title: Tumor cell entry into the lymph node is controlled by CCL1 chemokine expressed by lymph node lymphatic sinuses.
abstract: Lymphatic vessels are thought to contribute to metastasis primarily by serving as a transportation system. It is widely believed that tumor cells enter lymph nodes passively by the flow of lymph. We demonstrate that lymph node lymphatic sinuses control tumor cell entry into the lymph node, which requires active tumor cell migration. In human and mouse tissues, CCL1 protein is detected in lymph node lymphatic sinuses but not in the peripheral lymphatics. CCR8, the receptor for CCL1, is strongly expressed by human malignant melanoma. Tumor cell migration to lymphatic endothelial cells (LECs) in vitro is inhibited by blocking CCR8 or CCL1, and recombinant CCL1 promotes migration of CCR8(+) tumor cells. The proinflammatory mediators TNF, IL-1β, and LPS increase CCL1 production by LECs and tumor cell migration to LECs. In a mouse model, blocking CCR8 with the soluble antagonist or knockdown with shRNA significantly decreased lymph node metastasis. Notably, inhibition of CCR8 led to the arrest of tumor cells in the collecting lymphatic vessels at the junction with the lymph node subcapsular sinus. These data identify a novel function for CCL1-CCR8 in metastasis and lymph node LECs as a critical checkpoint for the entry of metastases into the lymph nodes.
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine, Mount Sinai, New York, NY 10029, USA.
authors.forename: Suvendu
authors.initials: S
authors.lastname: Das
authors.forename: Eliana
authors.initials: E
authors.lastname: Sarrou
authors.forename: Simona
authors.initials: S
authors.lastname: Podgrabinska
authors.forename: Melanie
authors.initials: M
authors.lastname: Cassella
authors.forename: Sathish Kumar
authors.initials: SK
authors.lastname: Mungamuri
authors.forename: Nikki
authors.initials: N
authors.lastname: Feirt
authors.forename: Ronald
authors.initials: R
authors.lastname: Gordon
authors.forename: Chandandeep S
authors.initials: CS
authors.lastname: Nagi
authors.forename: Yarong
authors.initials: Y
authors.lastname: Wang
authors.forename: David
authors.initials: D
authors.lastname: Entenberg
authors.forename: John
authors.initials: J
authors.lastname: Condeelis
authors.forename: Mihaela
authors.initials: M
authors.lastname: Skobe
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology; D054402:Chemokine CCL1 / Q000378:metabolism*; D002630:Chemotactic Factors / Q000378:metabolism; D002633:Chemotaxis / Q000276:immunology; D016207:Cytokines / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004729:Endothelium, Lymphatic / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D008207:Lymphatic Metastasis; D042601:Lymphatic Vessels / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D036641:Microscopy, Fluorescence, Multiphoton; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology*; D054401:Receptors, CCR8 / Q000037:antagonists & inhibitors / Q000378:metabolism; D059008:Time-Lapse Imaging
chemical_list: D054402:Chemokine CCL1; D002630:Chemotactic Factors; D016207:Cytokines; D018836:Inflammation Mediators; D054401:Receptors, CCR8