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An alternate route for metastatic cells Metastatic tumor cells are thought to reach distant organs by traveling through the blood circulation or the lymphatic system. Two studies of mouse models now suggest a hybrid route for tumor cell dissemination. Pereira et al. and Brown et al. used distinct methodologies to monitor the fate of tumor cells in lymph nodes. They found that tumor cells could invade local blood vessels within a node, exit the node by entering the blood circulation, then go on to colonize the lung. Whether this dissemination route occurs in cancer patients is unknown; the answer could potentially change the way that affected lymph nodes are treated in cancer. Science , this issue p. 1403 , p. 1408

A chemokine's sugary release As immune cells survey the body for pathogens, they circulate through the blood and migrate through the lymphatic system. The latter route allows for tissues and lymph nodes—the central hubs of the immune system—to communicate. Kiermaier et al. reveal the importance of the monosaccharide sialic acid in keeping immune cells in motion. Multiple sialic acids decorate the surface CCR7 on immune cells. CCR7 recognizes proteins called chemokines, which direct where cells move in the body. Sialic acids on CCR7 release one such chemokine present on lymph node endothelial cells from an inhibited state, allowing immune cells to enter lymph nodes. Science , this issue p. 186

A Well-Defined Path Although chemokines have long been thought to direct immune cell movements within tissues, a formal in vivo demonstration and detailed understanding are lacking. By tracking dendritic cell movements in the ears of mice, Weber et al. (p. 328 ) were able to provide both. Endogenous gradients of the chemokine CCL21 were observed in ear tissue and, at distances of up 90 µm, dendritic cells were able to use these gradients to migrate directionally toward lymphatic vessels. The CCL21 gradient was immobilized on heparan sulfates and disruption of the gradient inhibited dendritic cell migration.

Immune cells constantly circulate in the body in search of pathogens or tissue damage. Because they move autonomously, immune cell trafficking must be tightly controlled and coordinated by extracellular cues. The main signals that guide immune cells are chemokines, small polypeptides that modulate the migratory behavior of cells. Remarkably, most chemokines are not only sensed but also secreted by immune cells, indicating that immune cells might either attract more of their own kind or trigger complex patterns of feedbacks between different cell populations. Such cascades might allow different immune cell types to orchestrate their sequential arrival at a site of infection ( 1 ). On page 1071 of this issue, Lim et al. ( 2 ) show that this is indeed the case with neutrophils and cytotoxic T cells, the former leaving a trail of cues for the latter to follow during the eradication of a viral infection.