Lymphatic Endothelial Cells, Lymphangiogenesis, and Extracellular Matrix

Abstract

Exciting studies involving the molecular regulation of lymphangiogenesis in lymphatic-associated disorders (e.g., wound healing, lymphedema and tumor metastasis) have focused renewed attention on the intrinsic relationship between lymphatic endothelial cells (LECs) and extracellular matrix (ECM) microenvironment. ECM molecules and remodeling events play a key role in regulating lymphangiogenesis, and the "functionality"-relating molecules, especially hyaluronan, integrins, reelin, IL-7, and matrix metalloproteinases, provide the most fundamental and critical prerequisite for LEC growth, migration, tube formation, and survival, although lymphangiogenesis is directly or/and indirectly controlled by VEGF-C/-D/VEGFR- 3- Prox-1-, Syk/SLP76-, podoplanin/Ang-2/Nrp-2-, FOXC2-, and other signaling pathways in embryonic and pathological processes. New knowledge regarding the differentiation of initial lymphatics should enable improvements in understanding of a variety of cytokines, chemokines, and other factors. The lymphatic colocalization with histochemical staining by using the novel molecular markers (e.g., LYVE-1), along with subsequent injection technique with ferritin or some tracer, will reveal functional and structural features of newly formed and preexisting lymphatics. Growing recognition of the multiple functions of ECM and LEC molecules for important physiological and pathological events may be helpful in identifying the crucial changes in tissues subjected to lymph circulation and ultimately in the search for rational therapeutic approaches to prevent lymphatic-associated disorders.

Fluorescent LYVE-1 Antibody to Image Dynamically Lymphatic Trafficking of Cancer Cells In Vivo

“…This marker as well as other lymph-specific markers such as Podoplanin and VEGFR-3 have made it possible to distinguish between lymphatic and vascular endothelium in ex-vivo tissue staining, as these markers are generally not expressed on the endothelial cells lining arteries and veins [7]. Monoclonal antibodies specific for LYVE-1 have been used in immunohistochemical staining for some time, but to date have not been used for in vivo lymphangiography.…”

“…The discovery of lymphatic endothelium-specific markers have allowed the distinction of blood versus lymphatic vessels in histologic sections, greatly improving our ability to evaluate lymphatic-specific phenomena [7]. We have combined the staining specificity of a monoclonal antibody which binds to murine LYVE-1 on lymphatic endothelial cells with the power of in vivo fluorescence imaging to facilitate real-time color-coded imaging of lymphatic vessels and tumor cell trafficking in a living animal.…”

Critical role of CD11b+ macrophages and VEGF in inflammatory lymphangiogenesis, antigen clearance, and inflammation resolution

“…[6][7][8][9][10][11][12][13] In adult animals, new lymphatic vessels are formed mainly through lymphangiogenesis, which is a sequence of processes that include sprouting, migration, proliferation, and tubule formation by preexisting lymphatic endothelial cells (LECs). [14][15][16] Additional LECs may also be derived through transdifferentiation or incorporation of circulating bone marrow-derived cells and some macrophages. 9,11 The discovery of specific lymphangiogenic growth factors (VEGF-C and VEGF-D), receptors (VEGF receptor-3 [VEGFR3]), a transcription factor (Prox-1), and markers (lymphatic vessel endothelial hyaluronan receptor-1 [LYVE-1], podoplanin) for LECs has led to a renewed interest in the roles of lymphatic vessels and lymphangiogenesis in tissue fluid homeostasis, tumor metastasis, wound healing, antigen presentation, and digested lipid absorption.…”

Silencing of Yap Gene Inhibits Metastasis in a Severe Combined Immune Deficiency Mice Orthotopic Implantation Gastric Cancer Model

“…Although the relevance of lymphatic metastasis is well documented, the molecular mechanisms by which tumor cells enter the lymphatic vessels and give rise to lymph node metastases are not completely understood (20). In recent years, it has become clear that one mechanism that promotes metastasis to regional lymph nodes is tumor-induced lymphangiogenesis, the formation of new lymphatics, which are ultimately controlled by a complex network of growth factors, cytokines and chemokines (21)(22). Analysis of lymphatic vessels in cancer was problematic in the past, because of the lack in specific markers of lymphatic endothelial cells (LECs) allowed to discriminate between lymphatic vessels and blood vessels.…”