Lymphatic metastasis, an important initial step in tumor dissemination and is facilitated by lymphangiogenic growth factors such as VEGF-D and VEGF-C which are secreted by some primary tumors. Elevated levels of these proteins in some human tumors correlate with lymph node metastasis and poor patient prognosis. We have used a tumor model driven by VEGF-D over-expression to examine changes in gene expression within the collecting lymphatic vessels (1) during VEGF-D-driven tumor metastasis and in regional lymph nodes (2). Our study identified tissue-specific regulation of PGDH, the key enzyme in the prostaglandin degradation pathway, in endothelial cells of collecting lymphatic’s. The VEGF-D-dependent regulation of the prostaglandin pathway was supported by the finding that the dilation of collecting lymphatic vessels and subsequent ability to support metastasis was affected by NSAIDS, known inhibitors of prostaglandin synthesis. Our data suggests a key control point for cancer metastasis within the collecting lymphatic endothelium, which links the lymphangiogenic growth factors and the prostaglandin signaling network and has implications for anti-metastatic therapies. Collecting lymphatic vessels may therefore constitute a novel target for both NSAID and anti-VEGF-C/D therapeutics.
1. Karnezis et al., Cancer Cell 21:181-195, 2012
2. Farnsworth et al., Cancer Res, 71: 6547-6557, 2011