CCL27/CCL28-CCR10 CHEMOKINE SIGNALING MEDIATES MIGRATION OF LYMPHATIC ENDOTHELIAL CELLS

The formation of new lymphatic vessels (lymphangiogenesis) and remodeling of existing lymphatics are thought to facilitate the entry and transport of tumor cells into lymphatic vessels and on to distant organs. The migration of lymphatic endothelial cells (LEC) toward guidance cues is critical for lymphangiogenesis. While chemokines are known to provide directional navigation for migrating immune cells, their role in mediating LEC migration during tumor-associated lymphangiogenesis is not well defined. Here we undertook gene profiling studies to identify chemokine-chemokine receptor pairs that are involved in tumor lymphangiogenesis associated with lymph node metastasis. CCL27 and CCL28 were expressed in tumor cells with metastatic potential, while their cognate receptor, CCR10, was expressed by LEC and upregulated by the lymphangiogenic growth factor VEGF-D and the pro-inflammatory cytokine TNF-α. LEC were attracted to both CCL27 and CCL28 in a CCR10-dependent manner. Abnormal lymphatic vessel patterning in CCR10-deficient mice confirmed the role of CCR10 in lymphatic patterning. In vivo analyses showed that LEC are recruited to a CCL27 or CCL28 source, while VEGF-D was required in combination with these chemokines to enable formation of coherent lymphatic vessels. Moreover, tumor xenograft experiments demonstrated that even though CCL27 expression by tumors enhanced LEC recruitment, the ability to metastasize was dependent on the expression of VEGF-D. These studies demonstrate that CCL27 and CCL28 act through CCR10 to cooperate with inflammatory mediators and VEGF-D during tumor lymphangiogenesis.

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