Slipping through the middle

In the 1960s scientists saw evidence in electron micrographs that leukocytes migrate through the middle of endothelial cells in vivo. But when others couldn't replicate the findings in vitro and instead saw the immune cells slip between the endothelial cells, the field largely abandoned the idea of transcellular movement. Finally, on page 377, Carman and Springer show in vitro evidence that leukocytes can pass through the middle of cells as they leave the blood vessels and move into the tissue.

The team found that once a leukocyte attaches to the surface of an endothelial cell, microvilli protrude from the vascular cell surface, partially surrounding the immune cell. Adhesion proteins in the microvilli appear to realign the integrin molecules in the leukocytes, providing them with directional information. Meanwhile, a pore in the membrane of the endothelial cell forms and the leukocyte squeezes through.

So why did Carman and Springer see transmigration where others have not? Unlike previous studies, which relied on junctional vascular markers, the Harvard team also used antibodies against ICAM-1, an adhesion protein that lines the whole intravascular surface of the endothelial cells. With high resolution imaging, they could distinguish endothelial surface from junctional events even if the surface events occurred near a junction. Lower resolution images just couldn't distinguish exactly where the changes were happening. Other groups now hint that they see similar results.

Carman speculates that transcellular migration and passage between cells are probably used in different tissues and under different inflammatory conditions. But just what molecules regulate how an immune cell chooses its route remains unclear.

Meanwhile, on page 223, Weis et al. provide insight into how tumor cells move from the blood into surrounding tissue. Tumor cells in the blood secrete VEGF, an angiogenesis factor that compromises the integrity of the endothelial barrier. When the team injected tumor cells into mice deficient for either Src or Yes signaling kinases, few cancer cells passed through the endothelial barrier, relative to wild-type controls. VEGF appears to work through the kinases to disrupt VE-cadherin-β-catenin complexes, which maintain junctions between endothelial cells.