LYVE-1 (Lymphatic Vessel Endothelial Receptor 1) is a CD44 homolog found primarily on lymphatic endothelial cells.1 While LYVE-1 functions continue to be defined, potential roles have been suggested in hyaluronan (HA) transport and turnover, or in promoting HA localization to the surfaces of lymphatic endothelium. In addition, several studies have demonstrated the utility of LYVE-1 as a marker for lymphoid tissues and/or lymphangiogenesis.
Like CD44, LYVE-1 is a transmembrane receptor for the extracellular matrix (ECM) glycosaminoglycan HA. HA is an abundant component of skin and connective tissues with putative roles in cell migration, tissue morphogenesis, inflammation, and tumor metastases.2 Metabolic studies suggest that, relative to other ECM constituents, HA turnover is fairly rapid with a half-life of approximately 24 hours.3 The majority of HA degradation occurs in the lymph node following transport from local tissues via afferent lymphatics.3 Fragments also leave the lymph node and enter blood circulation for further degradation primarily by the liver.4
|Figure 1. The hyaluronan (HA) receptor LYVE-1 is expressed on the surface of lymphatic endo- thelial cells. Putative roles include the transport of HA to the lumen of lymphatic vessels, or in the localization of HA to lymphatics providing a substrate for transmigrating CD44+ cells. [Note: figure adapted from Jackson, D.G. et al. (2001) Trends Immunol. 22:317.]|
LYVE-1 is expressed on both the lumenal and ablumenal surfaces of lymphatic endothelium, and also on hepatic blood sinusoidal endothelia.5,6 This expression pattern, combined with studies showing that LYVE-1 can support cellular HA internalization in vitro, may suggest LYVE-1 participation in HA internalization for degradation, or transport of HA from tissues into the lumen of lymphatic vessels (Figure 1).5 LYVE-1-directed HA localization to lymphatic surfaces might also affect aspects of the immune response or tumor metastases. HA binding to CD44 can still occur in the presence of LYVE-1 in vitro.7 Therefore, LYVE-1-directed HA localization to lymphatics could provide a substrate for transmigrating CD44+ leukocytes or tumor cells (Figure 1).8 In addition to hepatic and lymphatic endothelia, some expression of LYVE-1 has been reported on Kupffer cells, the islets of Langerhans, cortical neurons, and renal epithelium.6,7 Roles for LYVE-1 on these cell and tissue types remain to be determined.
Because of its expression on lymphatic endothelia, LYVE-1 antibodies have been used to identify lymphangio-genesis in cornea and skin, and in inflammatory diseases.9-14 Several forms of epithelial tumors (carcinomas) exhibit initial metastatic spread via the lymphatics.15 The specificity of LYVE-1 antibodies to the lymphatics has also been utilized as a marker for lymphangiogenesis in cancer models and naturally occurring tumors.16-18 Although it remains unclear how much lymphangiogenesis contributes to metastatic spread, LYVE-1 and/or other useful markers for monitoring these processes might help to identify those at high risk for nodal metastases, relapse, or poor overall prognosis.12,15,18-20