LYVE-1 is not restricted to the lymph vessels: Expression in normal liver blood sinusoids and down-regulation in human liver cancer and cirrhosis

Lymphatic vessel endothelial hyaluronan receptor (LYVE)-1 is thought to be restricted to lymph vessels and has been used as such to show that tumor ly mphangiogenesis occurs on overexpression of lymphangiogenic factors in mous e tumor models. However, these studies have not yet been corroborated in hu man tumors. Here we show, first, that LYVE-1 is not exclusive to the lymph vessels. Indeed, LYVE-1 is also present in normal hepatic blood sinusoidal endothelial cells in mice and humans. Surprisingly, LYVE-1 is absent from t he angiogenic blood vessels of human liver tumors and only weakly present i n the microcirculation of regenerative hepatic nodules in cirrhosis, though both vessels are largely derived from the liver sinusoids. Second, we prop ose a novel approach to identify lymphatics in human and murine liver. By c ombining LYVE-1 and Prox 1 (a transcription factor) immunohistochemistry, w e demonstrate that lymphatics are abundant in cirrhosis. In contrast, in hu man hepatocellular carcinoma and liver metastases, they are restricted to t he tumor margin and surrounding liver. The absence of intratumor lymphatics in hepatocellular carcinomas and liver metastases may impair molecular and cellular transport in these tumors. Finally, the presence of LYVE-1 in liv er sinusoidal endothelia suggests that LYVE-1 has functions beyond the lymp h vascular system.