Metastasis continues to be the leading cause of mortality for patients with
cancer. Several years ago, it became clear that
chemokines and their receptors could control the
tumor progress. CXCR3 has now been identified in many
cancers including
osteosarcoma and CXCR3
ligands were expressed by lungs that are the primary sites to which this
tumor metastasize. This study tested the hypothesis that disruption of the CXCR3/CXCR3
ligands complexes could lead to a decrease in lungs
metastasis. The experimental design involved the use of the CXCR3 antagonist,
AMG487 and 2 murine models of
osteosarcoma lung
metastases. After tail vein injection of
osteosarcoma cells, mice that were systematically treated with
AMG487 according to preventive or curative protocols had a significant reduction in metastatic disease. Treatment of
osteosarcoma cells in vitro with
AMG487 led to decreased migration, decreased
matrix metalloproteinase activity, decreased proliferation/survival and increased
caspase-independent death. Taken together, our results support the hypothesis that CXCR3 and their
ligands intervene in the initial dissemination of the
osteosarcoma cells to the lungs and stimulate the growth and expansion of the metastatic foci in later stages. Moreover, these studies indicate that targeting CXCR3 may specifically inhibit
tumor metastasis without adversely affecting antitumoral host response.