Lymphangiogenesis, inflammation and metastasis.

The lymphatic vascular system is necessary for the return of extravasated interstitial fluid and macromolecules to the blood circulation, for immune defense, and for the uptake of dietary fats. Impaired functioning of lymphatic vessels results in lymphedema, whereas tumor-associated lymphangiogenesis may contribute to the spread of cancer cells from solid tumors. Recent studies have identified lymphatic molecular markers and growth factors necessary for lymphangiogenesis. In particular, lymphatic endothelial receptor tyrosine kinase VEGFR-3, and its ligands VEGF-C and VEGF-D, are major players in promoting lymphatic vascular growth both during development and in pathological conditions. Lymphatic vessels play a crucial role in a variety of human cancers, since invasion of lymphatic vessels by tumor cells and subsequent development of lymph node metastases significantly influence the prognosis of cancer patients and, therefore, represent an integral part of tumor staging. Recent evidence on the important influence of lymphangiogenic growth factors on intralymphatic cancer growth and metastasis raises hopes that lymphatic vessels and factors inducing their growth could serve as additional targets for tumor therapy. Nevertheless, in contrast to blood vessel angiogenesis, the mechanisms of new lymphatic vessel formation in human cancers, i.e. lymphangiogenesis, are still relatively unclear. In the framework of possible antilymphangiogenic therapies, this review focuses on the mechanisms of lymphangiogenesis in general, and especially on the role of lymphatic vessels in the process of metastasis.