Lymphatic Endothelial Cells Actively Regulate Tumor Cell Entry

Tumor cell metastasis to local lymph nodes is indicative of increased tumor aggressiveness and associated with decreased survival. The entry of tumor cells into lymph nodes was previously thought to be a passive process, but recent studies have suggested that chemokine signaling may actively regulate tumor cell passage through lymphatic vessels. Das and colleagues found that chemokine (C-C motif) ligand 1 (CCL1) enhances melanoma and breast cancer cell chemotaxis to lymphatic endothelial cells (LEC) via its G-protein–coupled receptor, chemokine (C-C motif) receptor 8 (CCR8). CCL1 expression in LECs was induced by proinflammatory cytokines, including TNF and interleukin-1β, and was detected in the lymphatic endothelium within the lymph node subcapsular sinus (SCS) but not in peripheral lymphatic vessels, whereas CCR8 was expressed by melanoma cells and lymph node metastases in human tumor samples. Inhibition of CCR8 prevented CCL1-stimulated cytoskeletal rearrangements and intracellular calcium influx in tumor cells and impaired tumor cell migration to LECs, supporting a role for CCR8 activation in lymph node metastasis. Consistent with this idea, CCR8 blockade diminished the formation of sentinel lymph node metastases in vivo and resulted in accumulation and arrest of tumor cells in afferent lymphatic vessels at the junction with the lymph node SCS, suggesting that LECs within the SCS form a barrier to tumor cell entry into the lymph node. Furthermore, lymph node metastasis proceeded in a controlled, stepwise manner consisting of initial dilation of the SCS prior to tumor cell arrival, followed by entry of tumor cells into the SCS and subsequent passage into the lymph node cortex via active migration. These results identify CCL1–CCR8 and LECs as critical regulators of lymph node metastasis and suggest CCR8 as a potential therapeutic target to limit metastatic spread.

Das S, Sarrou E, Podgrabinska S, Cassella M, Mungamuri SK, Feirt N, et al. Tumor cell entry into the lymph node is controlled by CCL1 chemokine expressed by lymph node lymphatic sinuses. J Exp Med 2013 Jul 22 [Epub ahead of print].