motif) receptor 5 (CCR5) that belongs to the family of G protein-coupled receptors is exploited by macrophage tropic (R5) human immunodeficiency virus type 1 (HIV-1) to enter cells. Maraviroc, a small molecule CCR antagonist, is used as a part of combination antiretroviral therapy to treat persons infected by R5 HIV-1. CCR5 is expressed in various cancers, and its level of expression is a negative predictor of patients' survival in gastric cancers. Here, we report MKN45, MKN74, and KATOIII cells, three human gastric cancer cell lines with different stages of differentiation, which express CCR5 as detected by flow cytometry and reverse transcription-polymerase chain reaction (RT-PCR), and its ligand RANTES. In vitro experiments demonstrate that CCR5 antagonism reduces gastric cancer cell migration induced by macrophage inflammatory protein 1 alpha (MIP-1 alpha), MIP-1 alpha, and RANTES and adhesion to the explanted murine peritoneum. Administration of maraviroc from days 3 to 10 after MKN45 cell inoculation to severe combined immunodeficient (SCID) mice effectively reduced the extent of peritoneal disease and increased survival. Maraviroc treatment also reduced the tumor burden in a xenograft model. Gene expression and RT-PCR analyses revealed that CCR5 antagonism in vivo modulates the expression of genes known for their role in cancer growth including interleukin-10 receptor B; hepatocyte growth factor receptor (MET); the homolog of the atypical cadherin gene, FAT1; Nm23-H1; and lymphotoxin beta receptor. In summary, we have shown that CCR5 is mechanistically involved in dissemination of gastric cancer cells, suggesting that small molecule inhibitors of CCR5 might be exploited for their anticancer potential.