The lymphatic system in health and disease

Abstract

The lymphatic vascular system has an important role in the regulation of tissue pressure, immune surveillance and the absorption of dietary fat in the intestine. There is growing evidence that the lymphatic system also contributes to a number of diseases, such as lymphedema, cancer metastasis and different inflammatory disorders. The discovery of various molecular markers allowing the distinction of blood and lymphatic vessels, together with the availability of a increasing number of in vitro and in vivo models to study various aspects of lymphatic biology, has enabled tremendous progress in research into the development and function of the lymphatic system. This review discusses recent advances in our understanding of the embryonic development of the lymphatic vasculature, the molecular mechanisms mediating lymphangiogenesis in the adult, the role of lymphangiogenesis in chronic inflammation and lymphatic cancer metastasis, and the emerging importance of the lymphatic vasculature as a therapeutic target.

FIG. 1

Lymphatic vasculature development and growth. During early embryonic development, all endothelial cells of the cardinal vein display lymphatic competence and express the lymphatic markers LYVE-1 and VEGFR-3. Induction of Prox1 expression in a subset of endothelial cells on one side of the vein marks commitment to the lymphatic lineage. Subsequent budding and migration of these cells to form the primary lymph sacs depends on VEGF-C signals. Several genes are required for the sustained separation of the developing lymphatic and blood vasculature, while others become important for the remodeling of the initial lymphatic network into capillaries and collecting vessels. During these processes, lymphatic endothelial cells adopt the expression of additional lineage markers. The relevance of lymphangioblasts and circulating progenitor cells for mammalian lymphatic development is unclear. Postnatally, lymphatic vessel growth is promoted by numerous factors. AM, adrenomedullin; Ang, angiopoietin; Angptl, angiopoietin-like protein; E, mouse embryonic day; FGF, fibroblast growth factor; GH, growth hormone; HGF, hepatocyte growth factor; IGF, insulin-like growth factor; Nrp2, neuropilin-2; PDGF, platelet-derived growth factor; VEGF, vascular endothelial growth factor.

FIG. 2

Tumor and lymph node lymphangiogenesis promotes cancer metastasis. Tumor-derived VEGF-A and/or VEGF-C/-D induce lymphangiogenesis at the site of the primary tumor and within sentinel LNs, even before metastasis, possibly preparing the LN for the arrival of metastatic tumor cells. Once in the sentinel LN, these cells maintain their lymphangiogenic activity, likely promoting further cancer spread to distant lymph nodes and organs. The lymphatic endothelial-derived chemokine CCL21 attracts CCR7-expressing cancer cells towards the lymphatic vessels, facilitating their entry into the lymphatic system. CCR7, CC-chemokine receptor 7; LN, lymph node; VEGF, vascular endothelial growth factor.