Metastasis: Active Lymph Nodes

RESEARCH HIGHLIGHTS

METASTASIS subcapsular sinus. Further investiga- tions in vivo revealed that CCR8 acti- vation in tumour cells was required Active lymph nodes for tumour cell extravasation from lymphatic vessels, specifically for the Lymph node metastases are CCL1 activates CCR8-mediated transmigration of tumour cells from indicative of poor prognosis but intracellular signalling in tumour the subcapsular sinus into the lymph tumour cell the mechanisms of tumour cell cells, which resulted in cellular node cortex. entry into the dissemination via the lymphatics changes that are consistent with cell These data unpick the process of are poorly understood. Although it migration. lymphatic dissemination and iden- lymph node is widely believed that tumour cells Is the CCR8–CCL1 paracrine tify the sequence of steps leading to requires active enter the lymph nodes passively with pathway important in lymphatic lymph node metastasis. The authors cell migration the flow of lymph, previous data have metastasis? The suppression of showed that CCR8 is expressed by indicated that some chemokines may CCR8 expression or activity in a large subset of human melanoma promote lymphatic extravasation human melanoma cells did not samples, and it will be interesting and metastasis. Das et al. now dem- affect tumour growth or vasculariz to determine whether this pathway onstrate that tumour cell entry into ation on implantation into immuno can be targeted to prevent lymph the lymph node requires active cell deficient mice, but significantly node metastasis. migration and they also identify the reduced the incidence of lymph Gemma K. Alderton lymphatic endothelium of the lymph node metastasis. Furthermore, ORIGINAL RESEARCH PAPER Das, S. et al. node subcapsular sinus as a critical CCL1 was not detected in the Tumor cell entry into the lymph node is controlled gatekeeper. tumour microenvironment but by CCL1 chemokine expressed by lymph node lymphatic sinuses. J. Exp. Med. 210, 1509–1528 The authors investigated was detected in the lymphatic (2013) whether conditioned media from endothelium of the lymph node cultured lymphatic endothelial cells (LECs) was chemotactic for several metastatic cancer cell lines. The conditioned media induced the migration of metastatic melanoma cells (and not poorly metastatic melanoma cells) and this could be attributed to the chemokine CCL1. CCR8, a G protein-coupled receptor (GPCR), is activated by CCL1, and the authors found that the cell lines that responded to LEC-conditioned media expressed CCR8, and that chemotaxis was inhibited when the cells were treated with MC148 (a CCR8 antagonist) or with blocking antibodies to CCL1. Further experi- ments confirmed that LEC-derived GETTY

NATURE REVIEWS | CANCER VOLUME 13 | SEPTEMBER 2013