Angiogenesis, Metastasis, and the Cellular Microenvironment New Insight into the SDF-1/CXCR4 Axis in a Breast Carcinoma Model: Hypoxia-Induced Endothelial SDF-1 and Tumor Cell CXCR4 Are Required for Tumor Cell Intravasation

The SDF-1/CXCR4 axis has been implicated in breast cancermetastasis. In contrast to its well-established role in organ-specific homing and colonization of tumor cells, the involvement in intravasation, especially in a hypoxic environment, is still poorly understood. Initially, we detected both, the chemokine SDF-1 and its receptor CXCR4 in microvessels in invasive ductal cancer samples. To elucidate the role of the SDF-1/CXCR4 axis in vascular endothelium for tumor intravasation, we evaluated the effects of CXCR4 activation in human umbilical vein and dermal microvascular endothelial cells (HUVEC andHDMEC) and in cultured mammary carcinoma cells (MDA MB231, and MCF7). We observed an upregulation of SDF-1 and CXCR4 in HUVECs in hypoxia, which led to proliferation, migration, and tube formation. Hypoxia induced adhesion of tumor cells to endothelial cells and stimulated transendothelial migration. The effects of hypoxia were dependent on the activity of the transcription factor hypoxia-inducible factor. Adhesion to and migration through a HUVEC monolayer were significantly reduced by lentiviral inhibition of CXCR4 in breast carcinoma cells or treatment of endothelial cells with an anti-SDF-1 neutralizing antibody. These data show that the interaction of SDF-1 secreted by ECs with tumor cell CXCR4 is sufficient to stimulate transendothelial migration of the tumor cells. Our results suggest that the SDF-1/ CXCR4 axis is important in angiogenesis and tumor cell intravasation. Because both proteins were readily identifiable in a significant fraction of human breast cancer samples by immunohistochemistry, CXCR4 may constitute a molecular target for therapy when both, SDF-1, and CXCR4 are expressed. Mol Cancer Res; 10(8); 1021–31. 2012 AACR