Trends in Immunology
OpinionLYVE-1, the lymphatic system and tumor lymphangiogenesis
Section snippets
HA and the lymphatic system
HA (a copolymer of N-acetyl d-glucosamine and d-glucuronic acid) is a large mucopolysaccharide (103–104 kDa), initially identified as a structural component of connective tissue and a constituent of synovial fluid and vitreous humor 3. HA is a key mediator of cell migration, both during embryonic morphogenesis and in adult processes such as wound healing and tumor metastasis 4.
In the immune system, HA acts primarily as a substrate for leukocyte migration. For example, during inflammation,
Molecular details of LYVE-1 and its similarity to CD44
The human LYVE-1 cDNA was identified by searching the expressed sequence tag (EST) database with the amino acid sequence of the CD44 Link module 1. Unlike CD44, LYVE-1 transcripts do not appear to be alternatively spliced and the single major cDNA species encodes a 322-residue type I integral membrane glycoprotein with a 21-residue transmembrane domain and a 63-residue cytoplasmic tail. Like CD44, the LYVE-1 molecule has a single HA-binding domain at the N-terminus followed by a juxtamembrane
A role for LYVE-1 in lymphatic HA transport?
Detailed immunohistochemical analysis with polyclonal antibodies to both human and mouse LYVE-1 has revealed that the receptor is expressed on the endothelia of small vessels identifiable as lymphatics on the basis of their irregular morphology, lack of basement membrane and absence of red blood cells (Fig. 2) 1, 2. In support of this identification, we found, using immunofluorescence microscopy, that LYVE-1+ vessels co-express the vascular endothelial growth factor C (VEGF-C) receptor (VEGFR3)
LYVE-1 and tumor lymphangiogenesis
Aside from their roles in immunity and fluid homeostasis, the lymphatics are an important route for early metastasis in cancer. Yet, the means by which tumor cells gain access to the lymphatics has been the subject of a long-running controversy in the field of metastasis research, which even now is unresolved. Two essentially conflicting views have been advanced. The first maintains that tumors metastasize solely by invasion of pre-existing tissue lymphatics at the tumor margin. The second
Concluding remarks
Identification of the novel lymphatic HA receptor LYVE-1 has provided a new impetus to study the biology of HA within the lymphatic system, and has provided a new reagent to study tumor lymphangiogenesis. Studies are currently in progress to develop anti-LYVE-1 function-blocking antibodies and LYVE-1-knockout mice to explore the role of this fascinating receptor in HA transport, leukocyte migration and tumor metastasis.
Acknowledgements
We gratefully acknowledge the financial support of the Medical Research Council and the Association for International Cancer Research (Project grant 00-311 to D.J.).
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