VEGF-D Promotes Tumor Metastasis by Regulating Prostaglandins Produced by the Collecting Lymphatic Endothelium

SummaryLymphatic metastasis is facilitated by lymphangiogenic growth factors VEGF-C and VEGF-D that are secreted by some primary tumors. We identified regulation of PGDH, the key enzyme in prostaglandin catabolism, in endothelial cells of collecting lymphatics, as a key molecular change during VEGF-D-driven tumor spread. The VEGF-D-dependent regulation of the prostaglandin pathway was supported by the finding that collecting lymphatic vessel dilation and subsequent metastasis were affected by nonsteroidal anti-inflammatory drugs (NSAIDs), known inhibitors of prostaglandin synthesis. Our data suggest a control point for cancer metastasis within the collecting lymphatic endothelium, which links VEGF-D/VEGFR-2/VEGFR-3 and the prostaglandin pathways. Collecting lymphatics therefore play an active and important role in metastasis and may provide a therapeutic target to restrict tumor spread.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (253 K)Download as PowerPoint slideHighlights► Collecting lymphatics undergo critical morphological changes during metastasis ► Isolated and characterized collecting lymphatic endothelial cells (cLECs) ► VEGF-D regulation of prostaglandins in cLECs facilitates metastasis ► NSAIDs as potential antimetastatic therapies for VEGF-D-driven spread