CXCR4 and CXCR7 regulate angiogenesis and CT26.WT tumor growth independent from SDF-1.

Recent studies have shown that the chemokine stromal cell-derived factor (SDF)-1 and its receptor CXCR4 are involved in the metastatic process of colorectal cancer. The impact of SDF-1 on the stimulated metastatic growth during hepatectomy-associated liver regeneration is unknown. With the use of a heterotopic murine colon cancer model, we analyzed whether blockade of SDF-1 inhibits angiogenesis and extrahepatic growth of colorectal cancer after liver resection. Functional neutralization of SDF-1 by 1 mg/kg body weight anti-SDF-1 antibody only slightly delayed the initial tumor cell engraftment but also did not reduce the size of established extrahepatic tumors compared with controls. Tumor cell apoptosis was increased by anti-SDF-1 treatment only during the early 5-9-day period of tumor cell engraftment, but was found significantly decreased during the late phase of tumor growth. The initial delay of tumor cell engraftment was associated with an increase of tumor capillary density and microvascular permeability. This was associated with an increased vascular endothelial growth factor (VEGF) expression and an enhanced tumor cell invasion of the neighboring tissue. In contrast to the neutralization of SDF-1, blockade of the SDF-1 receptors CXCR4 and CXCR7 significantly reduced tumor capillary density and tumor growth. Thus, our study indicates that neutralization of SDF-1 after hepatectomy is not capable of inhibiting angiogenesis and growth of extrahepatic colorectal tumors, because it is counteracted by the compensatory actions through an alternative VEGF-dependent pathway.