Lymphangiogenic factors, mechanisms, and applications

Abstract

Lymphangiogenesis, the growth of lymphatic vessels, is essential in embryonic development. In adults, it is involved in many pathological processes such as lymphedema, inflammatory diseases, and tumor metastasis. Advances during the past decade have dramatically increased the knowledge of the mechanisms of lymphangiogenesis, including the roles of transcription factors, lymphangiogenic growth factors and their receptors, and intercellular and intracellular signaling cascades. Strategies based on these mechanisms are being tested in the treatment of various human diseases such as cancer, lymphedema, and tissue allograft rejection. This Review summarizes the recent progress on lymphangiogenic mechanisms and their applications in disease treatment.

Figure 1. Growth factor and cytokine signaling pathways in lymphangiogenesis.

Growth factors derived from tumor cells, inflammatory cells, or other cell types activate their receptors on the surface of LECs and initiate various signaling cascades, leading to lymphatic vessel growth. Coordinately, these factors regulate cell migration, proliferation, and survival and vessel dilation and remodeling. Interactions between adjacent LECs via ANG/TIE2, DLL4/Notch1, and EFNB2/EPHB4 also contribute to the regulation of lymphangiogenic activity. Note that in contrast to ANG1, ANG2 is predominantly an autocrine ligand and that both angiopoietins bind with equal affinity to TIE2 and induce in trans ligand receptor complexes among ECs (103). Inhibitors that target the various involved molecules are indicated in red, and some of the key signaling consequences in blue.

Figure 2. Inhibition of tumor-induced lymphangiogenesis and vessel remodeling.

VEGFC/D is commonly produced by tumor cells and by inflammatory cells in tumors, and the resulting growth factor gradient induces the sprouting and growth of lymphatic vessels toward the tumor. Tumor-derived VEGFC/D also induces dilation, SMC remodeling, and increased pulsation of the collecting vessels. These tumor-induced processes can be attenuated by antibodies targeting the VEGFC/VEGFD/VEGFR3 signaling pathway. TKI, tyrosine kinase inhibitor.

Figure 3. VEGFC-induced regeneration of lymphatic vessels for the treatment of lymphedema.

Surgery, infection, or trauma damages the lymphatic vessels, leading to secondary lymphedema. Adenoviral VEGFC treatment with or without LN transplantation may be used to restore functional lymphatic vessels at the damaged site. Adenoviral VEGFC expression reaches peak levels soon after injection and lasts for about two to three weeks. The newly generated lymphatic vessels undergo intrinsic remodeling processes, finally maturing into collecting vessels with associated SMCs and intraluminal valves within six months in mice and pigs (125, 131). The blue curve indicates the quantitative dynamics of VEGFC expression. Original magnification, ×40.