title: CCR7 mediates directed growth of melanomas towards lymphatics.
abstract: OBJECTIVE
  To determine whether chemotactic-metastasis, the preferential growth of melanomas towards areas of high lymphatic density, is CCL21/CCR7 dependent in vivo. Lymphatic endothelial cells (LECs) produce the chemokine CCL21. Metastatic melanoma cells express CCR7, its receptor, and exhibit chemotactic-metastasis, whereby metastatic cells recognise and grow towards areas of higher lymphatic density.
  
  
  METHODS
  We used two in vivo models of directional growth towards depots of LECs of melanoma cells over-expressing CCR7. Injected LEC were tracked by intravital fluorescence microscopy, and melanoma growth by bioluminescence.
  
  
  RESULTS
  Over-expression of the chemokine receptor CCR7 enables non-metastatic tumor cells to recognise and grow towards LECs (3.9 fold compared with control), but not blood endothelial cells (0.9 fold), in vitro and in vivo in the absence of increased lymphatic clearance. Chemotactic metastasis was inhibited by a CCL21 neutralising antibody (4-17% of control). Furthermore, CCR7 expression in mouse B16 melanomas resulted in in-transit metastasis (50-100% of mice) that was less often seen with control tumors (0-50%) in vivo.
  
  
  CONCLUSIONS
  These results suggest that recognition of LEC by tumors expressing receptors for lymphatic specific ligands contributes towards the identification and invasion of lymphatics by melanoma cells and provides further evidence for a chemotactic metastasis model of tumor spread.
authors.affiliation: Microvascular Research Laboratories, Department of Physiology and Pharmacology, Bristol Heart Institute, School of Veterinary Sciences, University of Bristol, Bristol, UK.
authors.forename: Maxine S
authors.initials: MS
authors.lastname: Emmett
authors.forename: Silvia
authors.initials: S
authors.lastname: Lanati
authors.forename: Darryl B A
authors.initials: DB
authors.lastname: Dunn
authors.forename: Oliver A
authors.initials: OA
authors.lastname: Stone
authors.forename: David O
authors.initials: DO
authors.lastname: Bates
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D054421:Chemokine CCL21 / Q000502:physiology; D042783:Endothelial Cells; D042601:Lymphatic Vessels / Q000473:pathology*; D008545:Melanoma / Q000473:pathology*; D051379:Mice; D009362:Neoplasm Metastasis / Q000473:pathology*; D054400:Receptors, CCR7 / Q000502:physiology*
chemical_list: C515371:Ccr7 protein, mouse; D054421:Chemokine CCL21; D054400:Receptors, CCR7