Trends in Immunology
Volume 22, Issue 6, 1 June 2001, Pages 317-321
Journal home page for Trends in Immunology

Opinion
LYVE-1, the lymphatic system and tumor lymphangiogenesis

https://doi.org/10.1016/S1471-4906(01)01936-6Get rights and content

Abstract

Previous research into hyaluronan (HA) has focused on the role of this abundant tissue glycosaminoglycan in promoting cell migration through interactions with its transmembrane receptor CD44 on inflammatory leukocytes and tumor cells. The recent discovery of a new HA receptor, LYVE-1 (lymphatic vessel endothelial HA receptor), expressed predominantly in lymphatic vessels, highlights another aspect of HA biology: its continuous transit through the lymphatic system and its potential involvement in lymph node homing by CD44+ leukocytes and tumor cells. The functional role of LYVE-1 in lymphatic vessels and its application as a marker to study tumor lymphangiogenesis are important areas of investigation.

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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