Major finding: VEGF-D–induced collecting lymphatic vessel (CLV) dilation promotes metastasis.

Mechanism: VEGF signaling increases circulating prostaglandin levels.

Impact: Inhibition of CLV dilation may represent an anti-metastatic therapeutic strategy.

The vascular endothelial growth factors VEGF-C and VEGF-D promote the development of intra- and peritumoral lymphatic vessels that facilitate metastasis. The potential effects of lymphangiogenic growth factors on more distal collecting lymphatic vessels (CLV) that drain into regional lymph nodes are less clear. Using mouse models for VEGF-D–expressing tumors, Karnezis and colleagues investigated the mechanisms by which VEGF-D induces lymphogenous metastasis outside of the primary tumor. The authors first observed VEGF-D–dependent dilation of CLVs that drain metastatic tumors compared with those draining nonmetastatic tumors. Subsequent gene expression profiling done on collecting lymphatic endothelial cells isolated from mice with VEGF-D–driven metastasis showed reduced expression of Pgdh, which encodes 15-hydroxyprostaglandin dehydrogenase (PGDH). PGDH is an enzyme that degrades prostaglandins (PG), the cyclooxygenase (COX)-produced lipid compounds that mediate vasodilation. VEGF-D specifically induced downregulation of PDGH and an increase in PGs in CLVs, and inhibition of the tyrosine kinase receptors VEGFR2 or VEGFR3 abolished these changes. The authors therefore hypothesized that VEGF-D–mediated downregulation of PGDH in lymphatic endothelial cells results in a relative increase in local PG levels that in turn causes CLV dilation during metastasis. Importantly, CLV dilation, circulating PGs, and the number of tumor cells in draining lymph nodes were all found to be reduced when mice with VEGF-D–expressing metastatic tumors were treated with nonsteroidal anti-inflammatory drugs, which inhibit COX enzymes and PG production. These findings demonstrate that VEGF-D/VEGFR2/VEGFR3 signaling axes play a critical role in the regulation of metastasis by modulating PG expression within CLVs, thereby preparing them for metastatic tumor cells.

Karnezis T, Shayan R, Caesar C, Roufail S, Harris NC, Ardipradja K, et al. VEGF-D promotes tumor metastasis by regulating prostaglandins produced by the collecting lymphatic endothelium. Cancer Cell 2012;21:181–95.