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 1α (MIP-1α), MIP-1β, and
RANTES and adhesion to the ex-planted 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 β 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.