Inhibition of the CXCR4/CXCL12 chemokine pathway reduces the development of murine pulmonary metastases

Abstract

Metastasis continues to be the leading cause of mortality for patients with cancer. High expression of the chemokine receptor CXCR4 correlates with poor prognosis in many cancers, including osteosarcoma and melanoma. CXCL12, the ligand for CXCR4, is expressed at high levels in the lung and lymph node, which are the primary sites to which these tumors metastasize respectively. These findings suggest that therapy aimed at disruption of this specific receptor/ligand complex may lead to a decrease in metastases. CTCE-9908, a small peptide CXCR4 antagonist was utilized in two murine metastasis models to test this hypothesis. Treatment of osteosarcoma cells in vitro with CTCE-9908 led to the following changes: decreased adhesion, decreased migration, decreased invasion, and decreased growth rate. Following tail vein injection of osteosarcoma cells, mice that were treated with CTCE-9908 had a 50% reduction in the number of gross metastatic lung nodules and a marked decrease in micrometastatic disease. Similar findings were observed following injection of melanoma cells and treatment with CTCE-9908. However, these results could only be consistently reproduced when the cells were pre-treated with the inhibitor. A novel ex vivo luciferase assay showed decreased numbers of cells in the lung immediately after injection into mice, when treated with CTCE-9908, suggesting the importance of interactions between the receptor and the ligand. Our findings show that inhibition of the CXCR4/CXCL12 pathway decreases metastatic disease in two murine tumor models and expands on previous reports to describe potential mechanisms of action.

CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers

“…CTCE-9908 decreases growth and adhesion of osteosarcoma cells and the metastatic dissemination of cancer cells in two murine models. 101 CTCE-9908 is developed by Chemokine Therapeutics Corp., Vancouver, BC, Canada.…”

Chemokines in cancer related inflammation

“…In pre-clinical settings, CXCR4 antagonists significantly reduced the size of primary tumors and had anti-metastatic effects in mouse models of melanoma, osteosarcoma, breast and prostate tumors [123][124][125][126][127]. AMD3100 was unexpectedly found to mobilize CD34+ stem cells from the bone marrow [128].…”

Osteosarcoma

“…Similar to the integrin family of proteins, expression of chemokines and the chemokine receptors have been linked to osteosarcoma progression and metastasis in a number of preclinical and correlative studies. (47,48) Interactions between chemokines and integrin family members further contribute to the ability of metastatic cells to interact with their microenvironment and promote metastatic cell survival. (49) The insulin-like growth factor 1 (IGF-1) pathway.…”