Mouse LYVE-1 Is an Endocytic Receptor for Hyaluronan in Lymphatic Endothelium

Abstract

The glycosaminoglycan hyaluronan is a key substrate for cell migration in tissues during inflammation, wound healing, and neoplasia. Unlike other matrix components, hyaluronan (HA) is turned over rapidly, yet most degradation occurs not locally but within distant lymph nodes, through mechanisms that are not yet understood. While it is not clear which receptors are involved in binding and uptake of hyaluronan within the lymphatics, one likely candidate is the lymphatic endothelial hyaluronan receptor LYVE-1 recently described in our laboratory (Banerji, S., Ni, J., Wang, S., Clasper, S., Su, J., Tammi, R., Jones, M., and Jackson, D.G. (1999) J. Cell Biol. 144, 789 -801). Here we present evidence that LYVE-1 is involved in the uptake of hyaluronan by lymphatic endothelial cells using a new murine LYVE-1 orthologue identified from the EST data base. We show that mouse LYVE-1 both binds and internalizes hyaluronan in transfected 293T fibroblasts in vitro and demonstrate using immunoelectron microscopy that it is distributed equally among the luminal and abluminal surfaces of lymphatic vessels in vivo. In addition, we show by means of specific antisera that expression of mouse LYVE-1 remains restricted to the lymphatics in homozygous knockout mice lacking a functional gene for CD44, the closest homologue of LYVE-1 and the only other Link superfamily HA receptor known to date. Together these results suggest a role for LYVE-1 in the transport of HA from tissue to lymph and imply that further novel hyaluronan receptors must exist that can compensate for the loss of CD44 function.The extracellular matrix glycosaminoglycan hyaluronan (HA) 1 is a large polymer of N-acetyl-D-glucosamine and D-glucuronic acid (molecular mass 10 5

Concurrent Induction of Lymphangiogenesis, Angiogenesis, and Macrophage Recruitment by Vascular Endothelial Growth Factor-C in Melanoma

“…9,54,55 Moreover, the direct visualization of lymphatic vessels in tissue sections has been problematic because of the lack of molecular markers that reliably distinguish the lymphatic from the blood vasculature. 56 By using a recently derived antibody to the mouse hyaluronan receptor LYVE-1, that is selectively expressed on lymphatic vessels in normal tissues 39,45 and in tumors, 33 we were able to demonstrate intratumoral lymphatics in experimental melanomas overexpressing VEGF-C. All lymphatic vessels selectively expressed VEGFR-3. These results extend our recent findings that demonstrated, for the first time, the occurrence of intratumoral lymphangiogenesis in an orthotopical model of breast cancer.…”

“…To visualize tumor-associated lymphatic vessels we used an antibody against LYVE-1, a recently discovered specific marker of lymphatic vessels in normal tissues 39,45 and in tumors. 33 We detected lymphatic vessels with mostly compressed lumina in the skin surrounding control tumors (Figure 2A, arrowheads).…”

Expression of Lymphangiogenic Factors and Evidence of Intratumoral Lymphangiogenesis in Pancreatic Endocrine Tumors

“…For the specific immunohistochemical recognition of lymph vessels, we used an antiserum against podoplanin, a marker of lymphatic endothelial cells that was shown to co-localize with LYVE-1, a CD44-related hyaluronan receptor expressed mainly in lymphatic endothelial cells 33,34 . Apart from lymphatic endothelial cells, podoplanin was also found to be expressed in glomerular podocytes and occasionally in tumor-associated myofibroblasts.…”

Significance of lymph vessel invasion identified by the endothelial lymphatic marker D2-40 in node negative breast cancer

“…23 However, it is also expressed in some blood vessels of the lung and in hepatic sinusoids. [23][24][25] Prox-1, a homeobox gene product is expressed in lymphatic endothelium throughout lymphatic development but its use in the immunohistochemical analysis of human neoplasms has been limited. 26 Podoplanin, a membrane glycoprotein originally detected on glomerular podocytes, 27 has been demonstrated in lymphatic endothelium and identified lymphatic invasion in cervical and breast cancers.…”