Lymphatic-specific expression of dipeptidyl peptidase IV and its dual role in lymphatic endothelial function

Lymphatic vessels play an important role in the maintenance of tissue fluid homeostasis and in the transport of immune cells to lymph nodes, but they also serve as the major conduit for cancer metastasis to regional lymph nodes. However, the molecular mechanisms regulating these functions are poorly understood. Based on transcriptional profiling studies of cultured human dermal lymphatic (LEC) versus blood vascular endothelial cells (BEC), we found that dipeptidyl peptidase IV (DPPIV) mRNA and protein are much more strongly expressed by cultured lymphatic endothelium than by blood vascular endothelium that only expressed low levels of DPPIV in culture. The enzymatic cleavage activity of DPPIV was significantly higher in cultured LEC than in BEC. Differential immunofluorescence analyses of human organ tissue microarrays for DPPIV and several vascular lineage-specific markers revealed that DPPIV is also specifically expressed in situ by lymphatic vessels of the skin, esophagus, small intestine, breast and ovary. Moreover, siRNA-mediated DPPIV knockdown inhibited LEC adhesion to collagen type I and to fibronectin, and also reduced cell migration and formation of tube-like structures. These results identify DPPIV as a novel lymphatic marker and mediator of lymphatic endothelial cell functions.