Contribution of CXCR4 and CXCR7 to tumor invasion, intravasation, and metastasis. (A) At the primary tumor site, CXCR4 alone enhances invasion through the extracellular membrane via induction of MMP12 in response to CXCL12. (B) CXCR4+CXCR7+ cells are less invasive in response to CXCL12 due to downregulation of MMP12. (C) According to Zabel and colleagues [7, 8], CXCR4+ cells show somewhat limited transendothelial migration compared with CXCR4+CXCR7+ cells as shown in (D). (E) The combination of a CXCR4 inhibitor and CXCR7 antagonist would reduce invasion, transendothelial migration, and finally metastasis.