Showing the way home

Circulating bone-marrow-derived progenitor cells are known to home to actively remodelling tissues, such as a developing tumour. However, the mechanisms involved have been unclear. Judy Varner and colleagues now report that integrin α₄β₁ promotes homing of these progenitor cells to the tumour neovasculature, and that the cells also actively participate in tumour growth.

First, human CD34⁺ progenitor cells were labelled with a fluorescent dye and injected into the tail vein of nude mice implanted with mouse breast carcinoma spheroids on mammary fat pads. Real-time intravital microscopy was used to track the CD34⁺ cells and showed that within a few minutes they were circulating in the tumour vasculature, and a few minutes after that arresting in blood vessels at the tumour periphery, but not in the tumour centre, surrounding normal fat pad or uninvolved mouse skin. These results discount non-specific leakage from tumour vessels because, if that were so, you would expect to find CD34⁺ cells in central tumour vessels as well. CD34⁺ progenitor cells were also seen within the tumour parenchyma near to blood vessels, implying that the cells migrated out of the vessel into the tumour tissue.

Adhesion proteins, such as integrins, are known to home haematopoietic cells to the bone marrow, so could the same mechanism be used to guide CD34⁺ cells to neovasculature? All circulating CD34⁺ cells expressed significant levels of integrin α₄β₁. When fluorescently labelled CD34⁺ cells were injected with anti-α₄β₁ antibodies into nude mice bearing breast carcinomas, or into nude mice bearing lung carcinomas, no CD34⁺-cell arrest was seen. Antagonists of other integrins had no such effect.

To investigate whether α₄β₁ promotes the participation of CD34⁺ cells in blood vessel formation, Varner and colleagues isolated murine bone-marrow-derived progenitor cells, which had previously been shown to participate in blood vessel formation, from enhanced green fluorescent protein (EGFP) mice. These cells expressed high levels of integrin α₄β₁. EGFP⁺ cells not only homed to tumours but also formed EGFP⁺blood vessels at the tumour periphery — both properties were inhibited by anti-α₄β₁ antibodies. In addition, the integrin α₄β₁ ligands, vascular cell adhesion molecule and fibronectin, were expressed in tumour endothelium, primarily at the tumour periphery.

This work identifies integrin α₄β₁–ligand binding as a key mechanism regulating progenitor cell homing to target tissues. It also shows that once at the target site the cells can differentiate into endothelial cells. Antagonists of these bone marrow-derived progenitors, or of integrin α₄β₁ or its ligands, could form a useful part of anti-angiogenic tumour therapy.