CXCR4 expression increases liver and lung metastasis in a mouse model of pancreatic cancer

Abstract

Expression of the Gi-protein-coupled chemokine receptor CXCR4 has recently been linked to increased proliferation, invasion and migration of human pancreatic cancer cell lines. However, the relevance of CXCR4 for organ specific pancreatic cancer metastasis in vivo remains unclear. Here we have studied the role of CXCR4 in vivo using noninvasive bioluminescent imaging of metastasis in a mouse model of pancreatic cancer. Murine TD–2 cells, established from pancreatic carcinoma of a TGFα/p53±transgenic mouse, display poor metastatic potential, as demonstrated by tail vein metastatic assay in nude mice. CXCR4 mRNA and cell surface protein expression levels were at the lower detection limit in TD–2 cells. To study the role of CXCR4 in pancreatic cancer invasion and metastasis, we generated stable cell lines with similar CXCR4 expression levels as human pancreatic cancer cell lines derived from metastatic lesions. Addition of the CXCR4 ligand CXCL12 induced calcium influx and migration in a dose dependent manner in stable CXCR4, but not in mock or CCR7 transfected TD–2 cell lines. CXCR4, but not CCR7 expression dramatically increased the in vivo metastatic potential of TD–2 cells, resulting in liver and lung metastasis in nude mice. Systemic administration of the selective CXCR4 inhibitor AMD 3100 effectively blocked the enhanced metastatic potential of CXCR4 expressing pancreatic cancer cells. These results indicate that CXCR4 expression accelerates organ specific metastasis of pancreatic carcinoma cells and provide evidence that blockade of the CXCL12/CXCR4 axis is a target for anti-metastatic therapy.