Tumor cell entry into the lymph node is controlled by CCL1 chemokine expressed by lymph node lymphatic sinuses

Suvendu Das, Eliana Sarrou, Simona Podgrabinska, Melanie Cassella, Sathish Kumar Mungamuri, Nikki Feirt, Ronald Gordon, Chandandeep S. Nagi, Yarong Wang, David Entenberg, John Condeelis, Mihaela Skobe

Research output: Contribution to journalArticlepeer-review

93 Scopus citations

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, inhibitionof 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.

Original languageEnglish (US)
Pages (from-to)1509-1528
Number of pages20
JournalJournal of Experimental Medicine
Volume210
Issue number8
DOIs
StatePublished - 2013

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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